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  • 1.
    Ahlberg, Richard
    et al.
    School of Medical Sciences, Örebro University, Örebro, Sweden.
    Garcia-Argibay, Miguel
    Örebro University, School of Medical Sciences.
    Hirvikoski, Tatja
    Karolinska Institutet, Stockholm, Sweden; Stockholm Health Care Services, Region Stockholm, Stockholm, Sweden.
    Boman, Marcus
    Karolinska Institutet. Stockholm, Sweden.
    Chen, Qi
    Karolinska Institutet, Stockholm, Sweden.
    Taylor, Mark J.
    Karolinska Institutet, Stockholm, Sweden.
    Frans, Emma
    Karolinska Institutet, Stockholm, Sweden.
    Bölte, Sven
    Karolinska Institutet, Stockholm, Sweden; Center for Psychiatry Research Stockholm Health Care Services, Region Stockholm Stockholm Sweden; Stockholm Health Care Services, Region Stockholm, Stockholm, Sweden; Curtin University, Perth, WA, Australia.
    Larsson, Henrik
    Örebro University, School of Medical Sciences. Karolinska Institutet, Stockholm, Sweden.
    Shared familial risk factors between autism spectrum disorder and obesity: a register‐based familial coaggregation cohort study2022In: Journal of Child Psychology and Psychiatry, ISSN 0021-9630, E-ISSN 1469-7610, Vol. 63, no 8, p. 890-899Article in journal (Refereed)
    Abstract [en]

    Background: Meta-analyses suggest an association between autism spectrum disorder (ASD) and obesity, but the factors underlying this association remain unclear. This study investigated the association between ASD and obesity stratified on intellectual disability (ID). In addition, in order to gain insight into possible shared etiological factors, the potential role of shared familial liability was examined.

    Method: We studied a cohort of 3,141,696 individuals by linking several Swedish nationwide registers. We identified 35,461 individuals with ASD and 61,784 individuals with obesity. Logistic regression models were used to estimate the association between ASD and obesity separately by ID and sex and by adjusting for parental education, psychiatric comorbidity, and psychotropic medication. Potential shared familial etiologic factors were examined by comparing the risk of obesity in full siblings, maternal and paternal half-siblings, and full- and half-cousins of individuals with ASD to the risk of obesity in relatives of individuals without ASD.

    Results: Individuals with ASD + ID (OR = 3.76 [95% CI, 3.38-4.19]) and ASD-ID (OR = 3.40 [95% CI, 3.23-3.58]) had an increased risk for obesity compared with individuals without ASD. The associations remained statistically significant when adjusting for parental education, psychiatric comorbidity, and medication. Sex-stratified analyses indicated a higher relative risk for males compared with females, with statistically significant interaction effects for ASD-ID, but not for ASD+ID in the fully adjusted model. First-degree relatives of individuals with ASD+ID and ASD-ID had an increased risk of obesity compared with first-degree relatives of individuals without ASD. The obesity risk was similar in second-degree relatives of individuals with ASD+ID but was lower for and ASD-ID. Full cousins of individuals with ASD+ID had a higher risk compared with half-cousins of individuals with ASD+ID). A similar difference in the obesity risk between full cousins and half-cousins was observed for ASD-ID.

    Conclusions: Individuals with ASD and their relatives are at increased risk for obesity. The risk might be somewhat higher for males than females. This warrants further studies examining potential common pleiotropic genetic factors and shared family-wide environmental factors for ASD and obesity. Such research might aid in identifying specific risks and underlying mechanisms in common between ASD and obesity.

  • 2.
    Ahlberg, Rickard
    et al.
    Örebro University, School of Medical Sciences.
    Du Rietz, E.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Ahnemark, E.
    Department of Neuropsychiatry, Region Stockholm, Stockholm, Sweden.
    Andersson, L. M.
    Takeda Pharma AB, Stockholm, Sweden.
    Werner-Kiechle, T
    Global Medical Affairs, Shire International GmbH, Zug, Switzerland.
    Lichtenstein, P.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Larsson, Henrik
    Örebro University, School of Medical Sciences. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Garcia-Argibay, Miguel
    Örebro University, School of Medical Sciences.
    Real-life instability in ADHD from young to middle adulthood: a nationwide register-based study of social and occupational problems2023In: BMC Psychiatry, E-ISSN 1471-244X, Vol. 23, no 1, article id 336Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Studies using self-reports indicate that individuals with ADHD are at increased risk for functional impairments in social and occupational settings, but evidence around real-life instability remains limited. It is furthermore unclear if these functional impairments in ADHD differ across sex and across the adult lifespan.

    METHOD: A longitudinal observational cohort design of 3,448,440 individuals was used to study the associations between ADHD and residential moves, relational instability and job shifting using data from Swedish national registers. Data were stratified on sex and age (18-29 years, 30-39 years, and 40-52 years at start of follow up).

    RESULTS: 31,081 individuals (17,088 males; 13,993 females) in the total cohort had an ADHD-diagnosis. Individuals with ADHD had an increased incidence rate ratio (IRR) of residential moves (IRR 2.35 [95% CI, 2.32-2.37]), relational instability (IRR = 1.07 [95% CI, 1.06-1.08]) and job shifting (IRR = 1.03 [95% CI, 1.02-1.04]). These associations tended to increase with increasing age. The strongest associations were found in the oldest group (40-52 years at start of follow). Women with ADHD in all three age groups had a higher rate of relational instability compared to men with ADHD.

    CONCLUSION: Both men and women with a diagnosis of ADHD present with an increased risk of real-life instability in different domains and this behavioral pattern was not limited to young adulthood but also existed well into older adulthood. It is therefore important to have a lifespan perspective on ADHD for individuals, relatives, and the health care sector.

  • 3.
    Ahlberg, Rickard
    et al.
    Örebro University, School of Medical Sciences.
    Garcia-Argibay, Miguel
    Örebro University, School of Medical Sciences.
    Du Rietz, Ebba
    Karolinska Institutet, Stockholm, Sweden.
    Butwicka, Agnieszka
    Karolinska Institutet, Stockholm, Sweden; Child and Adolescent Psychiatry Stockholm, Stockholm Health Care Services, Region Stockholm, Sweden.
    Cortese, Samuele
    Centre for Innovation in Mental Health, School of Psychology, Faculty of Environmental and Life sciences, University of Southampton, Southampton, United Kingdom; Solent NHS Trust, Southampton, United Kingdom; Division of Psychiatry and Applied Psychology, School of Medicine, University of Nottingham, Nottingham, United Kingdom; Clinical and Experimental Sciences (CNS and Psychiatry), Faculty of Medicine, University of Southampton, Southampton, United Kingdom; Hassenfeld Children´s Hospital at NYU Langone, New York University Child Study Center, New York City, New York; The Division of Psychiatry and Applied Psychology, School of Medicine, University of Nottingham, Nottingham, United Kingdom.
    D'Onofrio, Brian M.
    Karolinska Institutet, Stockholm, Sweden; Indiana University, Bloomington, Indiana, USA.
    Ludvigsson, Jonas F.
    Örebro University, School of Medical Sciences. Örebro University Hospital. Karolinska Institutet, Stockholm, Sweden; Örebro University Hospital, Örebro University, Örebro, Sweden.
    Larsson, Henrik
    Örebro University, School of Medical Sciences.
    Associations Between Attention-Deficit/Hyperactivity Disorder (ADHD), ADHD Medication and Shorter Height: A Quasi-Experimental and Family-based Study2023In: Journal of the American Academy of Child and Adolescent Psychiatry, ISSN 0890-8567, E-ISSN 1527-5418, Vol. 62, no 12, p. 1316-1325Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: The association between attention-deficit/hyperactivity disorder (ADHD) and shorter height is unclear. This study examined the risk of shorter height in individuals with ADHD, and the influence of prenatal factors, ADHD medication, psychiatric comorbidity, socioeconomic factors and familial liability.

    METHOD: We draw on Swedish National Registers for two different study designs. First, height data for 14,268 individuals with ADHD and 71,339 controls were stratified into two groups: 1: Before and 2: After stimulant treatment were introduced in Sweden. Second, we used a family-based design including 833,172 relatives without ADHD with different levels of relatedness to the individuals with ADHD and matched controls.

    RESULTS: ADHD was associated with shorter height both before (below average height: OR=1.31, 95 % CI=1.22-1.41) and after (below average height: OR=1.21, 95 % CI=1.13-1.31) stimulants for ADHD were introduced in Sweden and was of similar magnitude in both cohorts. The association between ADHD and shorter height attenuated after adjustment for prenatal factors, psychiatric disorders and SES. Relatives of individuals with ADHD had an increased risk of shorter height (below average height in full siblings: OR=1.14, 95 % CI=1.09-1.19; maternal half siblings: OR=1.10, 95 % CI=1.01-1.20; paternal half siblings: OR=1.15, 95 % CI=1.07-1.24, first full cousins: OR=1.10, 95 % CI=1.08-1.12).

    CONCLUSION: Our findings suggest that ADHD is associated with shorter height. On a population level, this association was present both before and after ADHD-medications were available in Sweden. The association between ADHD and height was partly explained by prenatal factors, psychiatric comorbidity, low SES and a shared familial liability for ADHD.

  • 4.
    Ahlberg, Rickard
    et al.
    Örebro University, School of Medical Sciences.
    Garcia-Argibay, Miguel
    Örebro University, School of Medical Sciences. Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden.
    Taylor, Marc
    Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden; Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Lichtenstein, Paul
    Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden; Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    D'Onofrio, Brian M
    Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden; Department of Psychological and Brain Sciences, Indiana University Bloomington, Bloomington, Indiana, USA.
    Butwicka, Agniezska
    Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden; Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Child and Adolescent Psychiatry, Stockholm Health Care Services, Region Stockholm, Stockholm, Sweden.
    Hill, Catherine
    School of Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, UK; Department of Sleep Medicine, Southampton Children's Hospital, University Hospital Southampton NHS Foundation Trust, Southampton, UK, Southampton, UK.
    Cortese, Samuele
    Centre for Innovation in Mental Health, School of Psychology, University of Southampton Faculty of Environmental and Life Sciences, Southampton, UK; Solent NHS Trust; Division of Psychiatry and Applied Psychology, School of Medicine, University of Nottingham, Nottingham, UK.
    Larsson, Henrik
    Örebro University, School of Medical Sciences. Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden; Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Du Rietz, Ebba
    Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden; Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Prevalence of sleep disorder diagnoses and sleep medication prescriptions in individuals with ADHD across the lifespan: a Swedish nationwide register-based study2023In: BMJ mental health, E-ISSN 2755-9734, Vol. 26, no 1, article id e300809Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Consistent evidence suggests a strong association between attention-deficit/hyperactivity disorder (ADHD) and subjectively reported sleep problems. However, the prevalence of clinically ascertained sleep disorder diagnoses and sleep medication prescriptions in individuals with ADHD remains unclear.

    OBJECTIVE: To determine the rates of sleep disorder diagnoses and sleep medication prescriptions in children, adolescents and adults with ADHD.

    METHODS: We linked Swedish national registers to create a cohort of individuals born 1945-2008. We estimated the absolute and relative risks (using logistic regression models) of different sleep disorder diagnoses and medication prescriptions in individuals with and without ADHD. The analyses were performed across five different age groups: children (5-11 years), adolescents (12-17 years), young adults (18-30 years), middle-aged adults (31-45 years) and older adults (46-60 years).

    FINDINGS: Among individuals with ADHD (N=145 490, 2.25% of the cohort), 7.5% had a sleep disorder diagnosis and 47.5% had been prescribed sleep medication. Individuals with ADHD, across all age groups, had a statistically significantly increased risk of having any sleep disorder diagnosis (ORrange=6.4-16.1) and any sleep medication prescription (ORrange=12.0-129.4) compared with individuals without ADHD. While rates of sleep disorders were highest in older adults, the relative risks were highest in youth.

    CONCLUSIONS: Individuals with ADHD have a substantially increased risk of sleep disorder diagnoses and sleep medication prescriptions, from childhood into older adulthood.

    CLINICAL IMPLICATIONS: More clinical efforts are needed to tackle impairing sleep problems in individuals with ADHD via systematic sleep assessment, appropriate diagnosis, and pharmacological and non-pharmacological interventions. Sleep medication use should be informed by sleep disorder diagnosis.

  • 5.
    Andersson, Anneli
    et al.
    Örebro University, School of Medical Sciences.
    Garcia-Argibay, Miguel
    Örebro University, School of Medical Sciences.
    Oskarsson, Sofi
    Örebro University, School of Law, Psychology and Social Work.
    Tuvblad, Catherine
    Örebro University, School of Law, Psychology and Social Work. Department of Psychology, University of Southern California, United States.
    Ghirardi, Laura
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Sweden .
    Larsson, Henrik
    Örebro University, School of Medical Sciences. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Sweden.
    Adverse Pregnancy Outcomes in Women Diagnosed with ADHD: A Population-Based Register StudyManuscript (preprint) (Other academic)
  • 6.
    Andersson, Anneli
    et al.
    Örebro University, School of Medical Sciences.
    Garcia-Argibay, Miguel
    Örebro University, School of Medical Sciences.
    Viktorin, Alexander
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Sweden .
    Ghirardi, Laura
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Sweden .
    Butwicka, Agnieszka
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Sweden; Department of Child Psychiatry, Medical University of Warsaw, Warsaw, Poland .
    Skoglund, Charlotte
    Department of clinical neuroscience, Karolinska Institutet, Stockholm, Sweden; Department of Neuroscience, Uppsala University, Uppsala Sweden.
    D’onofrio, Brian M.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Sweden; The Department of Psychological and Brain Sciences at Indiana University, Bloomington, Indiana.
    Lichtenstein, Paul
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Sweden.
    Tuvblad, Catherine
    Örebro University, School of Law, Psychology and Social Work. Department of Psychology, University of Southern California, United States.
    Larsson, Henrik
    Örebro University, School of Medical Sciences. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Sweden.
    Depression and Anxiety Disorders During the Postpartum Period – in Women Diagnosed with ADHDManuscript (preprint) (Other academic)
  • 7.
    Andersson, Anneli
    et al.
    Örebro University, School of Medical Sciences.
    Garcia-Argibay, Miguel
    Örebro University, School of Medical Sciences.
    Viktorin, Alexander
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Sweden.
    Ghirardi, Laura
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Sweden.
    Butwicka, Agnieszka
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Sweden; Department of Child Psychiatry, Medical University of Warsaw, Warsaw, Poland; Child and Adolescent Psychiatry Stockholm, Stockholm Health Care Services, Region Stockholm, Sweden.
    Skoglund, Charlotte
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden; Department of Neuroscience, Uppsala University, Uppsala, Sweden.
    Madsen, Kathrine Bang
    National Centre for Register-based Research, Business and Social Sciences, Aarhus University, Denmark; iPSYCH, the Lundbeck Foundation Initiative for Integrative Psychiatric Research, Denmark.
    D'onofrio, Brian M.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Sweden; The Department of Psychological and Brain Sciences at Indiana University, Bloomington, IN, United States.
    Lichtenstein, Paul
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Sweden.
    Tuvblad, Catherine
    Örebro University, School of Law, Psychology and Social Work. Department of Psychology, University of Southern California, United States.
    Larsson, Henrik
    Örebro University, School of Medical Sciences. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Sweden .
    Depression and anxiety disorders during the postpartum period in women diagnosed with attention deficit hyperactivity disorder2023In: Journal of Affective Disorders, ISSN 0165-0327, E-ISSN 1573-2517, Vol. 325, p. 817-823Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Attention deficit hyperactivity disorder (ADHD) is associated with an increased risk of poor mental health. However, the understanding of ADHD-related burden and impairments in women during the postpartum period is limited. The aim with the present study was to examine the risk of depression and anxiety disorders during the postpartum period among women with and without an ADHD diagnosis.

    METHODS: We used register-based data to identify women who gave birth to their first and/or second child between 2005 and 2013 in Sweden (n = 773,047), of which 0.5 % (n = 3515) had a diagnosis of ADHD prior to pregnancy. Diagnoses of depression and anxiety disorders up to one year after delivery were collected from the national patient register.

    RESULTS: A total of 16.76 % of the women with an ADHD diagnosis were also diagnosed with depression disorders in the postpartum period, prevalence ratio (PR) 5.09 (95 % confidence interval (CI), 4.68-5.54). A total of 24.92 % of the women with an ADHD diagnosis were also diagnosed with anxiety disorders in the postpartum period, PR 5.41 (5.06-5.78). Stratified results revealed that having a diagnosis of ADHD increased the risk for both depression and anxiety disorders postpartum, beyond other well-known risk factors.

    LIMITATIONS: There is a potential risk of surveillance bias as women diagnosed with ADHD are more likely to have repeated visits to psychiatric care and might have an enhanced likelihood of also being diagnosed with depression and anxiety disorders postpartum, compared to women without ADHD.

