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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.
    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.

  • 3.
    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.

  • 4.
    Chang, Zheng
    et al.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden.
    Lichtenstein, Paul
    Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden.
    Halldner, Linda
    Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden; Karolinska Institute Center of Neurodevelopmental Disorders (KIND), Stockholm, Sweden.
    D'Onofrio, Brian
    Department of Psychological and Brain Sciences, Indiana University, Bloomington, USA.
    Serlachius, Eva
    Department of Clinical Neuroscience, Centre for Psychiatric Research and Education, Karolinska Institute, Stockholm, Sweden.
    Fazel, Seena
    Department of Psychiatry, University of Oxford, Oxford, UK.
    Långström, Niklas
    Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden.
    Larsson, Henrik
    Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden.
    Stimulant ADHD medication and risk for substance abuse2014In: Journal of Child Psychology and Psychiatry, ISSN 0021-9630, E-ISSN 1469-7610, Vol. 55, no 8, p. 878-885Article in journal (Refereed)
    Abstract [en]

    Background: There are persistent concerns of long-term effects of stimulant ADHD medication on the development of substance abuse.

    Methods: Using Swedish national registers, we studied all individuals born between 1960 and 1998 and diagnosed with ADHD (26,249 men and 12,504 women). We investigated the association between stimulant ADHD medication in 2006 and substance abuse during 2009. Substance abuse was indexed by substance-related death, crime, or hospital visits.

    Results: ADHD medication was not associated with increased rate of substance abuse. Actually, the rate during 2009 was 31% lower among those prescribed ADHD medication in 2006, even after controlling for medication in 2009 and other covariates (hazard ratio: 0.69; 95% confidence interval: 0.57-0.84). Also, the longer the duration of medication, the lower the rate of substance abuse. Similar risk reductions were suggested among children and when investigating the association between stimulant ADHD medication and concomitant short-term abuse.

    Conclusions: We found no indication of increased risks of substance abuse among individuals prescribed stimulant ADHD medication; if anything, the data suggested a long-term protective effect on substance abuse. Although stimulant ADHD medication does not seem to increase the risk for substance abuse, clinicians should remain alert to the potential problem of stimulant misuse and diversion in ADHD patients.

  • 5.
    Cheesman, Rosa
    et al.
    PROMENTA Research Center, Department of Psychology, University of Oslo, Oslo, Norway.
    Eilertsen, Espen M.
    PROMENTA Research Center, Department of Psychology, University of Oslo, Oslo, Norway; Centre for Fertility and Health, Norwegian Institute of Public Health, Oslo, Norway.
    Ayorech, Ziada
    PROMENTA Research Center, Department of Psychology, University of Oslo, Oslo, Norway.
    Borgen, Nicolai T.
    Department of Special Needs Education, University of Oslo, Oslo, Norway.
    Andreassen, Ole A.
    NORMENT, Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway; Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
    Larsson, Henrik
    Örebro University, School of Medical Sciences. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Zachrisson, Henrik
    Department of Special Needs Education, University of Oslo, Oslo, Norway.
    Torvik, Fartein A.
    PROMENTA Research Center, Department of Psychology, University of Oslo, Oslo, Norway; Centre for Fertility and Health, Norwegian Institute of Public Health, Oslo, Norway.
    Ystrom, Eivind
    PROMENTA Research Center, Department of Psychology, University of Oslo, Oslo, Norway; Department of Mental Disorders, Norwegian Institute of Public Health, Oslo, Norway .
    How interactions between ADHD and schools affect educational achievement: a family-based genetically sensitive study.2022In: Journal of Child Psychology and Psychiatry, ISSN 0021-9630, E-ISSN 1469-7610, Vol. 63, no 10, p. 1174-1185Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Children with ADHD tend to achieve less than their peers in school. It is unknown whether schools moderate this association. Nonrandom selection of children into schools related to variations in their ADHD risk poses a methodological problem.

    METHODS: We linked data on ADHD symptoms of inattention and hyperactivity and parent-child ADHD polygenic scores (PGS) from the Norwegian Mother, Father, and Child Cohort Study (MoBa) to achievement in standardised tests and school identifiers. We estimated interactions of schools with individual differences between students in inattention, hyperactivity, and ADHD-PGS using multilevel models with random slopes for ADHD effects on achievement over schools. In our PGS analyses, we adjust for parental selection of schools by adjusting for parental ADHD-PGS (a within-family PGS design). We then tested whether five school sociodemographic measures explained any interactions.