    CONCLUSIONS: ADHD is an important risk factor for both depression and anxiety disorders postpartum. Therefore, ADHD needs to be considered in the maternal care, regardless of sociodemographic factors and the presence of other psychiatric disorders.

  • 8.
    Andersson, Anneli
    et al.
    Örebro University, School of Medical Sciences.
    Hegvik, Tor-Arne
    Department of Biomedicine, University of Bergen, Bergen, Norway; Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Solna, Sweden.
    Chen, Qi
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Solna, Sweden.
    Rosenqvist, Mina A.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Solna, Sweden.
    Kvalvik, Liv Grimstvedt
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Solna, Sweden; Department of Global Public Health and Primary Care, University of Bergen, Bergen, Norway.
    Almqvist, Catarina
    Karolinska Inst, Dept Med Epidemiol & Biostat, Solna, Sweden.;Karolinska Univ Hosp, Astrid Lindgren Childrens Hosp, Pediat Allergy & Pulmonol Unit, Solna, Sweden; Pediatric Allergy and Pulmonology Unitat Astrid Lindgren Children’s Hospital, Karolinska University Hospital, Solna, Sweden.
    D'Onofrio, Brian M.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Solna, Sweden; The Department of Psychological and Brain Sciences at Indiana University, Bloomington Indiana, United States of America.
    Hartman, Catharina
    Department of Psychiatry,University of Groningen University Medical Center, Groningen, The Netherlands.
    Klungsøyr, Kari
    Department of Global Public Health and Primary Care, University of Bergen, Bergen, Norway; Division for Mental and PhysicalHealth, Norwegian Institute of Public Health, Bergen, Norway.
    Haavik, Jan
    Department of Biomedicine, University of Bergen, Bergen, Norway; Division of Psychiatry, Haukeland University Hospital, Bergen, Norway.
    Tuvblad, Catherine
    Örebro University, School of Law, Psychology and Social Work. Department of Psychology, University of Southern California, Los Angeles California, United States of America.
    Larsson, Henrik
    Örebro University, School of Medical Sciences. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Solna, Sweden.
    Attention-deficit/hyperactivity disorder and smoking habits in pregnant women2020In: PLOS ONE, E-ISSN 1932-6203, Vol. 15, no 6, article id e0234561Article in journal (Refereed)
    Abstract [en]

    Background: Attention-deficit/hyperactivity disorder (ADHD) has been associated with an increased risk of tobacco smoking, and more difficulties with smoking cessation compared to non-ADHD individuals. Women with ADHD may therefore show elevated rates of smoking during pregnancy.

    Aims: To examine the association between ADHD and smoking habits among pregnant women in Sweden and Norway.

    Methods: Women pregnant for the first time were identified in Sweden (n = 622,037), and Norway (n = 293,383), of which 1.2% (n = 7,444), and 1.7% (n = 4,951) were defined as having ADHD, respectively. Data on smoking habits were collected early and late in pregnancy.

    Results: In Sweden, ADHD was associated with an increased risk of smoking early in pregnancy, adjusted risk ratio (adjRR) 2.69 (95% confidence interval, 2.58-2.81), and late in pregnancy, adjRR 2.95 (2.80-3.10). Similar findings were observed in the Norwegian data, early in pregnancy, adjRR 2.31 (2.21-2.40), and late in pregnancy, adjRR 2.56 (2.42-2.70). Women with ADHD were more likely to continue smoking during pregnancy, compared to women without ADHD, both in Sweden adjRR 1.13 (1.10-1.17), and in Norway, adjRR 1.16 (1.12-1.20). Having a sibling diagnosed with ADHD was associated with an increased risk of smoking early and late in pregnancy, in both Sweden and Norway.

    Conclusions: Women with ADHD are considerably more likely to smoke early and late in (their first) pregnancy and are less likely to stop smoking between the two time points. Smoking, early and late in pregnancy, co-aggregates in families with ADHD. Smoking prevention and intervention programs should be targeted towards women with ADHD, specifically during their childbearing years, to ensure better mother and child outcomes.

  • 9.
    Andersson, Anneli
    et al.
    Örebro University, School of Medical Sciences.
    Tuvblad, Catherine
    Örebro University, School of Law, Psychology and Social Work. Department of Psychology, University of Southern California, Los Angeles, CA, USA.
    Chen, Qi
    Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Solna, Sweden.
    Du Rietz, Ebba
    Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Solna, Sweden.
    Cortese, Samuele
    Centre for Innovation in Mental Health, School of Psychology, Faculty of Environmental and Life sciences & Clinical and Experimental Sciences (CNS and Psychiatry), Faculty of Medicine, University of Southampton, Southampton, UK; Solent NHS Trust, Southampton, UK; Division of Psychiatry and Applied Psychology, School of Medicine, University of Nottingham, Nottingham, UK; New York University Child Study Center, New York, NY, USA.
    Kuja-Halkola, Ralf
    Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Solna, Sweden.
    Larsson, Henrik
    Örebro University, School of Medical Sciences. Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Solna, Sweden.
    Research Review: The strength of the genetic overlap between ADHD and other psychiatric symptoms - a systematic review and meta-analysis2020In: Journal of Child Psychology and Psychiatry, ISSN 0021-9630, E-ISSN 1469-7610, Vol. 61, no 11, p. 1173-1183Article, review/survey (Refereed)
    Abstract [en]

    Background: Attention-deficit/hyperactivity disorder (ADHD) frequently co-occurs with other psychiatric disorders. Twin studies have established that these co-occurrences are in part due to shared genetic risks. However, the strength of these genetic overlaps and the potential heterogeneity accounted for by type of psychiatric symptoms, age, and methods of assessment remain unclear. We conducted a systematic review to fill this gap.

    Methods: We searched PubMed, PsycINFO, Embase, and Web of Science until March 07, 2019. Genetic correlations (r(g)) were used as effect size measures.

    Results: A total of 31 independent studies fulfilled the inclusion criteria. The pooled estimates showed that the associations between ADHD and other psychiatric symptoms were partly explained by shared genetic factors, with a pooled genetic correlation of 0.50, 95% confidence interval: 0.46-0.60. The genetic correlations (r(g)) between ADHD and externalizing (r(g) = .49 [0.37-0.61]), internalizing (r(g) = .50 [0.39-0.69]), and neurodevelopmental (r(g) = .56 [0.47-0.66]) symptoms were similar in magnitude. The genetic correlations in childhood and adulthood werer(g) = .53 (0.43-0.63) andr(g) = .51 (0.44-0.56), respectively. For methods of assessment, the genetic correlations were also similar in strength, self-reportsr(g) = .52 (0.47-0.58), other informantsr(g) = .55 (0.41-0.69), and combined ratersr(g) = .50 (0.33-0.65).

    Conclusions: These findings indicate that the co-occurrence of externalizing, internalizing, and neurodevelopmental disorder symptoms in individuals with ADHD symptoms in part is due to a shared genetic risk.

  • 10.
    Andersson, Anneli
    et al.
    Örebro University, School of Medical Sciences.
    Tuvblad, Catherine
    Örebro University, School of Law, Psychology and Social Work. University of Southern California, Department of Psychology, Los Angeles CA, USA.
    Kuja-Halkola, Ralf
    Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden.
    Chen, Qi
    Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden.
    Larsson, Henrik
    Örebro University, School of Medical Sciences. Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden.
    Genetic overlap between ADHD and externalizing, internalizing and neurodevelopmental disorder symptoms: a systematic review and meta-analysis2018In: Behavior Genetics, ISSN 0001-8244, E-ISSN 1573-3297, Vol. 48, no 6, p. 455-456Article in journal (Other academic)
    Abstract [en]

    Attention-Deficit/Hyperactivity Disorder (ADHD) is a neurodevelopmental disorder (Wilens, Biederman & Spencer 2002) and affects approximately 5% of children (Polanczyk, de Lima, Horta, Biederman & Rohde 2007). About half of those diagnosed in childhood continue to have the diagnosis and symptoms in adulthood (Kessler et al. 2006). The co-occurrence of ADHD with other psychiatric disorder symptoms (Burt et al. 2001; Cole et al. 2009; Polderman et al. 2014) has been suggested to be partly explained by a shared genetic vulnerability (Polderman et al. 2014). However, the strength of the genetic overlap is currently unclear. Also, no study has examined whether the genetic correlations differs between age groups (childhood versus adulthood), by rater (self-report, other informant, combined (parent-teacher, parent-twin, teacher-twin)), or by type of psychiatric disorder symptoms (externalizing, internalizing, neu-rodevelopmental). To address this gap, we conducted a systematic literature search to identify relevant twin studies, in PubMed, PsycINFO, and EMBASE. A total of 31 articles were identified and included in the present study. The pooled estimates showed that the comorbidity between ADHD and diverse psychiatric disorder symptoms were explained by shared genetic effectsrg= 0.50 (0.43–0.56). A similar shared genetic overlap between ADHD and psychiatric disorder symptoms was observed in both childhood rg= 0.51(0.42–0.61) and adulthood rg= 0.47 (0.40–0.53). Similar results werealso found for self-reports rg= 0.49 (0.42–0.55), other informants rg= 0.50 (0.40–0.60), and combined raters rg= 0.51 (0.30–0.69). Further, the strength of the genetic correlations of ADHD with the externalizing rg= 0.49 (0.39–0.59), internalizing rg= 0.55 (0.40–0.68) and neurodevelopmental rg= 0.47 (0.40–0.53) spectrums were similar in magnitude. These findings emphasize the presence of a shared genetic liability between ADHD and externalizing, internalizing and neurodevelopmental disorder symptoms, independent of age and rater.

    References

    Burt, S. A., Krueger, R. F., McGue, M., Iacono, W. G. (2001).Sources of covariation among attention-deficit/hyperactivity disorder,oppositional defiant disorder, and conduct disorder: the importance ofshared environment.Journal of Abnormal Psychology, 4, 516–525.

    Cole, J., Ball, H. A., Martin, N. C., Scourfield, J., McGuffin, P.(2009). Genetic overlap between measures of hyperactivity/inatten-tion and mood in children and adolescents.J Am Acad Child AdolescPsychiatry48, 1094–1101.

    Kessler, R. C., Adler, L., Barkley, R., Biederman, J., Conners, C.K., Demler, O., Faraone, S. V., Greenhill, L. L., Howes, M. J., Secnik,K., Spencer, T., Ustun, T. B., Walters, E. E., Zaslavsky, A. M. (2006).The prevalence and correlates of adult ADHD in the United States:results from the National Comorbidity Survey Replication.Am JPsychiatry, 163, 716–723.

    Polanczyk, G., de Lima, M. S., Horta, B. L., Biederman, J., Rohde,L. A. (2007). The worldwide prevalence of ADHD: a systematicreview and metaregression analysis.Am J Psychiatry, 164, 942-8.

    Polderman, T. J., Hoekstra, R. A., Posthuma, D., Larsson, H.(2014). The co-occurrence of autistic and ADHD dimensions inadults: an etiological study in 17,770 twins.Transl Psychiatry2014;4: e435.

    Wilens, T. E., Biederman, J., Spencer, T. J. (2002). Attentiondeficit/hyperactivity disorder across the lifespan.Annual Review Med53:113–131.

  • 11.
    Arrondo, Gonzalo
    et al.
    Mind-Brain Group, Institute for Culture and Society, University of Navarra, Pamplona, Spain; Centre for Innovation in Mental Health, School of Psychology, Faculty of Environmental and Life Sciences, University of Southampton, Southampton, UK.
    Solmi, Marco
    Centre for Innovation in Mental Health, School of Psychology, Faculty of Environmental and Life Sciences, University of Southampton, Southampton, UK; Department of Psychiatry, University of Ottawa, Ottawa, ON, Canada; Department of Mental Health, The Ottawa Hospital, Ottawa, ON, Canada; Early Psychosis, Interventions and Clinical-detection (EPIC) Lab, Department of Psychosis Studies, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK.
    Dragioti, Elena
    Pain and Rehabilitation Centre and Department of Health, Medicine and Caring Sciences, Linköping University, Linköping, Sweden; Research Laboratory Psychology of Patients, Families & Health Professionals, Department of Nursing, School of Health Sciences, University of Ioannina, Ioannina, Greece.
    Eudave, Luis
    Faculty of Education and Psychology, University of Navarra, Pamplona, Spain.
    Ruiz-Goikoetxea, Maite
    Servicio Navarro de Salud-Osasunbidea, Navarra, Spain.
    Ciaurriz-Larraz, Amaia M.
    Faculty of Education and Psychology, University of Navarra, Pamplona, Spain.
    Magallon, Sara
    Faculty of Education and Psychology, University of Navarra, Pamplona, Spain.
    Carvalho, Andre F.
    Innovation in Mental and Physical Health and Clinical Treatment (IMPACT) Strategic Research Centre, Deakin University, Geelong, VIC, Australia.
    Cipriani, Andrea
    Department of Psychiatry, Warneford Hospital, University of Oxford, Oxford, UK; Oxford Health NHS Foundation Trust, Warneford Hospital, Oxford, UK.
    Fusar-Poli, Paolo
    Early Psychosis, Interventions and Clinical-detection (EPIC) Lab, Department of Psychosis Studies, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK; National Institute for Health Research, Maudsley Biomedical Research Centre, South London and Maudsley NHS Foundation Trust, London, UK; OASIS Service, South London and Maudsley NHS Foundation Trust, London, UK; Department of Brain and Behavioral Sciences, University of Pavia, Pavia, Italy.
    Larsson, Henrik
    Örebro University, School of Medical Sciences. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Correll, Christoph
    The Zucker Hillside Hospital, Division of Psychiatry Research, Northwell Health, Glen Oaks, New York, New York, USA; Department of Psychiatry and Molecular Medicine, The Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, New York, New York, USA; Department of Child and Adolescent Psychiatry, Charité Universitäts medizin, Berlin, Germany.
    Cortese, Samuele
    Centre for Innovation in Mental Health, School of Psychology, Faculty of Environmental and Life Sciences, University of Southampton, Southampton, UK; Clinical and Experimental Sciences (CNS and Psychiatry), Faculty of Medicine, University of Southampton, Southampton, UK; Solent NHS Trust, Southampton, UK; Division of Psychiatry and Applied Psychology, School of Medicine, University of Nottingham, Nottingham, UK; Hassenfeld Children's Hospital at NYU Langone, New York University Child Study Center, New York City, New York, US.
    Associations between mental and physical conditions in children and adolescents: an umbrella review2022In: Neuroscience and Biobehavioral Reviews, ISSN 0149-7634, E-ISSN 1873-7528, Vol. 137, article id 104662Article, review/survey (Refereed)
    Abstract [en]

    We mapped the evidence on the type and strength of associations between a broad range of mental and physical conditions in children and adolescents, by carrying out an umbrella review, i.e., a quantitative synthesis of previous systematic reviews and meta-analyses. We also assessed to which extent the links between mental and physical conditions vary across disorders or, by contrast, are transdiagnostic. Based on a pre-established protocol, we retained 45 studies, encompassing around 12.5 million of participants. In analyses limited to the most rigorous estimates, we found evidence for the following associations: ADHD-asthma, ADHD-obesity, and depression-asthma. A transdiagnostic association was confirmed between asthma and anxiety/ASD/depression/bipolar disorder, between obesity and ADHD/ASD/depression, and between dermatitis and ASD/ADHD. We conclude that obesity and allergic conditions are likely to be associated with mental disorders in children and adolescents. Our results can help clinicians explore potential links between mental and physical conditions in children/adolescent and provide a road map for future studies aimed at shading light on the underlying factors.

  • 12.
    Asherson, Philip
    et al.
    MRC SGDP Centre, Institute of Psychiatry Psychology and Neuroscience, King’s College London, London, United Kingdom.
    Larsson, Henrik
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Family, twin, and adoption studies of childhood onset psychiatric and neurodevelopmental disorders2016In: American Journal of Medical Genetics Part B: Neuropsychiatric Genetics, ISSN 1552-4841, E-ISSN 1552-485X, Vol. 171, no 7, p. 923-924Article in journal (Refereed)
  • 13.
    Bachar-Wikstrom, Etty
    et al.
    Dermatology and Venereology Division, Department of Medicine (Solna), Karolinska Institutet, Stockholm, Sweden.
    Curman, Philip
    Dermatology and Venereology Division, Department of Medicine (Solna), Karolinska Institutet, Stockholm, Sweden; Dermato-Venereology Clinic, Karolinska University Hospital, Stockholm, Sweden.
    Ahanian, Tara
    Dermatology and Venereology Division, Department of Medicine (Solna), Karolinska Institutet, Stockholm, Sweden; Dermato-Venereology Clinic, Karolinska University Hospital, Stockholm, Sweden.
    Leong, Ivone U. S.
    Dermatology and Venereology Division, Department of Medicine (Solna), Karolinska Institutet, Stockholm, Sweden.
    Larsson, Henrik
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Martin, Cederlöf
    Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet, and Stockholm Health Care Services, Stockholm, Sweden.
    Wikstrom, Jakob D.
    Dermatology and Venereology Division, Department of Medicine (Solna), Karolinska Institutet, Stockholm, Sweden; Dermato-Venereology Clinic, Karolinska University Hospital, Stockholm, Sweden.
    Darier disease is associated with heart failure: a cross-sectional case-control and population based study2020In: Scientific Reports, E-ISSN 2045-2322, Vol. 10, no 1, article id 6886Article in journal (Refereed)
    Abstract [en]

    Human data supporting a role for endoplasmic reticulum (ER) stress and calcium dyshomeostasis in heart disease is scarce. Darier disease (DD) is a hereditary skin disease caused by mutations in the ATP2A2 gene encoding the sarcoendoplasmic-reticulum Ca2+ ATPase isoform 2 (SERCA2), which causes calcium dyshomeostasis and ER stress. We hypothesized that DD patients would have an increased risk for common heart disease. We performed a cross-sectional case-control clinical study on 25 DD patients and 25 matched controls; and a population-based cohort study on 935 subjects with DD and matched comparison subjects. Main outcomes and measures were N-terminal pro-brain natriuretic peptide, ECG and heart diagnosis (myocardial infarction, heart failure and arrythmia). DD subjects showed normal clinical heart phenotype including heart failure markers and ECG. The risk for heart failure was 1.59 (1,16-2,19) times elevated in DD subjects, while no major differences were found in myocardial infarcation or arrhythmias. Risk for heart failure when corrected for cardivascular risk factors or alcohol misuse was 1.53 (1.11-2.11) and 1.58 (1,15-2,18) respectively. Notably, heart failure occurred several years earlier in DD patients as compared to controls. We conclude that DD patients show a disease specific increased risk of heart failure which should be taken into account in patient management. The observation also strenghtens the clinical evidence on the important role of SERCA2 in heart failure pathophysiology.

  • 14.
    Baker, J. H.
    et al.
    Virginia Institute for Psychiatric and Behavioral Genetics, Department of Psychiatry, Medical College of Virginia of Virginia Commonwealth University, Richmond, USA; Department of Psychology, Virginia Commonwealth University, Richmond, USA.
    Maes, H. H.
    Virginia Institute for Psychiatric and Behavioral Genetics, Department of Psychiatry, Medical College of Virginia of Virginia Commonwealth University, Richmond, USA; Department of Human Genetics, Virginia Commonwealth University, Richmond, USA; Massey Cancer Center, Virginia Commonwealth University, Richmond, USA.
    Larsson, Henrik
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Lichtenstein, P.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Kendler, K. S.
    Virginia Institute for Psychiatric and Behavioral Genetics, Department of Psychiatry, Medical College of Virginia of Virginia Commonwealth University, Richmond, USA; Department of Human Genetics, Virginia Commonwealth University, Richmond, USA; Department of Psychiatry, Virginia Commonwealth University, Richmond, USA.
    Sex differences and developmental stability in genetic and environmental influences on psychoactive substance consumption from early adolescence to young adulthood2011In: Psychological Medicine, ISSN 0033-2917, E-ISSN 1469-8978, Vol. 41, no 9, p. 1907-1916Article in journal (Refereed)
    Abstract [en]

    Background: Genetic and environmental factors are important in the etiology of substance use. However, little is known about the stability of these factors across development. We aimed to answer three crucial questions about this etiology that have never been addressed in a single study: (1) Is there a general vulnerability to substance consumption from early adolescence to young adulthood? (2) If so, do the genetic and environmental influences on this vulnerability change across development? (3) Do these developmental processes differ in males and females?

    Method: Subjects included 1480 twin pairs from the Swedish Twin Study of Child and Adolescent Development who have been followed since 1994. Prospective, self-reported regular smoking, alcohol intoxication and illicit drug use were assessed at ages 13-14, 16-17 and 19-20 years. Structural modeling was performed with the program Mx.

    Results: An underlying common factor accounted for the association between smoking, alcohol and illicit drug consumption for the three age groups. Common genetic and shared environmental effects showed substantial continuity. In general, as participants aged, the influence of the shared environment decreased, and genetic effects became more substance specific in their effect.

    Conclusions: The current report answers three important questions in the etiology of substance use. The genetic and environmental risk for substance consumption is partly mediated through a common factor and is partly substance specific. Developmentally, evidence was strongest for stability of common genetic effects, with less evidence for genetic innovation. These processes seem to be the same in males and females.

  • 15.
    Baker, Jessica H.
    et al.
    Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
    Brosof, Leigh C.
    Department of Psychological and Brain Sciences, University of Louisville, Louisville, Kentucky, USA.
    Munn-Chernoff, Melissa A.
    Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
    Lichtenstein, Paul
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Larsson, Henrik
    Örebro University, School of Medical Sciences. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Maes, Hermine H.
    Department of Genetics, Virginia Commonwealth University, Richmond, Virginia, USA.
    Kendler, Kenneth S.
    Department of Psychiatry, Virginia Commonwealth University, Richmond, Virginia, USA.
    Associations Between Alcohol Involvement and Drive for Thinness and Body Dissatisfaction in Adolescent Twins: A Bivariate Twin Study2018In: Alcoholism: Clinical and Experimental Research, ISSN 0145-6008, E-ISSN 1530-0277, Vol. 42, no 11, p. 2214-2223Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Alcohol involvement has familial associations with bulimic symptoms (i.e., binge eating, inappropriate compensatory behaviors), with several studies indicating a genetic overlap between the two. It is unclear whether overlapping familial risk with alcohol involvement extends to other eating disorder symptoms. Understanding the genetic overlap between alcohol involvement and other eating disorder symptoms may aid in more targeted interventions for comorbid alcohol use-eating disorder symptoms. Thus, we investigated associations between alcohol involvement and 2 core eating disorder symptoms: drive for thinness and body dissatisfaction in adolescent female and male twins.

    METHODS: We assessed 3 levels of alcohol involvement: alcohol use in the last month, having ever been intoxicated, and alcohol intoxication frequency via self-report. The Eating Disorder Inventory-II assessed drive for thinness and body dissatisfaction. Sex-specific biometrical twin modeling examined the genetic overlap between alcohol involvement and eating disorder symptoms.

    RESULTS: Phenotypic associations between alcohol involvement, drive for thinness, and body dissatisfaction were significantly greater in girls compared with boys. A majority of the associations between alcohol involvement, drive for thinness, and body dissatisfaction in girls, but not boys, met our threshold for twin modeling (phenotypic r > 0.20). Moderate genetic correlations were observed between the 3 aspects of alcohol involvement and drive for thinness. Moderate genetic correlations were observed between alcohol use and intoxication frequency and body dissatisfaction.

    CONCLUSIONS: Together with the literature on alcohol involvement and bulimic symptoms, these findings suggest a generalized association between alcohol involvement and eating disorder symptoms in girls, whereas this association may be symptom specific in boys. Genetic correlations indicate that the amount and direction of this genetic overlap differs across specific symptoms. When intervening on comorbid alcohol involvement and eating disorder symptoms, it may be important to target-specific eating disorder symptoms.

  • 16.
    Baker, Jessica H.
    et al.
    Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill North Carolina, USA.
    Johnson, Nicole K.
    Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill North Carolina, USA; Department of Psychology, Illinois Institute of Technology, Chicago Illinois, USA.
    Munn-Chernoff, Melissa A.
    Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill North Carolina, USA.
    Lichtenstein, Paul
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Larsson, Henrik
    Örebro University, School of Medical Sciences. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Maes, Hermine H.
    Department of Genetics, Virginia Commonwealth University, Richmond Virginia, USA.
    Kendler, Kenneth S.
    Department of Psychiatry, Virginia Commonwealth University, Richmond Virginia, USA.
    Illicit Drug Use, Cigarette Smoking, and Eating Disorder Symptoms: Associations in an Adolescent Twin Sample2018In: Journal of Studies on Alcohol and Drugs, ISSN 1937-1888, E-ISSN 1938-4114, Vol. 79, no 5, p. 720-724Article in journal (Refereed)
    Abstract [en]

    Objective: Twin studies have shown that genetic factors in part explain the established relation between alcohol use (i.e., problematic use or abuse/dependence) and eating disorder symptoms in adolescent and adult females. However, studies have yet to elucidate if there are similar shared genetic factors between other aspects of substance involvement, such as illicit drug use and repeated cigarette smoking.

    Method: For those sex-specific phenotypic correlations above our threshold of.20, we used a behavioral genetic design to examine potential shared genetic overlap between self-reported lifetime illicit drug use and repeated cigarette smoking and the eating disorder symptoms of drive for thinness (DT), bulimia (BU), and body dissatisfaction (BD), as assessed with the Eating Disorder Inventory-II in 16- to 17-year-old female and male twin pairs.

    Results: Only phenotypic correlations with illicit drug use met our threshold for twin modeling. Small to moderate genetic correlations were observed between illicit drug use and BU in both girls and boys and between illicit drug use and in girls.

    Conclusions: Similar etiological factors are at play in the overlap between illicit drug use and certain eating disorder symptoms in girls and boys during adolescence, such that genetic factors are important for covariance. Specifically, illicit drug use was associated with bulimia nervosa symptoms in girls and boys, which parallels previous substance use research finding a genetic overlap between alcohol use and bulimia nervosa symptoms. Future research should prospectively examine developmental trajectories to further understand the etiological overlap between substance involvement and eating disorder symptoms.

  • 17.
    Baker, Jessica H.
    et al.
    Department of Psychiatry, University of North Carolina, Chapel Hill, United States.
    Munn-Chernoff, Melissa A.
    Department of Psychiatry, University of North Carolina, Chapel Hill, United States.
    Lichtenstein, Paul
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Larsson, Henrik
    Örebro University, School of Medical Sciences. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Maes, Hermine
    Department of Genetics, VA Commonwealth University, Richmond, United States.
    Kendler, Kenneth S.
    Department of Psychiatry, VA Commonwealth University, Richmond, United States.
    Shared Familial Risk Between Bulimic Symptoms and Alcohol Involvement During Adolescence2017In: Journal of Abnormal Psychology, ISSN 0021-843X, E-ISSN 1939-1846, Vol. 126, no 5, p. 506-518Article in journal (Refereed)
    Abstract [en]

    Twin studies show the established relation between bulimic symptoms and problematic alcohol involvement in adult females is partly due to shared familial factors, specifically shared genetic effects. However, it is unclear if similar shared etiological factors exist during adolescence or in males. We examined the familial overlap (i.e., genetic and common environmental correlations) between bulimic symptoms and various levels of alcohol involvement in 16- to 17-year-old female and male same-sex twin pairs using sex-specific biometrical twin modeling. Bulimic symptoms were assessed with the Eating Disorder Inventory-2. Alcohol involvement included alcohol use in the last month, having ever been intoxicated, and alcohol intoxication frequency. Results revealed 3 distinct patterns. First, in general, phenotypic correlations indicated statistically similar associations between bulimic symptoms and alcohol involvement in girls and boys. Second, common environmental overlap was significant for the bivariate associations including having ever been intoxicated. Third, moderate genetic correlations were observed between all bulimic symptoms and alcohol involvement in girls and moderate common environmental correlations were observed in boys for the more risky/deviant levels of involvement. Similar to adults, there is familial overlap between bulimic symptoms and alcohol involvement in adolescent girls and boys. These results could inform symptom-and sex-specific, developmentally targeted prevention and intervention programs for the comorbidity between bulimic symptoms and alcohol involvement.

  • 18.
    Baker, Jessica H.
    et al.
    Department of Psychiatry, University of North Carolina at Chapel Hill, United States.
    Neyland, M. K. Higgins
    Department of Psychiatry, University of North Carolina at Chapel Hill, United States.
    Thornton, Laura M.
    Department of Psychiatry, University of North Carolina at Chapel Hill, United States.
    Runfola, Cristin D.
    Department of Psychiatry, Stanford University, United States.
    Larsson, Henrik
    Örebro University, School of Medical Sciences. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Sweden.
    Lichtenstein, Paul
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Sweden.
    Bulik, Cynthia
    Department of Psychiatry, University of North Carolina at Chapel Hill, United States; Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Sweden.
    Body Dissatisfaction in Adolescent Boys2019In: Developmental Psychology, ISSN 0012-1649, E-ISSN 1939-0599, Vol. 55, no 7, p. 1566-1578Article in journal (Refereed)
    Abstract [en]

    Body dissatisfaction is a significant mental health symptom present in adolescent girls and boys. However, it is often either disregarded in adolescent boys or examined using assessments that may not resonate with males. The present study addresses these issues, examining the manifestation, etiology, and correlates of 3 facets of body dissatisfaction in adolescent boys. Adolescent male twins aged 16- to 17-years-old from the Swedish Twin Study of Child and Adolescent Development were included along with a female comparison group: 915 monozygotic and 671 dizygotic same-sex twins. Body dissatisfaction was defined using measures of height dissatisfaction, muscle dissatisfaction, and the body dissatisfaction subscale of the Eating Disorder Inventory (EDI-BD). We examined the prevalence of body dissatisfaction, whether the facets of body dissatisfaction were phenotypically and etiologically distinct, and associations with specific externalizing and internalizing symptoms. For boys, muscle dissatisfaction scores were greater than height dissatisfaction scores. Results also indicated that height and muscle dissatisfaction were phenotypically and etiologically distinct from the EDI-BD. Unique associations were observed with externalizing and internalizing symptoms: muscle dissatisfaction with symptoms of bulimia nervosa and the EDI-BD with internalizing symptoms, body mass index, and drive for thinness. The facets of body dissatisfaction were also largely distinct in girls and unique between-sex associations with externalizing and internalizing symptoms emerged. Overall, male-oriented aspects of body dissatisfaction are distinct from female-oriented aspects of body dissatisfaction. To capture the full picture of male body dissatisfaction, multiple facets must be addressed.

  • 19.
    Baldwin, Jessie R.
    et al.
    Department of Clinical, Educational and Health Psychology, Division of Psychology and Language Sciences, University College London, London, UK; Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, UK.
    Sallis, Hannah M.
    MRC Integrative Epidemiology Unit at the University of Bristol, Bristol Medical School, University of Bristol, Bristol, UK; School of Psychological Science, University of Bristol, Bristol, UK; NIHR Biomedical Research Centre, University Hospitals Bristol NHS Foundation Trust and University of Bristol, Bristol, UK; Centre for Academic Mental Health, Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK.
    Schoeler, Tabea
    Department of Clinical, Educational and Health Psychology, Division of Psychology and Language Sciences, University College London, London, UK.
    Taylor, Mark J.
    Medical SchoolDepartment of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Kwong, Alex S. F.
    MRC Integrative Epidemiology Unit at the University of Bristol, Bristol Medical School, University of Bristol, Bristol, UK; stitutet, Nobels va ̈Division of Psychiatry, Edinburgh Medical School, University of Edinburgh, Edinburgh, UK.
    Howe, Laura D.
    MRC Integrative Epidemiology Unit at the University of Bristol, Bristol Medical School, University of Bristol, Bristol, UK.
    Danese, Andrea
    Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, UK; Department of Child & Adolescent Psychiatry, Institute of Psychiatry, Psychology & Neuroscience, King’s College London, London, United Kingdom; National and Specialist CAMHS Trauma, Anxiety, and Depression Clinic, South London and Maudsley NHS Foundation Trust, London, UK.
    McCrory, Eamon
    Department of Clinical, Educational and Health Psychology, Division of Psychology and Language Sciences, University College London, London, UK; Anna Freud National Centre for Children and Families, London, UK .
    Rijsdijk, Fruhling
    Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, UK.
    Tielbeek, Jorim J.
    CNCR, Amsterdam Neuroscience Campus, VU University, Amsterdam, The Netherlands.
    Barkhuizen, Wikus
    Department of Clinical, Educational and Health Psychology, Division of Psychology and Language Sciences, University College London, London, UK.
    Larsson, Henrik
    Örebro University, School of Medical Sciences. Bristol Medical School, Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Lundström, Sebastian
    Gillberg Neuropsychiatry Centre, Institute of Neuroscience and Physiology, University of Gothenburg, Gothenburg, Sweden; Centre for Ethics, Law and Mental Health (CELAM), Institute of Neuroscience and Physiology, University of Gothenburg, Gothenburg, Sweden.
    Karlsson, Robert
    Bristol Medical School, Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Lichtenstein, Paul
    Bristol Medical School, Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Munafo, Marcus
    MRC Integrative Epidemiology Unit at the University of Bristol, Bristol Medical School, University of Bristol, Bristol, UK; School of Psychological Science, University of Bristol, Bristol, UK; NIHR Biomedical Research Centre, University Hospitals Bristol NHS Foundation Trust and University of Bristol, Bristol, UK.
    Pingault, Jean-Baptiste
    Department of Clinical, Educational and Health Psychology, Division of Psychology and Language Sciences, University College London, London, UK; Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, UK.
    Adverse Childhood Experiences and Mental Health: A Genetically Informed Study2021In: Behavior Genetics, ISSN 0001-8244, E-ISSN 1573-3297, Vol. 51, no 6, p. 691-692Article in journal (Other academic)
    Abstract [en]

    Children exposed to adverse childhood experiences (ACEs) have an elevated risk of mental health problems, but it is unclear whether these associations reflect genetic confounding. We tested (1) whether children with genetic liability to psychopathology are more likely to experience ACEs, and (2) the extent to which the associations between ACEs and mental health are genetically confounded. Par-ticipants were 6411 children from the Avon Longitudinal Study of Parents and Children (ALSPAC). ACEs (including maltreatment, domestic violence, and parental psychopathology, substance abuse, criminality, and separation) were prospectively measured through parent reports at multiple assessments between birth and age 9. Internalizing and externalizing problems at age 9 were assessed through parent reports on the Development and Wellbeing Assessment. We derived polygenic scores for a range of psychiatric disorders. Children with greater genetic liability to psychopathology had a small elevation in risk of ACEs (pooled odds ratio = 1.05, 95% CI 1.01–1.09). Measured polygenic scores accounted for a very small proportion of the associations between ACEs with internalizing problems (pooled average across ACEs = 3.6%) and externalizing problems (pooled average = 4.8%). However, latent polygenic scores capturing SNP heritability in mental health outcomes explained a larger proportion of the associations between ACEs with internalizing problems (pooled average = 63%) and externalizing problems (pooled average = 17%). Risk of mental health problems in children exposed to ACEs is partly, but not completely driven by pre-existing genetic liability to psychopathology. Assuming the absence of nongenetic confounding, these findings are consistent with a partly causal effect of ACEs on mental health.