    RESULTS: Analysis of up to 23,598 students attending 2,579 schools revealed interactions between school and ADHD effects on achievement. The variability between schools in the effects of inattention, hyperactivity and within-family ADHD-PGS on achievement was 0.08, 0.07 and 0.05 SDs, respectively. For example, the average effect of inattention on achievement was β = -0.23 (SE = 0.009), but in 2.5% of schools with the weakest effects, the value was -0.07 or less. ADHD has a weaker effect on achievement in higher-performing schools. Schools make more of a difference to the achievements of students with higher levels of ADHD, explaining over four times as much variance in achievement for those with high versus average inattention symptoms. School sociodemographic measures could not explain the ADHD-by-school interactions.

    CONCLUSIONS: Although ADHD symptoms and genetic risk tend to hinder achievement, schools where their effects are weaker do exist. Differences between schools in support for children with ADHD should be evened out.

  • 6.
    Chen, Cen
    et al.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Lu, Yi
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Lundström, Sebastian
    Centre for Ethics, Law and Mental Health (CELAM), University of Gothenburg, Gothenburg, Sweden; Gillberg Neuropsychiatry Centre, University of Gothenburg, Gothenburg, Sweden.
    Larsson, Henrik
    Örebro University, School of Medical Sciences. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Lichtenstein, Paul
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Pettersson, Erik
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Associations between psychiatric polygenic risk scores and general and specific psychopathology symptoms in childhood and adolescence between and within dizygotic twin pairs2022In: Journal of Child Psychology and Psychiatry, ISSN 0021-9630, E-ISSN 1469-7610, Vol. 63, no 12, p. 1513-1522Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Although polygenic risk scores (PRS) predict psychiatric problems, these associations might be attributable to indirect pathways including population stratification, assortative mating, or dynastic effects (mediation via parental environments). The goal of this study was to examine whether PRS-psychiatric symptom associations were attributable to indirect versus direct pathways.

    METHODS: The sample consisted of 3,907 dizygotic (DZ) twin pairs. In childhood, their parents rated them on 98 symptoms. In adolescence (n = 2,393 DZ pairs), both the parents and the twins rated themselves on 20 symptoms. We extracted one general and seven specific factors from the childhood data, and one general and three specific factors from the adolescent data. We then regressed each general factor model onto ten psychiatric PRS simultaneously. We first conducted the regressions between individuals (β) and then within DZ twin pairs (βw ), which controls for indirect pathways.

    RESULTS: In childhood, the PRS for ADHD predicted general psychopathology (β = 0.09, 95% CI: [0.06, 0.12]; βw  = 0.07 [0.01, 0.12]). Furthermore, the PRS for ADHD predicted specific inattention (β = 0.04 [0.00, 0.08]; βw  = 0.09 [0.01, 0.17]) and specific hyperactivity (β = 0.07 [0.04, 0.11]; βw  = 0.09 [0.01, 0.16]); the PRS for schizophrenia predicted specific learning (β = 0.08 [0.03, 0.13]; βw  = 0.19 [0.08, 0.30]) and specific inattention problems (β = 0.05 [0.01, 0.09]; βw  = 0.10 [0.02, 0.19]); and the PRS for neuroticism predicted specific anxiety (β = 0.06 [0.02, 0.10]; βw  = 0.06 [0.00, 0.12]). Overall, the PRS-general factor associations were similar between individuals and within twin pairs, whereas the PRS-specific factors associations amplified by 84% within pairs.

    CONCLUSIONS: This implies that PRS-psychiatric symptom associations did not appear attributable to indirect pathways such as population stratification, assortative mating, or mediation via parental environments. Rather, genetics appeared to directly influence symptomatology.