  • 20.
    Baldwin, Jessie R.
    et al.
    Department of Clinical, Educational and Health Psychology, Division of Psychology and Language Sciences, University College London, London, UK; Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK. j.baldwin@ucl.ac.uk.
    Sallis, Hannah M.
    MRC Integrative Epidemiology Unit at the University of Bristol, Bristol Medical School, University of Bristol, Bristol, UK; School of Psychological Science, University of Bristol, Bristol, UK; NIHR Biomedical Research Centre, University Hospitals Bristol NHS Foundation Trust and University of Bristol, Bristol, UK; Centre for Academic Mental Health, Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK.
    Schoeler, Tabea
    Department of Clinical, Educational and Health Psychology, Division of Psychology and Language Sciences, University College London, London, UK.
    Taylor, Mark J.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Kwong, Alex S. F.
    MRC Integrative Epidemiology Unit at the University of Bristol, Bristol Medical School, University of Bristol, Bristol, UK; Division of Psychiatry, Edinburgh Medical School, University of Edinburgh, Edinburgh, UK.
    Tielbeek, Jorim J.
    CNCR, Amsterdam Neuroscience Campus, VU University, Amsterdam, the Netherlands.
    Barkhuizen, Wikus
    Department of Clinical, Educational and Health Psychology, Division of Psychology and Language Sciences, University College London, London, UK.
    Warrier, Varun
    Department of Psychiatry, University of Cambridge, Cambridge, UK.
    Howe, Laura D.
    MRC Integrative Epidemiology Unit at the University of Bristol, Bristol Medical School, University of Bristol, Bristol, UK.
    Danese, Andrea
    Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK; Department of Child & Adolescent Psychiatry, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK; National and Specialist CAMHS Trauma, Anxiety, and Depression Clinic, South London and Maudsley NHS Foundation Trust, London, UK.
    McCrory, Eamon
    Department of Clinical, Educational and Health Psychology, Division of Psychology and Language Sciences, University College London, London, UK; Anna Freud National Centre for Children and Families, London, UK.
    Rijsdijk, Fruhling
    Psychology Department, Faculty of Social Sciences, Anton de Kom University, Paramaribo, Suriname.
    Larsson, Henrik
    Örebro University, School of Medical Sciences. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Lundström, Sebastian
    Gillberg Neuropsychiatry Centre, Institute of Neuroscience and Physiology, University of Gothenburg, Gothenburg, Sweden; Centre for Ethics, Law and Mental Health (CELAM), Institute of Neuroscience and Physiology, University of Gothenburg, Gothenburg, Sweden.
    Karlsson, Robert
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Lichtenstein, Paul
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Munafò, Marcus
    MRC Integrative Epidemiology Unit at the University of Bristol, Bristol Medical School, University of Bristol, Bristol, UK; School of Psychological Science, University of Bristol, Bristol, UK; NIHR Biomedical Research Centre, University Hospitals Bristol NHS Foundation Trust and University of Bristol, Bristol, UK.
    Pingault, Jean-Baptiste
    Department of Clinical, Educational and Health Psychology, Division of Psychology and Language Sciences, University College London, London, UK; Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
    A genetically informed Registered Report on adverse childhood experiences and mental health2023In: Nature Human Behaviour, E-ISSN 2397-3374, Vol. 7, no 2, p. 269-290Article in journal (Refereed)
    Abstract [en]

    Children who experience adversities have an elevated risk of mental health problems. However, the extent to which adverse childhood experiences (ACEs) cause mental health problems remains unclear, as previous associations may partly reflect genetic confounding. In this Registered Report, we used DNA from 11,407 children from the United Kingdom and the United States to investigate gene-environment correlations and genetic confounding of the associations between ACEs and mental health. Regarding gene-environment correlations, children with higher polygenic scores for mental health problems had a small increase in odds of ACEs. Regarding genetic confounding, elevated risk of mental health problems in children exposed to ACEs was at least partially due to pre-existing genetic risk. However, some ACEs (such as childhood maltreatment and parental mental illness) remained associated with mental health problems independent of genetic confounding. These findings suggest that interventions addressing heritable psychiatric vulnerabilities in children exposed to ACEs may help reduce their risk of mental health problems.

  • 21.
    Bang Madsen, Kathrine
    et al.
    NCRR - National Centre for Register-based Research, School of Business and Social Sciences, Aarhus University, Aarhus, Denmark.
    Robakis, Thalia K.
    Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
    Liu, Xiaoqin
    NCRR - National Centre for Register-based Research, School of Business and Social Sciences, Aarhus University, Aarhus, Denmark.
    Momen, Natalie
    NCRR - National Centre for Register-based Research, School of Business and Social Sciences, Aarhus University, Aarhus, Denmark.
    Larsson, Henrik
    Örebro University, School of Medical Sciences. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Dreier, Julie Werenberg
    NCRR - National Centre for Register-based Research, School of Business and Social Sciences, Aarhus University, Aarhus, Denmark; Department of Clinical Medicine, University of Bergen, Bergen, Norway.
    Kildegaard, Helene
    Hans Christian Andersen's Children's Hospital, Odense University Hospital, Odense, Denmark; Clinical Pharmacology, Pharmacy and Environmental Medicine, University of Southern Denmark, Odense, Denmark.
    Groth, Jane Bjerg
    Department of Otorhinolaryngology and Audiology, Zealand University Hospital, Universty of Copenhagen, Køge, Denmark.
    Newcorn, Jeffrey H.
    Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
    Hove Thomsen, Per
    Department of Clinical Medicine, Aarhus University, Aarhus, Denmark; Research Center at the Department for Child- and Adolescent Psychiatry, Aarhus University Hospital, Skejby, Denmark.
    Munk-Olsen, Trine
    NCRR - National Centre for Register-based Research, School of Business and Social Sciences, Aarhus University, Aarhus, Denmark; Research Unit of Psychiatry, Institute for Clinical Research, University of Southern Denmark, Odense, Denmark.
    Bergink, Veerle
    Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Department of Psychiatry, Erasmus Medical Centre Rotterdam, Rotterdam, The Netherlands.
    In utero exposure to ADHD medication and long-term offspring outcomes2023In: Molecular Psychiatry, ISSN 1359-4184, E-ISSN 1476-5578, Vol. 28, no 4, p. 1739-1746Article in journal (Refereed)
    Abstract [en]

    Attention Deficit Hyperactivity Disorder (ADHD) medication is increasingly being used during pregnancy. Concerns have been raised as to whether ADHD medication has long-term adverse effects on the offspring. The authors investigated whether in utero exposure to ADHD medication was associated with adverse long-term neurodevelopmental and growth outcomes in offspring. The population-based cohort study in the Danish national registers included 1,068,073 liveborn singletons from 1998 to 2015 followed until any developmental diagnosis, death, emigration, or December 31, 2018. Children of mothers who continued ADHD medication (methylphenidate, amphetamine, dexamphetamine, lisdexamphetamine, modafinil, atomoxetine, clonidine) during pregnancy and children of mothers who discontinued ADHD medication before pregnancy were compared using Cox regression. Main outcomes were neurodevelopmental psychiatric disorders, impairments in vision or hearing, epilepsy, seizures, or growth impairment during childhood or adolescence. In total, 898 children were exposed to ADHD medication during pregnancy compared to 1270 children whose mothers discontinued ADHD medication before pregnancy. After adjustment for demographic and psychiatric characteristics of the mother, no increased risk of any offspring developmental disorders was found combined (aHR 0.97, 95% CI 0.81 to 1.17) or for separate subcategories. Similarly, no increased risk was found for any sub-categories of outcomes in the negative control or sibling controlled analyses. Neurodevelopment and growth in offspring do not differ based on antenatal exposure to ADHD medication. These findings provide reassurance for women with ADHD who depend on ADHD medication for daily functioning and who consider continuing medication in pregnancy.

  • 22.
    Beckman, K.
    et al.
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden; St Goran Hosp, Stockholm City Council, Stockholm, Sweden.
    Mittendorfer-Rutz, E.
    Department of Clinical Neuroscience, Insurance Medicine, Karolinska Institutet, Stockholm, Sweden.
    Lichtenstein, P.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Larsson, Henrik
    Örebro University, School of Medical Sciences. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Almqvist, C
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Astrid Lindgren Children’s Hospital, Karolinska University Hospital, Stockholm, Sweden.
    Runeson, B.
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden; St Goran Hosp, Stockholm City Council, Stockholm, Sweden.
    Dahlin, M.
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden; St Goran Hosp, Stockholm City Council, Stockholm, Sweden.
    Mental illness and suicide after self-harm among young adults: long-term follow-up of self-harm patients, admitted to hospital care, in a national cohort2016In: Psychological Medicine, ISSN 0033-2917, E-ISSN 1469-8978, Vol. 46, no 16, p. 3397-3405Article in journal (Refereed)
    Abstract [en]

    Background: Self-harm among young adults is a common and increasing phenomenon in many parts of the world. The long-term prognosis after self-harm at young age is inadequately known. We aimed to estimate the risk of mental illness and suicide in adult life after self-harm in young adulthood and to identify prognostic factors for adverse outcome.

    Method: We conducted a national population-based matched case-cohort study. Patients aged 18-24 years (n = 13 731) hospitalized after self-harm between 1990 and 2003 and unexposed individuals of the same age (n = 137 310 ) were followed until December 2009. Outcomes were suicide, psychiatric hospitalization and psychotropic medication in short-term (1-5 years) and long-term (>5 years) follow-up.

    Results: Self-harm implied an increased relative risk of suicide during follow-up [hazard ratio (HR) 16.4, 95% confidence interval (CI) 12.9-20.9). At long-term follow-up, 20.3% had psychiatric hospitalizations and 51.1% psychotropic medications, most commonly antidepressants and anxiolytics. There was a six-fold risk of psychiatric hospitalization (HR 6.3, 95% CI 5.8-6.8) and almost three-fold risk of psychotropic medication (HR 2.8, 95% CI 2.7-3.0) in long-term follow-up. Mental disorder at baseline, especially a psychotic disorder, and a family history of suicide were associated with adverse outcome among self-harm patients.

    Conclusion: We found highly increased risks of future mental illness and suicide among young adults after self-harm. A history of a mental disorder was an important indicator of long-term adverse outcome. Clinicians should consider the substantially increased risk of suicide among self-harm patients with psychotic disorders.

  • 23.
    Beckman, Karin
    et al.
    Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden; Stockholm Health Care Services, Stockholm City Council, St Göran's Hospital, Stockholm, Sweden.
    Mittendorfer-Rutz, Ellenor
    Department of Clinical Neuroscience, Insurance Medicine, Karolinska Institutet, Stockholm, Sweden.
    Waern, Margda
    Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Larsson, Henrik
    Örebro University, School of Medical Sciences. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Runeson, Bo
    Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden; Stockholm Health Care Services, Stockholm City Council, St Göran's Hospital, Stockholm, Sweden.
    Dahlin, Marie
    Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden; Stockholm Health Care Services, Stockholm City Council, St Göran's Hospital, Stockholm, Sweden.
    Method of self-harm in adolescents and young adults and risk of subsequent suicide2018In: Journal of Child Psychology and Psychiatry, ISSN 0021-9630, E-ISSN 1469-7610, Vol. 59, no 5, p. 948-956Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Self-harm is common in youth and an important risk factor for suicide. Certain self-harm methods might indicate a higher risk of suicide. The main aim of this study was to determine whether some methods of self-harm in adolescents (10-17 years) and young adults (18-24 years) are associated with a particularly high risk of suicide. A secondary aim was to ascertain how different self-harm methods might affect the probability of psychiatric follow-up.

    METHOD: Five Swedish registers were linked in a national population-based cohort study. All nonfatal self-harm events recorded in specialist health care, excluding psychiatry and primary care services, among 10-24 year olds between 2000 and 2009 were included. Methods were classified as poisoning, cutting/piercing, violent method (gassing, hanging, strangulation/suffocation, drowning, jumping and firearms), other and multiple methods. Hazard Ratios (HR) for suicide were calculated in Cox regression models for each method with poisoning as the reference. Odds Ratios (OR) for psychiatric inpatient care were determined in logistic regression models. Analyses were adjusted for important covariates and stratified by age group and treatment setting (inpatient/outpatient).

    RESULTS: Among adolescents with initial medical hospitalisation, use of a violent method was associated with a near eightfold increase in HR for suicide compared to self-poisoning in the adjusted analysis [HR 7.8; 95% confidence interval (CI) 3.2-19.0]. Among hospitalised young adult women, adjusted HRs were elevated fourfold for both cutting [4.0 (1.9-8.8)] and violent methods [3.9 (1.5-10.6)]. Method of self-harm did not affect suicide risk in young adult men. Adolescents using violent methods had an increased probability of psychiatric inpatient care following initial treatment for self-harm.

    CONCLUSIONS: Violent self-harm requiring medical hospitalisation may signal particularly high risk of future suicide in adolescents (both sexes) and in young adult women. For the latter group this is the case for cutting requiring hospitalisation as well.

  • 24.
    Bellato, Alessio
    et al.
    School of Psychology, University of Nottingham Malaysia, Semenyih, Malaysia.
    Cristea, Ioana Alina
    Department of General Psychology, University of Padova, Padova, Italy.
    Giovane, Cinzia Del
    Department of Medical and Surgical Sciences for Children and Adults, University-Hospital of Modena and Reggio Emilia, Modena, Italy; Institute of Primary Health Care (BIHAM) University of Bern, Bern, Switzerland.
    Fazel, Seena
    Department of Psychiatry, University of Oxford, Oxford, UK.
    Polanczyk, Guilherme V.
    Department of Psychiatry, Faculdade de Medicina FMUSP, Universidade de São Paulo, São Paulo, Brazil.
    Solmi, Marco
    Department of Psychiatry, University of Ottawa, Ottawa, Ontario, Canada; Regional Centre for the Treatment of Eating Disorders and On Track, The Champlain First Episode Psychosis Program, Department of Mental Health, The Ottawa Hospital, Ottawa, Ontario, Canada; Ottawa Hospital Research Institute (OHRI) Clinical Epidemiology Program, University of Ottawa, Ottawa, Ontario, Canada; Department of Child and Adolescent, Psychiatry Charité Universitätsmedizin, Berlin, Germany.
    Larsson, Henrik
    Örebro University, School of Medical Sciences.
    Evidence-based child and adolescent mental health care: The role of high-quality and transparently reported evidence synthesis studies2023In: JCPP Advances, E-ISSN 2692-9384, Vol. 3, no 3, article id e12197Article in journal (Other academic)
  • 25.
    Berg, Venla
    et al.
    Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland; Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Solna, Sweden; Institute of Criminology and Legal Policy, University of Helsinki, Helsinki, Finland; Population Research Institute, Väestöliitto, Helsinki, Finland.
    Kuja-Halkola, Ralf
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Solna, Sweden.
    Khemiri, Lotfi
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Solna, Sweden.
    Larsson, Henrik
    Örebro University, School of Medical Sciences. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Solna, Sweden.
    Lichtenstein, Paul
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Solna, Sweden.
    Latvala, Antti
    Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland; Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Solna, Sweden; Institute of Criminology and Legal Policy, University of Helsinki, Helsinki, Finland.
    Parental alcohol and drug abuse and offspring mortality by age 10: a population-based register study2022In: European Journal of Public Health, ISSN 1101-1262, E-ISSN 1464-360X, Vol. 32, no 6, p. 933-938Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Parental substance abuse (SA) of alcohol and drugs is associated with offspring mortality, including sudden infant death syndrome (SIDS), in infancy, but research on cause-specific mortality and mortality in later childhood is scarce.