  • 7.
    Chen, Qi
    et al.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Brikell, Isabell
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Lichtenstein, Paul
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Serlachius, Eva
    Department of Clinical Neuroscience, Centre for Psychiatry Research, Karolinska Institutet, Stockholm, Sweden; Stockholm Health Care Services, Stockholm County Council, Stockholm, Sweden.
    Kuja-Halkola, Ralf
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Sandin, Sven
    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 aggregation of attention-deficit/hyperactivity disorder2017In: Journal of Child Psychology and Psychiatry, ISSN 0021-9630, E-ISSN 1469-7610, Vol. 58, no 3, p. 231-239Article in journal (Refereed)
    Abstract [en]

    Background: Attention-deficit/hyperactivity disorder (ADHD) aggregates in families. To date, the strength, pattern, and characteristics of the familial aggregation have not been thoroughly assessed in a population-based family sample.

    Methods: In this cohort study, we identified relative pairs of twins, full and half-siblings, and full and half cousins from 1,656,943 unique individuals born in Sweden between 1985 and 2006. The relatives of index persons were followed from their third birthday to 31 December 2009 for ADHD diagnosis. Birth year adjusted hazard ratio (HR), that is, the rate of ADHD in relatives of ADHD-affected index persons compared with the rate of ADHD in relatives of unaffected index persons, was estimated in the different types of relatives using Cox proportional hazards model.

    Results: During the follow-up, 31,865 individuals were diagnosed with ADHD (male to female ratio was 3.7). The birth year adjusted HRs were as follows: 70.45 for monozygotic twins; 8.44 for dizygotic twins; 8.27 for full siblings; 2.86 for maternal half-siblings; 2.31 for paternal half-siblings; 2.24 for full cousins; 1.47 for half cousins. Maternal half-siblings had significantly higher HR than in paternal half-siblings. The HR did not seem to be affected by index person's sex. Full siblings of index persons with ADHD diagnosis present at age 18 or older had a higher rate of ADHD (HR: 11.49) than full siblings of index persons with ADHD diagnosis only before age 18 (HR: 4.68).

    Conclusions: Familial aggregation of ADHD increases with increasing genetic relatedness. The familial aggregation is driven by not only genetic factors but also a small amount of shared environmental factors. Persistence of ADHD into adulthood indexes stronger familial aggregation of ADHD.

  • 8.
    Chen, Qi
    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.
    Sjölander, Arvid
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Serlachius, Eva
    Department of Clinical Neuroscience, Centre for Psychiatry Research, Karolinska Institutet, Stockholm, Sweden; Stockholm Health Care Services, Stockholm County Council, Stockholm, Sweden.
    Cortese, Samuele
    Department of Psychology, Developmental Brain-Behavior Laboratory, University of Southampton, Southampton, UK; Solent NHS Trust, Southampton, UK; Langone Medical Center, New York University Child Study Center, New York NY, USA.
    Faraone, Stephen V.
    Departments of Psychiatry and Neuroscience and Physiology, SUNY Upstate Medical University, New York NY, USA; The K.G. Jebsen Centre for Research on Neuropsychiatric Disorders, University of Bergen, Bergen, Norway.
    Almqvist, Catarina
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Lung and Allergy Unit, 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.
    Shared familial risk factors between attention-deficit/hyperactivity disorder and overweight/obesity: a population-based familial coaggregation study in Sweden2017In: Journal of Child Psychology and Psychiatry, ISSN 0021-9630, E-ISSN 1469-7610, Vol. 58, no 6, p. 711-718Article in journal (Refereed)
    Abstract [en]

    Background: Despite meta-analytic evidence for the association between attention-deficit/hyperactivity disorder (ADHD) and overweight/obesity, the mechanisms underlying the association are yet to be fully understood.

    Methods By linking multiple Swedish national and regional registers, we identified 472,735 index males born during 1973-1992, with information on body weight and height directly measured before they were conscripted for military service. We further identified 523,237 full siblings born during 1973-2002 for the index males. All individuals were followed up from their third birthday to December 31, 2009 for ADHD diagnosis. Logistic regression models were used to estimate the association between overweight/obesity in index males and ADHD in their full siblings.

    Results: Siblings of index males with overweight/obesity had increased risk for ADHD (overweight: OR = 1.14, 95% CI = 1.05-1.24; obesity: OR = 1.42, 95% CI = 1.24-1.63), compared with siblings of index males with normal weight. The results were adjusted for birth year of the index male and sex of the sibling. After further adjustment for ADHD status of the index male, the familial coaggregation remained significant (overweight: OR = 1.13, 95% CI = 1.04-1.22; obesity: OR = 1.38, 95% CI = 1.21-1.57). The results were similar across sex of the siblings.

    Conclusions: Attention-deficit/hyperactivity disorder and overweight/obesity share familial risk factors, which are not limited to those causing overweight/obesity through the mediation of ADHD. Future research aiming at identifying family-wide environmental risk factors as well as common pleiotropic genetic variants contributing to both traits is warranted.

  • 9.
    Du Rietz, Ebba
    et al.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Solna, Sweden.
    Jangmo, Andreas
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Solna, Sweden.
    Kuja-Halkola, Ralf
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Solna, Sweden.
    Chang, Zheng
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Solna, Sweden.
    D'Onofrio, Brian M.
    Department ofPsychological and Brain Sciences, Indiana University, Bloomington IN, USA.
    Ahnemark, Ewa
    Shire Sweden AB, a Takeda Company, Stockholm, Sweden.
    Werner-Kiechle, Tamara
    Shire International GmbH, a Takeda Company, Zug, Switzerland.
    Larsson, Henrik
    Örebro University, School of Medical Sciences. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Solna, Sweden.
    Trajectories of healthcare utilization and costs of psychiatric and somatic multimorbidity in adults with childhood ADHD: a prospective register-based study2020In: Journal of Child Psychology and Psychiatry, ISSN 0021-9630, E-ISSN 1469-7610, Vol. 61, no 9, p. 959-968Article in journal (Refereed)
    Abstract [en]

    Background: A better understanding of the trajectories and economic burden of psychiatric and somatic disorders (multimorbidity) in ADHD from childhood to adulthood is important for guiding more targeted areas for treatment of ADHD and prevention of multimorbidity, and for forecasting demands on the medical infrastructure. This study aimed to investigate patterns of healthcare utilization and costs of multimorbidity across young adulthood in individuals with a childhood ADHD diagnosis, and additionally in individuals who continue to have ADHD-related contact with health services (persisters) and those who do not (remitters).

    Methods: We prospectively followed a cohort (N = 445,790) born 1987-1990 from the ages of 18 to 26 years. Data on healthcare utilization were obtained from the Swedish National Patient Register (inpatient and outpatient care) and the Prescribed Drug Register (medication prescriptions).

    Results: Mean annual costs per capita from multimorbidity was euro890 ($1,223) in individuals with a childhood ADHD diagnosis (persisters/remitters: euro1,060[$1,456]/euro609[$837]) and euro304 ($418) in individuals without. Costs were largely driven by inpatient hospital admissions, mainly from drug abuse and injuries. Healthcare utilization and costs of psychiatric and somatic disorders at 18 years was significantly higher in individuals with childhood ADHD compared to those without. These group differences remained stable or increased across young adulthood for most outcomes and were generally larger in women than in men. ADHD remitters continued to show significantly greater healthcare utilization and costs compared to individuals without childhood ADHD, although their profiles were not as severe as ADHD persisters.

    Conclusions: Childhood ADHD has long-term associations with both psychiatric and somatic disorders. Findings demonstrate the individual and societal burden of ADHD in adulthood and highlight the importance of continued support from childhood-adolescent to adult health services and early prevention of multimorbidity. Findings also point to specific targets for intervention that may be effective, such as drug abuse and injuries.

  • 10.
    Forsman, Mats
    et al.
    Dept Med Epidemiol & Biostat, Karolinska Inst, Stockholm, Sweden.
    Lichtenstein, Paul
    Dept Med Epidemiol & Biostat, Karolinska Inst, Stockholm, Sweden.
    Andershed, Henrik
    Örebro University, School of Law, Psychology and Social Work.
    Larsson, Henrik
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    A longitudinal twin study of the direction of effects between psychopathic personality and antisocial behaviour2010In: Journal of Child Psychology and Psychiatry, ISSN 0021-9630, E-ISSN 1469-7610, Vol. 51, no 1, p. 39-47Article in journal (Refereed)
    Abstract [en]