    METHODS: Using population-based register data on all births in Sweden in 1973-2013 (N = 4.2 million) and Cox regressions, we examined the associations of mother's and father's SA registered between 2 years before and 12 years after the child birth with offspring all-cause and cause-specific mortality in infancy and childhood.

    RESULTS: Parental SA was associated with increased offspring all-cause and natural-cause mortality in infancy, but not in the neonatal period, and with external-cause mortality in ages 1-9. Risk of SIDS was 130-280% higher in infants with parental SA compared to infants with no parental SA. Adjusting for parental socioeconomic and immigrant status and severe psychiatric disorders, paternal SA was associated with 66% higher mortality due to communicable diseases and infections in infancy, and both maternal and paternal SA were associated with 40-174% higher mortality due to accidents in infancy and in ages 1-9. The associations between parental SA and offspring mortality were similar for male and female offspring.

    CONCLUSIONS: Child mortality is rare in contemporary Sweden, and parental SA has variable associations with elevated offspring mortality throughout the first 10 years of life, excluding the neonatal period, which is indicative of insufficient recognition of children at risk. Preventive measures should be long-term and targeted to both parental and offspring behaviour.

  • 26.
    Bergman, Olle
    et al.
    Department of Pharmacology, University of Gothenburg, Gothenburg, Sweden.
    Westberg, Lars
    Department of Pharmacology, University of Gothenburg, Gothenburg, Sweden.
    Lichtenstein, Paul
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Eriksson, Elias
    Department of Pharmacology, University of Gothenburg, Gothenburg, Sweden.
    Larsson, Henrik
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Center of Neurodevelopmental Disorders, Karolinska Institutet, Stockholm, Sweden.
    Study on the possible association of brain-derived neurotrophic factor polymorphism with the developmental course of symptoms of attention deficit and hyperactivity2011In: International Journal of Neuropsychopharmacology, ISSN 1461-1457, E-ISSN 1469-5111, Vol. 14, no 10, p. 1367-1376Article in journal (Refereed)
    Abstract [en]

    Several studies have, with conflicting results, investigated the relationship between the Val⁶⁶Met polymorphism in brain-derived neurotrophic factor (BDNF) and attention deficit hyperactivity disorder (ADHD). We assessed longitudinal, quantitative phenotypes of hyperactivity-impulsivity and inattention in order to determine whether the Val⁶⁶Met polymorphism is associated with age-specific and/or persistent symptoms of hyperactivity-impulsivity and/or inattention in a community-based cohort of 1236 Swedish individuals for which ADHD symptom data were collected when the participants were aged 8-9, 13-14 and 16-17 yr. The Met allele was associated with symptoms of ADHD at ages 8-9 and 13-14 yr. A multivariate regression analysis revealed that the observed effect of the Met allele on ADHD symptoms reflects an influence on persistent hyperactivity-impulsivity symptoms. The present findings support the hypothesis that BDNF is involved in the pathogenesis of ADHD. The results highlight the importance of distinguishing between hyperactivity-impulsivity and inattention, respectively, and demonstrate the value of using a longitudinal approach in genetic studies of ADHD symptoms.

  • 27.
    Bolhuis, Koen
    et al.
    Department of Child and Adolescent Psychiatry/Psychology, Erasmus Medical Centre-Sophia Children's Hospital, Rotterdam, The Netherlands; Department of Psychiatry, Royal College of Surgeons in Ireland, Dublin, Ireland; Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Ghirardi, Laura
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; MediNeos Observational Research-IQVIA, Data Management & Statistics, Modena, Italy.
    Kuja-Halkola, Ralf
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Lång, Ulla
    Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK; Finnish Institute for Health and Welfare, Helsinki, Finland; University of Oulu, School of Medicine, Oulu, Finland.
    Martin, Cederlöf
    Örebro University, School of Medical Sciences. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; School of Medical Sciences, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Metsala, Johanna
    Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK; Finnish Institute for Health and Welfare, Helsinki, Finland.
    Corcoran, Paul
    National Suicide Research Foundation, University College Cork, Cork, Ireland; School of Public Health, University College Cork, Cork, Ireland.
    O'Connor, Karen
    Rise, South Lee Mental Health Services, Cork & Department of Psychiatry, University College Cork, Cork, Ireland; National Clinical Programme for Early Intervention in Psychosis, Health Service Executive Dublin, Dublin, Ireland.
    Dodd, Philip
    National Office for Suicide Prevention, Health Service Executive Dublin, Dublin, Ireland.
    Larsson, Henrik
    Örebro University, School of Medical Sciences. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Kelleher, Ian
    Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK; University of Oulu, School of Medicine, Oulu, Finland; University College Dublin, School of Medicine, Dublin, Ireland.
    Risk of Psychosis Among Individuals Who Have Presented to Hospital With Self-harm: A Prospective Nationwide Register Study in Sweden2024In: Schizophrenia Bulletin, ISSN 0586-7614, E-ISSN 1745-1701, article id sbae002Article in journal (Refereed)
    Abstract [en]

    BACKGROUND AND HYPOTHESIS: Recent research showed that young people who presented to hospital with self-harm in Finland had a significantly elevated risk of later psychosis. We investigated the prospective relationship between hospital presentation for self-harm and risk of psychosis in an unprecedentedly large national Swedish cohort.

    STUDY DESIGN: We used inpatient and outpatient healthcare registers to identify all individuals born between 1981 and 1993 who were alive and living in Sweden on their 12th birthday and who presented to hospital one or more times with self-harm. We compared them with a matched cohort, followed up for up to 20 years, and compared the cumulative incidence of psychotic disorders. Furthermore, we examined whether the strength of the relationship between hospital presentation for self-harm and later psychosis changed over time by examining for cohort effects.

    STUDY RESULTS: In total, 28 908 (2.0%) individuals presented to hospital with self-harm without prior psychosis diagnosis during the follow-up. For individuals who presented to hospital with self-harm, the cumulative incidence of diagnosed psychosis was 20.7% at 20 years follow-up (hazard radio = 13.9, 95% CI 13.3-14.6, P-value <5 × 10-308). There was no evidence of a dilution of the effect over time: while the incidence of hospital self-harm presentation increased, this did not result in an attenuation over time of the strength of the relationship between hospital self-harm presentation and subsequent psychosis.

    CONCLUSIONS: Individuals who present to hospital with self-harm in their teens and 20s represent an important risk group for psychosis prediction and prevention.

  • 28.
    Bolhuis, Koen
    et al.
    Erasmus Medical Center-Sophia Children's Hospital, Rotterdam, Netherlands.
    Lubke, Gitta H.
    University of Notre Dame, Notre Dame IN, United States; Vrije Universiteit, Amsterdam, Netherlands.
    van der Ende, Jan
    Erasmus Medical Center-Sophia Children's Hospital, Rotterdam, Netherlands.
    Bartels, Meike
    Vrije Universiteit, Amsterdam, Netherlands.
    van Beijsterveldt, Catharina E. M.
    Vrije Universiteit, Amsterdam, Netherlands.
    Lichtenstein, Paul
    Karolinska Institutet, Stockholm, Sweden.
    Larsson, Henrik
    Örebro University, School of Medical Sciences. Karolinska Institutet, Stockholm, Sweden.
    Jaddoe, Vincent W. V.
    Erasmus Medical Center-Sophia Children's Hospital, Rotterdam, Netherlands.
    Kushner, Steven A.
    Erasmus Medical Center, Rotterdam, Netherlands.
    Verhulst, Frank C.
    Erasmus Medical Center-Sophia Children's Hospital, Rotterdam, Netherlands.
    Boomsma, Dorret I.
    Vrije Universiteit, Amsterdam, Netherlands.
    Tiemeier, Henning
    Erasmus Medical Center-Sophia Children's Hospital, Rotterdam, Netherlands.
    Disentangling Heterogeneity of Childhood Disruptive Behavior Problems Into Dimensions and Subgroups2017In: Journal of the American Academy of Child and Adolescent Psychiatry, ISSN 0890-8567, E-ISSN 1527-5418, Vol. 56, no 8, p. 678-686Article in journal (Refereed)
    Abstract [en]

    Objective: Irritable and oppositional behaviors are increasingly considered as distinct dimensions of oppositional defiant disorder. However, few studies have explored this multidimensionality across the broader spectrum of disruptive behavior problems (DBPs). This study examined the presence of dimensions and distinct subgroups of childhood DBPs, and the cross-sectional and longitudinal associations between these dimensions.

    Method: Using factor mixture models (FMMs), the presence of dimensions and subgroups of DBPs was assessed in the Generation R Study at ages 6 (n = 6,209) and 10 (n = 4,724) years. Replications were performed in two population-based cohorts (Netherlands Twin Registry, n = 4,402, and Swedish Twin Study of Child and Adolescent Development, n = 1,089) and a clinical sample (n = 1,933). We used cross-lagged modeling in the Generation R Study to assess cross-sectional and longitudinal associations between dimensions. DBPs were assessed using mother-reported responses to the Child Behavior Checklist.

    Results: Empirically obtained dimensions of DBPs were oppositional behavior (age 6 years), disobedient behavior, rule-breaking behavior (age 10 years), physical aggression, and irritability (both ages). FMMs suggested that one-class solutions had the best model fit for all dimensions in all three population-based cohorts. Similar results were obtained in the clinical sample. All three dimensions, including irritability, predicted subsequent physical aggression (range, 0.08-0.16).

    Conclusion: This study showed that childhood DBPs should be regarded as a multidimensional phenotype rather than comprising distinct subgroups. Incorporating multidimensionality will improve diagnostic accuracy and refine treatment. Future studies need to address the biological validity of the DBP dimensions observed in this study; herein lies an important opportunity for neuro-imaging and genetic measures.

  • 29.
    Borg, J.
    et al.
    Department of Clinical Neuroscience, Center for Psychiatry Research, Karolinska Institutet, Stockholm, Sweden; Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Cervenka, S.
    Department of Clinical Neuroscience, Center for Psychiatry Research, Karolinska Institutet, Stockholm, Sweden.
    Kuja-Halkola, R
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden .
    Matheson, G. J.
    Department of Clinical Neuroscience, Center for Psychiatry Research, Karolinska Institutet, Stockholm, Sweden.
    Jönsson, E. G.
    Department of Clinical Neuroscience, Center for Psychiatry Research, Karolinska Institutet, Stockholm, Sweden; NORMENT, KG Jebsen Centre for Psychosis Research, Institute of Clinical Medicine, Psychiatry Section, University of Oslo, Oslo, Norway.
    Lichtenstein, P.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Henningsson, S.
    Danish Research Centre for Magnetic Resonance, Copenhagen University Hospital, Hvidovre, Denmark.
    Ichimiya, T.
    Department of Clinical Neuroscience, Center for Psychiatry Research, Karolinska Institutet, Stockholm, Sweden; Department of Neuropsychiatry, Nippon Medical School, Tokyo, Japan.
    Larsson, Henrik
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Stenkrona, P.
    Department of Clinical Neuroscience, Center for Psychiatry Research, Karolinska Institutet, Stockholm, Sweden.
    Halldin, C.
    Department of Clinical Neuroscience, Center for Psychiatry Research, Karolinska Institutet, Stockholm, Sweden.
    Farde, L.
    Department of Clinical Neuroscience, Center for Psychiatry Research, Karolinska Institutet, Stockholm, Sweden; AstraZeneca Translational Science Center, Karolinska Institutet, Stockholm, Sweden.
    Contribution of non-genetic factors to dopamine and serotonin receptor availability in the adult human brain2016In: Molecular Psychiatry, ISSN 1359-4184, E-ISSN 1476-5578, Vol. 21, no 8, p. 1077-1084Article in journal (Refereed)
    Abstract [en]

    The dopamine (DA) and serotonin (5-HT) neurotransmission systems are of fundamental importance for normal brain function and serve as targets for treatment of major neuropsychiatric disorders. Despite central interest for these neurotransmission systems in psychiatry research, little is known about the regulation of receptor and transporter density levels. This lack of knowledge obscures interpretation of differences in protein availability reported in psychiatric patients. In this study, we used positron emission tomography (PET) in a twin design to estimate the relative contribution of genetic and environmental factors, respectively, on dopaminergic and serotonergic markers in the living human brain. Eleven monozygotic and 10 dizygotic healthy male twin pairs were examined with PET and [(11)C]raclopride binding to the D2- and D3-dopamine receptor and [(11)C]WAY100635 binding to the serotonin 5-HT1A receptor. Heritability, shared environmental effects and individual-specific non-shared effects were estimated for regional D2/3 and 5-HT1A receptor availability in projection areas. We found a major contribution of genetic factors (0.67) on individual variability in striatal D2/3 receptor binding and a major contribution of environmental factors (pairwise shared and unique individual; 0.70-0.75) on neocortical 5-HT1A receptor binding. Our findings indicate that individual variation in neuroreceptor availability in the adult brain is the end point of a nature-nurture interplay, and call for increased efforts to identify not only the genetic but also the environmental factors that influence neurotransmission in health and disease.

  • 30.
    Borg Skoglund, Lotta
    et al.
    Institutionen för neurovetenskap, Uppsala universitet, Uppsala; Smart psykiatri, Stockholm.
    Larsson, Henrik
    Örebro University, School of Medical Sciences.
    Petrovic, Predrag
    Centrum för kognitiv neuropsykiatri, Karolinska institutet, Stockholm; Norra Stockholms psykiatri, Stockholm.
    ADHD hos vuxna – historia, epidemiologi och neurobiologi: [ADHD in adults - history, epidemiology, and neuroscience]2022In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 119, no 8, article id 21179Article in journal (Refereed)
    Abstract [en]

    ADHD is defined by symptoms of hyperactivity, impulsivity and inattention, prevalent in 5-7 % of youth and 2-3 % of adults and caused by an interplay of multiple genetic and environmental risk factors. The ADHD-phenotype was first described in the medical literature in 1775. While neuroimaging studies show altered structure and function of the brain, and neuropsychological tests low capacity of executive functions on a group level, neither assessment can be used to diagnose ADHD on an individual level. ADHD poses increased risk for somatic and psychiatric comorbidities as well as low quality of life, social impairment, professional underachievement, and hazardous behaviors such as substance misuse, injuries, and premature death. The consequences of undiagnosed and untreated ADHD pose a great economic burden on society worldwide. Research strongly suggests that several medications are safe and effective by reducing negative outcomes associated with ADHD across the lifespan.

  • 31.
    Bramson, L. M.
    et al.
    Indiana University, Bloomington, United States .
    Rickert, M. E.
    Indiana University, Bloomington, United States.
    Class, Q. A.
    University of Chicago, Chicago, United States .
    Sariaslan, A.
    University of Oxford, Oxford, United Kingdom .
    Almqvist, C.
    Karolinska Institutet, Stockholm, Sweden .
    Larsson, Henrik
    Karolinska Institutet, Stockholm, Sweden.
    Lichtenstein, P.
    Karolinska Institutet, Stockholm, Sweden .
    D'Onofrio, B. M.
    Indiana University, Bloomington, United States.
    The association between childhood relocations and subsequent risk of suicide attempt, psychiatric problems, and low academic achievement2016In: Psychological Medicine, ISSN 0033-2917, E-ISSN 1469-8978, Vol. 46, no 5, p. 969-979Article in journal (Refereed)
    Abstract [en]

    Background: Given the frequency with which families change residences, the effects of childhood relocations have gained increasing research attention. Many researchers have demonstrated that childhood relocations are associated with a variety of adverse outcomes. However, drawing strong causal claims remains problematic due to uncontrolled confounding factors.

    Method: We utilized longitudinal, population-based Swedish registers to generate a nationally representative sample of offspring born 1983-1997 (n = 1 510 463). Using Cox regression and logistic regression, we examined the risk for numerous adverse outcomes after childhood relocation while controlling for measured covariates. To account for unmeasured genetic and environmental confounds, we also compared differentially exposed cousins and siblings.

    Results: In the cohort baseline model, each annual relocation was associated with risk for the adverse outcomes, including suicide attempt [hazard ratio (HR) 1.19, 95% confidence interval (CI) 1.19-1.20]. However, when accounting for offspring and parental covariates (HR 1.08, 95% CI 1.07-1.09), as well as genetic and environmental confounds shared by cousins (HR 1.07, 95% CI 1.05-1.09) and siblings (HR 1.00, 95% CI 0.97-1.04), the risk for suicide attempt attenuated. We found a commensurate pattern of results for severe mental illness, substance abuse, criminal convictions, and low academic achievement.

    Conclusions: Previous research may have overemphasized the independent association between relocations and later adverse outcomes. The results suggest that the association between childhood relocations and suicide attempt, psychiatric problems, and low academic achievement is partially explained by genetic and environmental confounds correlated with relocations. This study demonstrates the importance of using family-based, quasi-experimental designs to test plausible alternate hypotheses when examining causality.

  • 32.
    Brand, Judith
    et al.
    Örebro University, School of Medical Sciences. Örebro University Hospital. Medical Research Council Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom; Population Health Sciences, Bristol Medical School, Bristol, United Kingdom.
    Lawlor, Deborah A.
    Medical Research Council Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom; Population Health Sciences, Bristol Medical School, Bristol, United Kingdom.
    Larsson, Henrik
    Örebro University, School of Medical Sciences. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Montgomery, Scott
    Örebro University, School of Medical Sciences. Clinical Epidemiology Division, Department of Medicine, Solna, Karolinska Institutet, Stockholm, Sweden; Department of Epidemiology and Public Health, University College London, London, United Kingdom.
    Association Between Hypertensive Disorders of Pregnancy and Neurodevelopmental Outcomes Among Offspring2021In: JAMA pediatrics, ISSN 2168-6203, E-ISSN 2168-6211, Vol. 175, no 6, p. 577-585Article in journal (Refereed)
    Abstract [en]

    Importance: Hypertensive disorders of pregnancy (HDP) have been associated with poorer neurodevelopmental outcomes in offspring, but the role of familial confounding in these associations is unclear.

    Objective: To investigate associations of maternal HDP with risks in offspring of autism spectrum disorders (ASDs), attention-deficit/hyperactivity disorder (ADHD), and intellectual disability (ID), as well as variation in overall cognitive performance in offspring.

    Design, Setting, and Participants: This Swedish register-based study used data from a birth cohort divided into 1 085 024 individuals born between 1987 and 1996 and followed up until December 31, 2014, and 285 901 men born between 1982 and 1992 who attended assessments for military conscription, including a cognitive function test. Statistical analysis was performed from April 1, 2019, to June 1, 2020.

    Exposures: Diagnoses of HDP, which were provided by the Medical Birth Register.

    Main Outcomes and Measures: Diagnoses of ASDs, ADHD, and ID were extracted from the National Patient Register. Cognitive function was assessed using written tests and summarized as a single 9-point score. Whole-cohort and within-sibship analyses were performed; the latter accounted for unmeasured familial confounding factors shared by siblings.

    Results: The study included 1 085 024 individuals (556 912 male participants [51.3%]) born between 1987 and 1996 and 285 901 men born between 1982 and 1992 who attended assessments for military conscription. The prevalence of maternal HDP was 4.0% in the 1987-1996 birth cohort (n = 42 980) and 5.1% in the military conscription cohort (n = 14 515). A total of 15 858 participants received a diagnosis of ASD, 36 852 received a diagnosis of ADHD, and 8454 received a diagnosis of ID. The mean (SD) cognitive score among the men in the conscription cohort was 5.1 (1.9). In whole-cohort analyses with multivariable adjustment, HDP were associated with offspring ASDs (hazard ratio [HR], 1.22; 95% CI, 1.13-1.31), ADHD (HR, 1.10; 95% CI, 1.05-1.16), and ID (HR, 1.39; 95% CI, 1.27-1.53). Analyses comparing siblings discordant for HDP were less statistically powered but indicated estimates of similar magnitude for ASDs (HR, 1.19; 95% CI, 1.00-1.42) and possibly ADHD (HR, 1.09; 95% CI, 0.95-1.24), but not for ID (HR, 1.04; 95% CI, 0.83-1.29). Hypertensive disorders of pregnancy were associated with somewhat lower cognitive scores in whole-cohort analysis (mean difference comparing offspring exposed with those unexposed, -0.10; 95% CI, -0.13 to -0.07), but in within-sibship analysis, the association was null (mean difference, 0.00; 95% CI, -0.09 to 0.08).

    Conclusions and Relevance: The study results suggest that HDP are associated with small increased risks of ASDs and possibly ADHD in offspring, whereas associations with ID and cognitive performance are likely confounded by shared familial (environmental or genetic) factors.

  • 33.
    Brander, Gustaf
    et al.
    Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden; Stockholm Health Care Services, Stockholm County Council, Stockholm, Sweden.
    Isomura, Kayoko
    Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden; Stockholm Health Care Services, Stockholm County Council, Stockholm, Sweden.
    Chang, Zheng
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Kuja-Halkola, Ralf
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Almqvist, Catarina
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Astrid Lindgren Children's Hospital, Karolinska University Hospital, Stockholm, Sweden.
    Larsson, Henrik
    Örebro University, School of Medical Sciences. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Mataix-Cols, David
    Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden; Stockholm Health Care Services, Stockholm County Council, Stockholm, Sweden.
    Fernández de la Cruz, Lorena
    Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden; Stockholm Health Care Services, Stockholm County Council, Stockholm, Sweden.
    Association of Tourette Syndrome and Chronic Tic Disorder With Metabolic and Cardiovascular Disorders2019In: JAMA Neurology, ISSN 2168-6149, E-ISSN 2168-6157, Vol. 76, no 4, p. 454-461Article in journal (Refereed)
    Abstract [en]

    Importance: There are limited data concerning the risk of metabolic and cardiovascular disorders among individuals with Tourette syndrome (TS) or chronic tic disorder (CTD).

    Objective: To investigate the risk of metabolic and cardiovascular disorders among individuals with TS or CTD over a period of 40 years.

    Design, Settings, and Participants: This longitudinal population-based cohort study included all individuals living in Sweden between January 1, 1973, and December 31, 2013. Families with clusters of full siblings discordant for TS or CTD were further identified. Data analyses were conducted from August 1, 2017, to October 11, 2018.

    Exposures: Previously validated International Classification of Diseases diagnoses of TS or CTD in the Swedish National Patient Register.

    Main Outcomes and Measures: Registered diagnoses of obesity, dyslipidemia, hypertension, type 2 diabetes, and cardiovascular diseases (including ischemic heart diseases, arrhythmia, cerebrovascular diseases and transient ischemic attack, and arteriosclerosis).

    Results: Of the 14 045 026 individuals in the cohort, 7804 individuals (5964 males [76.4%]; median age at first diagnosis, 13.3 years [interquartile range, 9.9-21.3 years]) had a registered diagnosis of TS or CTD in specialist care. Of 2 675 482 families with at least 2 singleton full siblings, 5141 families included siblings who were discordant for these disorders. Individuals with TS or CTD had a higher risk of any metabolic or cardiovascular disorders compared with the general population (hazard ratio adjusted by sex and birth year [aHR], 1.99; 95% CI, 1.90-2.09) and sibling controls (aHR for any disorder, 1.37; 95% CI, 1.24-1.51). Specifically, individuals with TS or CTD had higher risks for obesity (aHR, 2.76; 95% CI, 2.47-3.09), type 2 diabetes (aHR, 1.67; 95% CI, 1.42-1.96), and circulatory system diseases (aHR, 1.76; 95% CI, 1.67-1.86). The risk of any cardiometabolic disorder was significantly greater in males than in females (aHR, 2.13; 95% CI, 2.01-2.26 vs aHR, 1.79; 95% CI, 1.64-1.96), as was the risk of obesity (aHR, 3.24; 95% CI, 2.83-3.70 vs aHR, 1.97; 95% CI, 1.59-2.44). The risks were already evident from childhood (the groups were significantly different by age 8 years) and were significantly reduced with the exclusion of individuals with comorbid attention-deficit/hyperactivity disorder (aHR, 1.52; 95% CI, 1.42-1.62), while excluding other comorbidities did not significantly affect the results. Compared with patients with TS or CTD who were not taking antipsychotics, patients with a longer duration of antipsychotic treatment (>1 year) had significantly lower risks of metabolic and cardiovascular disorders.

    Conclusions and Relevance: The findings of this study suggest that TS and CTD are associated with a substantial risk of metabolic and cardiovascular disorders. The results highlight the importance of carefully monitoring cardiometabolic health in patients with TS or CTD across the lifespan, particularly in those with comorbid attention-deficit/hyperactivity disorder.

  • 34.
    Brander, Gustaf
    et al.
    Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden; Stockholm Health Care Services, Region Stockholm, Stockholm, Sweden.
    Kuja-Halkola, Ralf
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Rosenqvist, Mina A.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Rück, Christian
    Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden; Stockholm Health Care Services, Region Stockholm, Stockholm, Sweden.
    Serlachius, Eva
    Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden; Stockholm Health Care Services, Region Stockholm, Stockholm, Sweden.
    Fernández de la Cruz, Lorena
    Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden; Stockholm Health Care Services, Region Stockholm, Stockholm, Sweden.
    Lichtenstein, Paul
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Crowley, James J.
    Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden; Department of Genetics, University of North Carolina, Chapel Hill, NC, USA.
    Larsson, Henrik
    Örebro University, School of Medical Sciences. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Mataix-Cols, David
    Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden; Stockholm Health Care Services, Region Stockholm, Stockholm, Sweden.
    A population-based family clustering study of tic-related obsessive-compulsive disorder2021In: Molecular Psychiatry, ISSN 1359-4184, E-ISSN 1476-5578, Vol. 26, no 4, p. 1224-1233Article in journal (Refereed)
    Abstract [en]

    In the latest edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5), obsessive-compulsive disorder (OCD) included a new "tic-related" specifier. However, strong evidence supporting tic-related OCD as a distinct subtype of OCD is lacking. This study investigated whether, at the population level, tic-related OCD has a stronger familial load than non-tic-related OCD. From a cohort of individuals born in Sweden between 1967 and 2007 (n = 4,085,367; 1257 with tic-related OCD and 20,975 with non-tic-related OCD), we identified all twins, full siblings, maternal and paternal half siblings, and cousins. Sex- and birth year-adjusted hazard ratios (aHR) were calculated to estimate the risk of OCD in relatives of individuals with OCD with and without comorbid tics, compared with relatives of unaffected individuals. We found that OCD is a familial disorder, regardless of comorbid tic disorder status. However, the risk of OCD in relatives of individuals with tic-related OCD was considerably greater than the risk of OCD in relatives of individuals with non-tic-related OCD (e.g., risk for full siblings: aHR = 10.63 [95% CI, 7.92-14.27] and aHR = 4.52 [95% CI, 4.06-5.02], respectively; p value for the difference < 0.0001). These differences remained when the groups were matched by age at first OCD diagnosis and after various sensitivity analyses. The observed familial patterns of OCD in relation to tics were not seen in relation to other neuropsychiatric comorbidities. Tic-related OCD is a particularly familial subtype of OCD. The results have important implications for ongoing gene-searching efforts.

  • 35.
    Brander, Gustaf
    et al.
    Karolinska Institutet, Stockholm, Sweden.
    Kuja-Halkola, Ralf
    Karolinska Institutet, Stockholm, Sweden.
    Rosenqvist, Mina
    Karolinska Institutet, Stockholm, Sweden.
    Rück, Christian
    Karolinska Institutet, Stockholm, Sweden.
    Serlachius, Eva
    Karolinska Institutet, Stockholm, Sweden.
    Larsson, Henrik
    Örebro University, School of Medical Sciences.
    Mataix-Cols, David
    Karolinska Institutet, Stockholm, Sweden.
    Is Tic-Related OCD a Familial Subtype of the Disorder?: A Swedish Population Cohort Study2019In: Biological Psychiatry, ISSN 0006-3223, E-ISSN 1873-2402, Vol. 85, no 10, p. S221-S221Article in journal (Other academic)
  • 36.
    Brander, Gustaf
    et al.
    Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Pérez-Vigil, Ana
    Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Larsson, Henrik
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Mataix-Cols, David
    Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden; Stockholm Health Care Services, Stockholm County Council, Stockholm, Sweden.
    Systematic review of environmental risk factors for Obsessive-Compulsive Disorder: A proposed roadmap from association to causation2016In: Neuroscience and Biobehavioral Reviews, ISSN 0149-7634, E-ISSN 1873-7528, Vol. 65, p. 36-62Article, review/survey (Refereed)
    Abstract [en]

    Objective: To synthesize the current knowledge on possible environmental risk factors for Obsessive-Compulsive Disorder (OCD).

    Method: We conducted a systematic review following PRISMA guidelines. The Embase, PubMed and Scopus databases were searched up until October 6, 2015, employing relevant keywords and MeSH terms.

    Results: 128 studies met inclusion criteria. Potential environmental risk factors for OCD have been identified in the broad areas of perinatal complications, reproductive cycle, and stressful life events. There is limited evidence regarding other potential risk factors, such as parental age, season of birth, socioeconomic status, parental rearing practices, infections, traumatic brain injury, substance use or vitamin deficiency. In general, studies were of limited methodological quality.

    Conclusions: At present, no environmental risk factors have convincingly been associated with OCD. We propose a roadmap for future studies, consisting of longitudinal, population-based research, employing quasi-experimental family and twin designs to identify risk factors that are not only associated with the disorder but also contribute to its causation either directly or moderating the effect of genes.

  • 37.
    Brander, Gustaf
    et al.
    Department of Clinical Neuroscience, Centre for Psychiatry Research, Karolinska Institutet, Stockholm, Sweden.
    Rydell, Mina
    Department of Clinical Neuroscience, Centre for Psychiatry Research, Karolinska Institutet, Stockholm, Sweden.
    Kuja-Halkola, Ralf
    Department of Clinical Neuroscience, Centre for Psychiatry Research, Karolinska Institutet, Stockholm, Sweden.
    Fernández de la Cruz, Lorena
    Department of Clinical Neuroscience, Centre for Psychiatry Research, Karolinska Institutet, Stockholm, Sweden.
    Lichtenstein, Paul S.
    Department of Clinical Neuroscience, Centre for Psychiatry Research, Karolinska Institutet, Stockholm, Sweden.
    Serlachius, Eva
    Department of Clinical Neuroscience, Centre for Psychiatry Research, Karolinska Institutet, Stockholm, Sweden.
    Rück, Christian
    Department of Clinical Neuroscience, Centre for Psychiatry Research, Karolinska Institutet, Stockholm, Sweden.
    Almqvist, Catarina
    Department of Clinical Neuroscience, Centre for Psychiatry Research, Karolinska Institutet, Stockholm, Sweden.
    D'Onofrio, Brian M.
    Department of Clinical Neuroscience, Centre for Psychiatry Research, Karolinska Institutet, Stockholm, Sweden.
    Larsson, Henrik
    Örebro University, School of Medical Sciences. Department of Clinical Neuroscience, Centre for Psychiatry Research, Karolinska Institutet, Stockholm, Sweden.
    Mataix-Cols, David
    Department of Clinical Neuroscience, Centre for Psychiatry Research, Karolinska Institutet, Stockholm, Sweden.
    Perinatal risk factors in Tourette's and chronic tic disorders: a total population sibling comparison study2018In: Molecular Psychiatry, ISSN 1359-4184, E-ISSN 1476-5578, Vol. 23, no 5, p. 1189-1197Article in journal (Refereed)
    Abstract [en]

    Adverse perinatal events may increase the risk of Tourette's and chronic tic disorders (TD/CTD), but previous studies have been unable to control for unmeasured environmental and genetic confounding. We aimed to prospectively investigate potential perinatal risk factors for TD/CTD, taking unmeasured factors shared between full siblings into account. A population-based birth cohort, consisting of all singletons born in Sweden in 1973-2003, was followed until December 2013. A total of 3 026 861 individuals were identified, 5597 of which had a registered TD/CTD diagnosis. We then studied differentially exposed full siblings from 947 942 families; of these, 3563 families included siblings that were discordant for TD/CTD. Perinatal data were collected from the Medical Birth Register and TD/CTD diagnoses were collected from the National Patient Register, using a previously validated algorithm. In the fully adjusted models, impaired fetal growth, preterm birth, breech presentation and cesarean section were associated with a higher risk of TD/CTD, largely independent from shared family confounders and measured covariates. Maternal smoking during pregnancy was associated with risk of TD/CTD in a dose-response manner but the association was no longer statistically significant in the sibling comparison models or after the exclusion of comorbid attention-deficit/hyperactivity disorder. A dose-response relationship between the number of adverse perinatal events and increased risk for TD/CTD was also observed, with hazard ratios ranging from 1.41 (95% confidence interval (CI): 1.33-1.50) for one event to 2.42 (95% CI: 1.65-3.53) for five or more events. These results pave the way for future gene by environment interaction and epigenetic studies in TD/CTD.

  • 38.
    Brander, Gustaf
    et al.
    Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Rydell, Mina
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden .
    Kuja-Halkola, Ralf
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden .
    Fernández de la Cruz, Lorena
    Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Lichtenstein, Paul
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Serlachius, Eva
    Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden; Stockholm Health Care Services, Stockholm County Council, Stockholm, Sweden .
    Rück, Christian
    Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden; Stockholm Health Care Services, Stockholm County Council, Stockholm, Sweden.
    Almqvist, Catarina
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Astrid Lindgren Children’s Hospital, Karolinska University Hospital, Stockholm, Sweden .
    D'Onofrio, Brian M.
    Department of Psychological and Brain Sciences, Indiana University, Bloomington IN, USA.
    Larsson, Henrik
    Örebro University, School of Medical Sciences. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden .
    Mataix-Cols, David
    Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden; Stockholm Health Care Services, Stockholm County Council, Stockholm, Sweden.
    Association of Perinatal Risk Factors With Obsessive-Compulsive Disorder: A Population-Based Birth Cohort, Sibling Control Study2016In: JAMA psychiatry, ISSN 2168-6238, E-ISSN 2168-622X, Vol. 73, no 11, p. 1135-1144Article in journal (Refereed)
    Abstract [en]

    Importance: Perinatal complications may increase the risk of obsessive-compulsive disorder (OCD). Previous reports were based on small, retrospective, specialist clinic-based studies that were unable to rigorously control for unmeasured environmental and genetic confounding.

    Objective: To prospectively investigate a wide range of potential perinatal risk factors for OCD, controlling for unmeasured factors shared between siblings in the analyses.

    Design, Setting, and Participants: This population-based birth cohort study included all 2 421 284 children from singleton births in Sweden from January 1, 1973, to December 31, 1996, who were followed up through December 31, 2013. From the 1 403 651 families in the cohort, differentially exposed siblings from the 743 885 families with siblings were evaluated; of these, 11 592 families included clusters of full siblings that were discordant for OCD. Analysis of the data was conducted from January, 26, 2015, to September, 5, 2016.

    Exposures: Perinatal data were collected from the Swedish Medical Birth Register and included maternal smoking during pregnancy, labor presentation, obstetric delivery, gestational age (for preterm birth), birth weight, birth weight in relation to gestational age, 5-minute Apgar score, and head circumference.

    Main Outcomes and Measures: Previously validated OCD codes (International Statistical Classification of Diseases and Health Related Problems, Tenth Revision, code F42) in the Swedish National Patient Register.

    Results: Of 2 421 284 individuals included in the cohort, 17 305 persons were diagnosed with OCD. Of these, 7111 were men (41.1%). The mean (SD) age of individuals at first diagnosis of OCD was 23.4 (6.5) years. An increased risk for OCD remained after controlling for shared familial confounders and measured covariates (including sex, year of birth, maternal and paternal age at birth, and parity), for smoking 10 or more cigarettes per day during pregnancy (hazard ratio [HR], 1.27; 95% CI, 1.02-1.58), breech presentation (HR, 1.35; 95% CI, 1.06-1.71), delivery by cesarean section (HR, 1.17; 95% CI, 1.01-1.34), preterm birth (HR, 1.24; 95% CI, 1.07-1.43), birth weight 1501 to 2500 g (HR, 1.30; 95% CI, 1.05-1.62) and 2501 to 3500 g (HR, 1.08; 95% CI, 1.01-1.16), being large for gestational age (HR, 1.23; 95% CI, 1.05-1.45), and Apgar distress scores at 5 minutes (HR, 1.50; 95% CI, 1.07-2.09). Gestational age and birth weight followed inverse dose-response associations, whereby an increasingly higher risk for OCD was noted in children with a shorter gestational age and lower birth weight. We also observed a dose-response association between the number of perinatal events and increased OCD risk, with HRs ranging from 1.11 (95% CI, 1.07-1.15) for 1 event to 1.51 (95% CI, 1.18-1.94) for 5 or more events.

    Conclusions and Relevance: A range of perinatal risk factors is associated with a higher risk for OCD independent of shared familial confounders, suggesting that perinatal risk factors may be in the causal pathway to OCD.

  • 39.
    Brew, Bronwyn K.
    et al.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Centre for Big Data Research in Health and School of Clinical Medicine, University of New South Wales, Sydney, Australia.
    Gong, Tong
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Ohlin, Emma
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Surgical Unit, Mora Hospital, Mora, Sweden.
    Hedman, Anna M.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Larsson, Henrik
    Örebro University, School of Medical Sciences. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Curman, Philip
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Department of Dermatology, Karolinska University Hospital, Stockholm, Sweden.
    Lundholm, Cecilia
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Almqvist, Catarina
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Pediatric Allergy and Pulmonology Unit at Astrid Lindgren Children's Hospital, Karolinska University Hospital, Stockholm, Sweden.
    Maternal mental health disorders and offspring asthma and allergic diseases: The role of child mental health2024In: Pediatric Allergy and Immunology, ISSN 0905-6157, E-ISSN 1399-3038, Vol. 35, no 2, article id e14085Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Maternal psychological stress during pregnancy and postnatally has been shown to be associated with offspring atopic diseases (asthma, atopic dermatitis and allergic rhinitis). The aim of this study was to assess whether this association may be attributable to the child's own mental health disorders.

    METHOD: The study population included 15,092 twin children born 2002-2010 in Sweden. Questionnaire data at age 9 years was linked to national patient- and prescription registers. Maternal mental health during pregnancy and 3 years postnatally were identified from diagnosis and medication data (depression, anxiety and stress disorders). Atopic diseases in children were identified from questionnaires, diagnosis and medication data. Child mental health status (depression and anxiety) was identified from questionnaires. Three-way decomposition methods tested for mediation or interaction by child mental health disorders.

    RESULTS: Maternal mental health disorders were associated with most child atopic diseases including asthma aRR1.36 (95% CI 1.12, 1.60), and child mental health disorders, aRR1.73 (95% CI 1.56, 1.92). Children with mental health disorders were comorbid for atopic diseases with only asthma reaching statistical significance, aRR1.29 (95% CI 1.14, 1.47). Three-way decomposition found that mediation or interaction by child mental health disorders did not account for the mother mental health and child atopy associations except in parent-report asthma, where child mental health disorders mediated 13.4% (95% CI 2.1, 24.7) of the effect, but not for objectively defined (diagnosis and medication) asthma.

    CONCLUSION: The associations between maternal mental health and child asthma and allergic diseases do not appear to be attributable to child mental health disorders.

  • 40.
    Brew, Bronwyn K.
    et al.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Gong, Tong
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Williams, Dylan M.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Larsson, Henrik
    Örebro University, School of Medical Sciences. Deptartment of Medicine, Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; School of Medical Sciences, Örebro University, Örebro, Sweden.
    Almqvist, Catarina
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Pediatric Allergy and Pulmonology Unit, Astrid Lindgren Children’s Hospital, Karolinska University Hospital, Stockholm, Sweden.
    Using fathers as a negative control exposure to test the Developmental Origins of Health and Disease Hypothesis: A case study on maternal distress and offspring asthma using Swedish register data2017In: Scandinavian Journal of Public Health, ISSN 1403-4948, E-ISSN 1651-1905, Vol. 45, no 17, p. 36-40Article in journal (Refereed)
    Abstract [en]

    Background: Developmental Origins of Health and Disease Hypothesis (DOHaD) studies are often observational in nature and are therefore prone to biases from loss to follow-up and unmeasured confounding. Register-based studies can reduce these issues since they allow almost complete follow-up and provide information on fathers that can be used in a negative control analysis to assess the impact of unmeasured confounding.

    Aim: The aim of this study was to propose a causal model for testing DOHaD using paternal exposure as a negative control, and its application to maternal distress in pregnancy and offspring asthma.

    Methods: A causal diagram including shared and parent-specific measured and unmeasured confounders for maternal (fetal) and paternal exposures is proposed. The case study consisted of all children born in Sweden from July 2006 to December 2008 (n=254,150). Information about childhood asthma, parental distress and covariates was obtained from the Swedish national health registers. Associations between maternal and paternal distress during pregnancy and offspring asthma at age five years were assessed separately and with mutual adjustment for the other parent's distress measure, as well as for shared confounders.

    Results: Maternal distress during pregnancy was associated with offspring asthma risk; mutually adjusted odds ratio (OR) (OR 1.32, 95% CI 1.23, 1.43). The mutually adjusted paternal distress-offspring asthma analysis (OR 1.05, 95% CI 0.97, 1.13) indicated no evidence for unmeasured confounding shared by the mother and father.

    Conclusions: Using paternal exposure in a negative control model to test the robustness of fetal programming hypotheses can be a relatively simple extension of conventional observational studies but limitations need to be considered.

  • 41.
    Brew, Bronwyn K.
    et al.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Lundholm, Cecilia
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Gong, Tong
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Woolcock Institute of Medical Research, University of Sydney, Sydney, Australia.
    Larsson, Henrik
    Örebro University, School of Medical Sciences. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Almqvist, Catarina
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet; Sweden Pediatric Allergy and Pulmonology Unit,t Astrid Lindgren Children's Hospital, Karolinska University Hospital, Stockholm, Sweden.
    The familial aggregation of atopic diseases and depression or anxiety in children2018In: Clinical and Experimental Allergy, ISSN 0954-7894, E-ISSN 1365-2222, Vol. 48, no 6, p. 703-711Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Children with asthma and atopic diseases have an increased risk of depression or anxiety. Each of these diseases have strong genetic and environmental components, therefore it seems likely that there is a shared liability rather than causative risk.

    OBJECTIVE: To investigate the existence and nature of familial aggregation for the comorbidity of atopic diseases and depression or anxiety.

    METHODS: Participants came from the Childhood and Adolescent Twin Study in Sweden (CATSS), n= 14197. Current and ever asthma, eczema, hayfever and food-allergy were reported by parents. Internalizing disorders were identified using validated questionnaires. Familial co-aggregation analysis compared monozygotic MZ twins and same-sex dizygotic DZ twins for atopic disease in one twin with internalizing disorder in the other to test for genetic liability. Several familial liability candidates were also tested including parental education, recent maternal psychological stress, childhood family trauma and parental country of birth.

    RESULTS: Familial co-aggregation analysis found that if one twin had at least one current atopic disease the partner twin was at risk of having an internalizing disorder regardless of their own atopic status (Adjusted OR 1.22 (95% CI 1.08, 1.37). Similar results were found for each atopic disease ever and current. MZ associations were not higher than DZ associations suggesting that the liability is not genetic in nature. Including other familial candidates to the models made little difference to effect estimates.

    CONCLUSIONS AND CLINICAL RELEVANCE: Atopic diseases and depression or anxiety tend to occur together in families, therefore when treating for one disease the physician should consider comorbidity in both the individual and the individual's siblings. We did not find evidence to support a genetic explanation for comorbidity and further exploration is needed to disentangle the environmental and epigenetic reasons for familial aggregation.

  • 42.
    Brew, Bronwyn K.
    et al.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Lundholm, Cecilia
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Viktorin, Alexander
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York NY, USA.
    Lichtenstein, Paul
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Larsson, Henrik
    Örebro University, School of Medical Sciences. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Almqvist, Catarina
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; School of Medical Sciences, Örebro University, Örebro, Sweden.
    Longitudinal depression or anxiety in mothers and offspring asthma: a Swedish population-based study2018In: International Journal of Epidemiology, ISSN 0300-5771, E-ISSN 1464-3685, Vol. 47, no 1, p. 166-174Article in journal (Refereed)
    Abstract [en]

    Background: Previous research has found that maternal stress during pregnancy increases the risk of offspring asthma. However, whether this association is consistent with a causal interpretation has never been tested. The objective is to determine whether there is a critical exposure period for maternal depression or anxiety on offspring asthma or whether cumulative exposure is most important, and to investigate evidence of confounding.

    Methods: The study population included all children born in Sweden from July 2006 to December 2009 (n = 360 526). Information about childhood asthma, maternal depression or anxiety (diagnosis or medication) and covariates was obtained from the Swedish national health registers. The associations between exposure periods (pre-conception, pregnancy, postnatal or current) and childhood asthma were estimated using structured life course approach hypothesis testing. Paternal and cousin analyses were used to test for evidence of confounding from shared genes and environment.

    Results: For childhood asthma, cumulative exposure best described the effect of exposure to maternal depression or anxiety up to a maximum of any two exposure periods [adjusted odds ratio 1.44, 95% confidence interval (CI) 1.38, 1.52]. The hypotheses of a critical period were not supported. The paternal and cousin analyses indicated minimal influence from familial confounding.

    Conclusions: These findings support an association between cumulative exposure to maternal depression or anxiety and asthma development in offspring. This association is unique for maternal depression or anxiety and not due to familial confounding. The clinical implication is that effective psychological management of women with chronic distress may reduce offspring asthma risk.

  • 43.
    Brew, Bronwyn K.
    et al.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Solna, Sweden; National Perinatal Epidemiology and Statistics Unit, Centre for Big Data Research in Health and School of Clinical Medicine, University of New South Wales, Kensington, New South Wales, Australia.
    Osvald, Emma Caffrey
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Solna, Sweden; Pediatric Allergy and Pulmonology Unit, Astrid Lindgren Children's Hospital, Karolinska University Hospital, Stockholm, Sweden.
    Gong, Tong
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Solna, Sweden.
    Hedman, Anna M.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Solna, Sweden.
    Holmberg, Kirsten
    Child Health and Parenting (CHAP), Department of Public Health and Caring Sciences, Uppsala University, Uppsala, Sweden.
    Larsson, Henrik
    Örebro University, School of Medical Sciences. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Solna, Sweden.
    Ludvigsson, Jonas F.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Solna, Sweden; Department of Pediatrics, Örebro University Hospital, Örebro, Sweden; .
    Mubanga, Mwenya
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Solna, Sweden.
    Smew, Awad I.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Solna, Sweden.
    Almqvist, Catarina
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Solna, Sweden; Pediatric Allergy and Pulmonology Unit, Astrid Lindgren Children's Hospital, Karolinska University Hospital, Stockholm, Sweden.
    Paediatric asthma and non-allergic comorbidities: A review of current risk and proposed mechanisms2022In: Clinical and Experimental Allergy, ISSN 0954-7894, E-ISSN 1365-2222, Vol. 15, no 9, p. 1035-1047Article, review/survey (Refereed)
    Abstract [en]

    It is increasingly recognized that children with asthma are at a higher risk of other non-allergic concurrent diseases than the non-asthma population. A plethora of recent research has reported on these comorbidities and progress has been made in understanding the mechanisms for comorbidity. The goal of this review was to assess the most recent evidence (2016-2021) on the extent of common comorbidities (obesity, depression and anxiety, neurodevelopmental disorders, sleep disorders and autoimmune diseases) and the latest mechanistic research, highlighting knowledge gaps requiring further investigation. We found that the majority of recent studies from around the world demonstrate that children with asthma are at an increased risk of having at least one of the studied comorbidities. A range of potential mechanisms were identified including common early life risk factors, common genetic factors, causal relationships, asthma medication and embryologic origins. Studies varied in their selection of population, asthma definition and outcome definitions. Next, steps in future studies should include using objective measures of asthma, such as lung function and immunological data, as well as investigating asthma phenotypes and endotypes. Larger complex genetic analyses are needed, including genome-wide association studies, gene expression-functional as well as pathway analyses or Mendelian randomization techniques; and identification of gene-environment interactions, such as epi-genetic studies or twin analyses, including omics and early life exposure data. Importantly, research should have relevance to clinical and public health translation including clinical practice, asthma management guidelines and intervention studies aimed at reducing comorbidities.

  • 44.
    Brikell, I.
    et al.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Ghirardi, L.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Chang, Z.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    D'Onofrio, B. M.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Department of Psychological and Brain Sciences, Indiana University, Bloomington, USA.
    Kuja-Halkola, R.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Larsson, Henrik
    Örebro University, School of Medical Sciences. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    ADHD medications and the risk of epileptic seizures: a pharmacoepidemiological study using nationwide register data2017In: European Neuropsychopharmacology, ISSN 0924-977X, E-ISSN 1873-7862, Vol. 27, no Suppl. 4, p. S1113-S1114Article in journal (Other academic)
    Abstract [en]

    Background: Attention-deficit/hyperactivity disorder (ADHD) affects 10–30% of children with epilepsy, making it one of the most common comorbidities in epilepsy. Stimulant medications are first line pharmacological treatment of ADHD, yet there areconcerns regarding the safety of stimulant treatment in patients with comorbid ADHD and epilepsy. This is due to the long held view that stimulants may lower the seizure threshold and increase seizure frequency [1]. Evidence for such an effect are however inconsistent and largely based on studies with small sample sizes, highly selected patient populations and observational studies that have not sufficiently addressed issues of confounding [2]. The aim of this pharmacoepidemiological register based study wastherefore to estimate the risk of seizures in relation to ADHD medication use in a population based cohort of individuals with a history of seizures.

    Methods: Using Swedish national registers, we identified a cohort of 62,361 individuals (48% female) born in Sweden between 1960 and 2004, with at least one seizure episode according to ICD codes. Each individual was followed from January 1st 2006, their first seizure or age five, up until December 31st 2013 or death, whichever came first. We identified periods of ADHD medication use (methylphenidate, amphetamine, dexamphetamine, lisdexamfetamine, and atomoxetine) from the Swedish National Prescribed Drug Register. A period was defined as on-medication when two consecutive prescriptions where no more than 183 days apart, and off-medication if more than 183 daysapart. We obtained information on medical visit for unplanned seizures events from the Swedish National Patient register using ICD codes. We estimated the population level association between ADHD medications and the rate of seizures during medicated and non-medication periods using a cox proportional hazards regression model. To adjust for individual-specific confounding that may influence both seizure risk and the likelihood of receiving ADHD medication, we used a stratified Cox regression model to estimate the rate of seizures during medicated and non-medicated periods, within the same individual.

    Preliminary Result: A total of 59,749 seizure events occurred during 361,501 person years of follow-up. ADHD medications were not associated with the rate of seizures at the population level (HR = 1.06, 95%CI 0.91–1.23). In the within-individual analysis, ADHD medication periods were associated with a reduced rate of seizures (HR = 0.70, 95%CI 0.62–0.79), compared to non-medicated periods. Estimates did not differ across sex, nor in age restricted analyses including only ages 5 and 20 years. All analyses were adjusted for age as a time-varying covariate. Population level analyses were additionally adjusted for sex.

    Conclusions: Our findings suggest that ADHD medications are not associated with an increased risk of seizures. Rather, results from the within-individual analysis, which adjusts for factors that are constant within the individual, such as genetic factors and underlying disorder severity, suggest a protective effect of ADHD medication treatment on seizure rates. Next, we will study the effect of concurrent antiepileptic medication use and whether the observed effect differs by stimulant and non-stimulant ADHD medications. We will also further investigate possible mechanisms contributing to the observed protective effect of ADHD medications on seizure rates.

    References

    [1] Williams, A.E., Giust, J.M., Kronenberger, W.G., Dunn, D.W., 2016. Epilepsy and attention-deficit hyperactivity disorder: links, risks, and challenges. Neuropsychiatr Dis Treat 12, 287–296.

    [2] Ravi, M., Ickowicz, A., 2016. Epilepsy, Attention-Deficit/Hyperactivity Disorder and Methylphenidate: Critical Examination of Guiding Evidence. Journal of the Canadian Academy of Child and Adolescent Psychiatry 25 (1), 50.

  • 45.
    Brikell, Isabell
    et al.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Chen, Qi
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Kuja-Halkola, Ralf
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    D'Onofrio, Brian M.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Department of Psychological and Brain Sciences, Indiana University, Bloomington, Indiana, USA.
    Wiggs, Kelsey K.
    Department of Psychological and Brain Sciences, Indiana University, Bloomington, Indiana, USA.
    Lichtenstein, Paul
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Almqvist, Catarina
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Pediatric Allergy and Pulmonology Unit at Astrid Lindgren Children's Hospital, Karolinska University Hospital, Stockholm, Sweden.
    Quinn, Patrick D.
    Department of Psychological and Brain Sciences, Indiana University, Bloomington, Indiana, USA.
    Chang, Zheng
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Larsson, Henrik
    Örebro University, School of Medical Sciences. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Medication treatment for attention-deficit/hyperactivity disorder and the risk of acute seizures in individuals with epilepsy2019In: Epilepsia, ISSN 0013-9580, E-ISSN 1528-1167, Vol. 60, no 2, p. 284-293Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: Attention-deficit/hyperactivity disorder (ADHD) affects 10%-30% of individuals with epilepsy, yet concerns remain regarding the safety of ADHD medication in this group. The objective of this study was to examine the risk of acute seizures associated with ADHD medication in individuals with epilepsy.

    METHODS: A total of 21 557 individuals with a seizure history born between 1987 and 2003 were identified from Swedish population registers. Within this study population, we also identified 6773 youth (<19 years of age) who meet criteria for epilepsy, and 1605 youth with continuous antiepileptic drug (AED) treatment. ADHD medication initiation and repeated medication periods were identified from the Swedish Prescribed Drug Register between January 1, 2006 and December 31, 2013. Acute seizures were identified via unplanned visits to hospital or specialist care with a primary seizure discharge diagnosis in the Swedish National Patient Register during the same period. Conditional Poisson regression was used to compare the seizure rate during the 24 weeks before and after initiation of ADHD medication with the rate during the same 48 weeks in the previous year. Cox regression was used to compare the seizure rate during ADHD medication periods with the rate during nonmedication periods. Comparisons were made within-individual to adjust for unmeasured, time?constant confounding.

    RESULTS: Among 995 individuals who initiated ADHD medication during follow-up, within-individual analyses showed no statistically significant difference in the rate of seizures during the 24 weeks before and after medication initiation, compared to the same period in the previous year. In the full study population 11 754 seizure events occurred during 136 846 person-years and 1855 individuals had at least one ADHD medication period. ADHD medication periods were associated with a reduced rate of acute seizures (hazard ratio [HR] 0.73, 95% confidence interval [CI] 0.57-0.94), compared to nonmedication periods within the same individual. Similar associations were found in youth with epilepsy and continuous AED treatment, when adjusting for AEDs, and across sex, age, and comorbid neurodevelopmental disorders.

    SIGNIFICANCE: We found no evidence for an overall increased rate of acute seizures associated with ADHD medication treatment among individuals with epilepsy. These results suggest that epilepsy should not automatically preclude patients from receiving ADHD medications.

  • 46.
    Brikell, Isabell
    et al.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Ghirardi, Laura
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    D'Onofrio, Brian M.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Department of Psychological and Brain Sciences, Indiana University, Bloomington, United States.
    Dunn, David W.
    Department of Psychiatry, Riley Child and Adolescent Psychiatry Clinic, Indiana University School of Medicine, Indiana University Health Physicians, Indianapolis Indiana, United States.
    Almqvist, Catarina
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Astrid Lindgren Children's Hospital, Karolinska University Hospital, Stockholm, Sweden.
    Dalsgaard, Søren
    National Centre for Register-Based Research, Department of Economics, Aarhus University, Aarhus, Denmark; The Lundbeck Foundation Initiative for Integrative Psychiatric Research, Aarhus University, Aarhus, Denmark; Department for Child and Adolescent Psychiatry, Hospital of Telemark, Kragerø, Norway.
    Kuja-Halkola, Ralf
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Larsson, Henrik
    Örebro University, School of Medical Sciences. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Familial Liability to Epilepsy and Attention-Deficit/Hyperactivity Disorder: A Nationwide Cohort Study2018In: Biological Psychiatry, ISSN 0006-3223, E-ISSN 1873-2402, Vol. 83, no 2, p. 173-180Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Epilepsy and attention-deficit/hyperactivity disorder (ADHD) are strongly associated; however, the underlying factors contributing to their co-occurrence remain unclear. A shared genetic liability has been proposed as one possible mechanism. Therefore, our goal in this study was to investigate the familial coaggregation of epilepsy and ADHD and to estimate the contribution of genetic and environmental risk factors to their co-occurrence.

    METHODS: We identified 1,899,654 individuals born between 1987 and 2006 via national Swedish registers and linked each individual to his or her biological relatives. We used logistic regression to estimate the association between epilepsy and ADHD within individual and across relatives. Quantitative genetic modeling was used to decompose the cross-disorder covariance into genetic and environmental factors.

    RESULTS: Individuals with epilepsy had a statistically significant increased risk of ADHD (odds ratio [OR] = 3.47, 95% confidence interval [CI] = 3.33-3.62). This risk increase extended to children whose mothers had epilepsy (OR = 1.85, 95% CI = 1.75-1.96), children whose fathers had epilepsy (OR = 1.64, 95% CI = 1.54-1.74), full siblings (OR = 1.56, 95% CI = 1.46-1.67), maternal half siblings (OR = 1.28, 95% CI = 1.14-1.43), paternal half siblings (OR = 1.10, 95% CI = 0.96-1.25), and cousins (OR = 1.15, 95% CI = 1.10-1.20). The genetic correlation was 0.21 (95% CI = 0.02-0.40) and explained 40% of the phenotypic correlation between epilepsy and ADHD, with the remaining variance largely explained by nonshared environmental factors (49%, nonshared environmental correlation = 0.36, 95% CI = 0.23-0.49). The contribution of shared environmental factors to the cross-disorder overlap was not statistically significant (11%, shared environmental correlation = 0.32, 95% CI = 20.16-0.79).

    CONCLUSIONS: This study demonstrates a strong and etiologically complex association between epilepsy and ADHD, with shared familial factors and risk factors unique to the individual contributing to co-occurrence of the disorders. Our findings suggest that epilepsy and ADHD may share less genetic risk as compared with other neurodevelopmental disorders.

  • 47.
    Brikell, Isabell
    et al.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Kuja-Halkola, Ralf
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Larsson, Henrik
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Heritability of attention-deficit hyperactivity disorder in adults2015In: American Journal of Medical Genetics Part B: Neuropsychiatric Genetics, ISSN 1552-4841, E-ISSN 1552-485X, Vol. 168, no 6, p. 406-413Article, review/survey (Refereed)
    Abstract [en]

    Attention-deficit/hyperactivity disorder (ADHD) is a common neurodevelopmental disorder. Symptoms often persist into adulthood, with a prevalence of 2.5-5% in adult populations. Twin studies in childhood consistently report high heritabilities of 70-80%, while studies in adult samples show only moderate heritability of 30-40% when estimated from self-ratings. This review summarizes the available research on the heritability of ADHD in adults. Three key findings are outlined: (i) self-ratings lead to relatively low heritability estimates of ADHD, independent of age and whether ratings refer to current or retrospective symptoms; (ii) studies relying on different informants to rate each twin within a pair (i.e., self-ratings and different parents/teachers rating each twin in a pair) consistently yield lower heritability estimates than studies relying on ratings from a single informant; (iii) studies using cross-informant data via either combined parent and self-ratings or clinical diagnoses information suggest that the heritability of ADHD in adults could be as high as 70-80%. Together, the reviewed studies suggest that the previously reported low heritability of ADHD in adults is unlikely to reflect a true developmental change. Instead, the drop in heritability is better explained by rater effects related to a switch from using one rater for both twins in a pair (parent/teacher) in childhood, to relying on self-ratings (where each twin rates themselves) of ADHD symptoms in adulthood. When rater effects are addressed using cross-informant approaches, the heritability of ADHD in adults appears to be comparable to the heritability of ADHD in childhood.

  • 48.
    Brikell, Isabell
    et al.
    Karolinska Institutet, Stockholm, Sweden.
    Kuja-Halkola, Ralf
    Karolinska Institutet, Stockholm, Sweden.
    Larsson, Jan-Olov
    Karolinska Institutet, Stockholm, Sweden.
    Lahey, Benjamin B.
    University of Chicago, Chicago, USA .
    Kuntsi, Jonna
    MRC Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, United Kingdom.
    Lichtenstein, Paul
    Karolinska Institutet, Stockholm, Sweden.
    Rydelius, Per-Anders
    Karolinska Institutet, Stockholm, Sweden; Center for Research on Child and Adolescent Mental Health, Karlstad University, Karlstad, Sweden.
    Larsson, Henrik
    Örebro University, School of Medical Sciences. Karolinska Institutet, Stockholm, Sweden.
    Relative Immaturity in Childhood and Attention-Deficit/Hyperactivity Disorder Symptoms From Childhood to Early Adulthood: Exploring Genetic and Environmental Overlap Across Development2016In: Journal of the American Academy of Child and Adolescent Psychiatry, ISSN 0890-8567, E-ISSN 1527-5418, Vol. 55, no 10, p. 886-895Article in journal (Refereed)
    Abstract [en]

    Objective: Attention-deficit/hyperactivity disorder (ADHD) has been linked to immaturity relative to peers in childhood, yet it is unclear how such immaturity is associated with ADHD across development. This longitudinal twin study examined the genetic and environmental contributions to the association between parents' perception of their child's immaturity relative to peers (RI) in childhood and ADHD symptoms across development.

    Method: 1,302 twin pairs from the Swedish Twin Study of Child and Adolescent Development were followed prospectively from childhood to early adulthood. Parent ratings of RI were collected at 8 to 9 years and parent and self-ratings of ADHD symptoms were collected at 8 to 9, 13 to 14, 16 to 17, and 19 to 20 years using the Child Behavior Checklist Attention Problems scale. In addition, ADHD symptoms corresponding to DSM criteria were used for sensitivity analysis. Analyses were conducted using longitudinal structural equation modeling with multiple raters.

    Results: RI-related etiologic factors, predominantly influenced by genes, explained 10-14% of the variance in ADHD symptoms from 8 to 9 up to 16 to 17 years. The influence of these RI-related factors on ADHD symptoms attenuated to 4% by 19 to 20 years of age. The remaining variance in ADHD symptoms was primarily explained by genetic factors independent of RI, which remained relatively stable across development, explaining 19% to 30% of the variance in ADHD symptoms from 13 to 14 up to 19 to 20 years.

    Conclusion: The results show that RI is significantly associated with ADHD symptoms, particularly during childhood and adolescence, and that the association is primarily explained by a shared genetic liability. Nevertheless, the magnitude of associations across development was modest, highlighting that RI is merely one aspect contributing to the complex etiology of ADHD symptoms.

  • 49.
    Brikell, Isabell
    et al.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Larsson, Henrik
    Örebro University, School of Medical Sciences. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Lu, Yi
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Statistical Genetics, Genetics and Computational Biology Department, QIMR Berghofer Medical Research Institute, Brisbane QLD, Australia.
    Pettersson, Erik
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Chen, Qi
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Kuja-Halkola, Ralf
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Karlsson, Robert
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Lahey, Benjamin B.
    Department of Public Health Sciences, University of Chicago, Chicago IL, USA.
    Lichtenstein, Paul
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Martin, Joanna
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, UK.
    The contribution of common genetic risk variants for ADHD to a general factor of childhood psychopathology2020In: Molecular Psychiatry, ISSN 1359-4184, E-ISSN 1476-5578, Vol. 25, no 8, p. 1809-1821Article in journal (Refereed)
    Abstract [en]

    Common genetic risk variants have been implicated in the etiology of clinical attention-deficit/hyperactivity disorder (ADHD) diagnoses and symptoms in the general population. However, given the extensive comorbidity across ADHD and other psychiatric conditions, the extent to which genetic variants associated with ADHD also influence broader psychopathology dimensions remains unclear. The aim of this study was to evaluate the associations between ADHD polygenic risk scores (PRS) and a broad range of childhood psychiatric symptoms, and to quantify the extent to which such associations can be attributed to a general factor of childhood psychopathology. We derived ADHD PRS for 13,457 children aged 9 or 12 from the Child and Adolescent Twin Study in Sweden, using results from an independent meta-analysis of genome-wide association studies of ADHD diagnosis and symptoms. We estimated associations between ADHD PRS, a general psychopathology factor, and several dimensions of neurodevelopmental, externalizing, and internalizing symptoms, using structural equation modeling. Higher ADHD PRS were statistically significantly associated with elevated neurodevelopmental, externalizing, and depressive symptoms (R 2  = 0.26-1.69%), but not with anxiety. After accounting for a general psychopathology factor, on which all symptoms loaded positively (mean loading = 0.50, range = 0.09-0.91), an association with specific hyperactivity/impulsivity remained significant. ADHD PRS explained ~ 1% (p value < 0.0001) of the variance in the general psychopathology factor and ~ 0.50% (p value < 0.0001) in specific hyperactivity/impulsivity. Our results suggest that common genetic risk variants associated with ADHD, and captured by PRS, also influence a general genetic liability towards broad childhood psychopathology in the general population, in addition to a specific association with hyperactivity/impulsivity symptoms.

  • 50.
    Brikell, Isabell
    et al.
    Karolinska Institutet, Stockholm, Sweden.
    Larsson, Henrik
    Örebro University, School of Medical Sciences. Karolinska Institutet, Stockholm, Sweden.
    Yi, Lu
    Karolinska Institutet, Stockholm, Sweden.
    Petterson, Erik
    Karolinska Institutet, Stockholm, Sweden.
    Chen, Qi
    Karolinska Institutet, Stockholm, Sweden.
    Kuja-Halkola, Ralf
    Karolinska Institutet, Stockholm, Sweden.
    Karlsson, Robert
    Karolinska Institutet, Stockholm, Sweden.
    Lichtenstein, Paul
    Karolinska Institutet, Stockholm, Sweden.
    Martin, Joanna
    Karolinska Institutet, Stockholm, Sweden; Institute of Psychological Medicine and Clinical Neurosciences, MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University School of Medicine, Cardiff, Wales.
    COMMON GENETIC RISK VARIANTS FOR ADHD CONTRIBUTE TO CHILDHOOD NEURODEVELOPMENTAL AND EXTERNALIZING TRAITS IN THE POPULATION2019In: European Neuropsychopharmacology, ISSN 0924-977X, E-ISSN 1873-7862, Vol. 29, no Suppl. 3, p. S811-S811Article in journal (Other academic)
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