    Background: Antisocial behaviour may partly develop as a consequence of psychopathic personality. However, neither the direction of effects nor the aetiology of the association has previously been clarified. The aim in this study was to investigate the direction of effects between psychopathic personality and antisocial behaviour, and to investigate the genetic and environmental contribution to this association. Method: Twins (n = 2,255) in the Swedish Twin Study of Child and Adolescent Development were prospectively followed from adolescence to adulthood. We used a longitudinal cross-lagged twin model to study the associations between psychopathic personality and antisocial behaviour. Results: Psychopathic personality in mid-adolescence predicted antisocial behaviour in adulthood (p < .001), but not the other way around. However, bidirectional effects were found when a measure of persistent antisocial behaviour (from age 8-9 to age 16-17) was used. Psychopathic personality predicted both rule-breaking behaviour (p < .001) and aggressive behaviour (p < .01). Genetic factors were of importance in mediating the longitudinal associations between psychopathic personality and antisocial behaviour. Conclusions: This study provides evidence that genetically influenced psychopathic personality is a robust predictor of adult antisocial behaviour, but also that persistent antisocial behaviour has an impact on adult psychopathic personality via genetic effects.

  • 11.
    Ghirardi, Laura
    et al.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Chen, Qi
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, 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.
    Skoglund, Charlotte
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Quinn, Patrick D.
    Department of Applied Health Science, School of Public Health, Indiana University, Bloomington, IN, USA.
    D'Onofrio, Brian M.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; 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.
    Use of medication for attention-deficit/hyperactivity disorder and risk of unintentional injuries in children and adolescents with co-occurring neurodevelopmental disorders2020In: Journal of Child Psychology and Psychiatry, ISSN 0021-9630, E-ISSN 1469-7610, Vol. 61, no 2, p. 140-147Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) is often associated with other neurodevelopmental disorders (NDs) and with risky behaviors and adverse health outcomes, including injuries. Treatment with ADHD medication has been associated with reduced risk of injuries. However, it is unknown whether the association is present in individuals with co-occurring NDs. The aim of the present study was to estimate the association between ADHD medication use and unintentional injuries in Sweden in children and adolescents with ADHD, including those with co-occurring NDs.

    METHODS: Using a linkage of several national registers via the unique personal identification number, we identified individuals with a diagnosis of ADHD and of other NDs, including autism spectrum disorder, intellectual disability, communication disorders, learning disorders and motor disorders. The primary outcome was unintentional injuries. Secondary outcome was traumatic brain injury (TBI). Individuals were followed from January 1st 2006 or their 5th birthday or the date of the first unintentional injury, whichever came last, to December 31st 2013 or their 18th birthday or death, whichever came first. We compared the rate of injuries during periods on-treatment with the rate of injuries during periods off-treatment within the same individual using stratified Cox regression to calculate hazard ratio (HR) with 95% confidence intervals (CIs).

    RESULTS: For children and adolescents with ADHD (N = 9,421) the rate of any unintentional injuries (HR = 0.85; 95% CI = 0.78-0.92) and TBIs (HR = 0.27; 95% CIs = 0.20-0.38) during medicated periods was lower than during non-medicated periods. Similar results were found among individuals with co-occurring NDs (N = 2,986), for unintentional injuries (HR = 0.88; 95% CI = 0.77-1.01) and for TBIs (HR = 0.27; 95% CI = 0.16-0.44).

    CONCLUSIONS: Beneficial effects of ADHD medication may extend beyond reduction of ADHD core symptoms to prevention of unintentional injuries in children and adolescents, including individuals with co-occurring NDs.

  • 12.
    Ghirardi, Laura
    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; Department of Child Psychiatry, Medical University of Warsaw, Warsaw, Poland; Child and Adolescent Psychiatry, Stockholm Health Care Service, Region Stockholm, Sweden.
    Butwicka, Agnieszka
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Martin, Joanna
    Division of Psychological Medicine and Clinical Neurosciences, MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, UK.
    Larsson, Henrik
    Örebro University, School of Medical Sciences. 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, IN, USA.
    Lichtenstein, Paul
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Taylor, Mark J.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Familial and genetic associations between autism spectrum disorder and other neurodevelopmental and psychiatric disorders2021In: Journal of Child Psychology and Psychiatry, ISSN 0021-9630, E-ISSN 1469-7610, Vol. 62, no 11, p. 1274-1284Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Familial and genetic associations between autism spectrum disorder (ASD) and other neurodevelopmental and psychiatric disorders have been reported, sometimes with conflicting results. We estimated familial and genetic associations between ASD and nine disorder groups, and explored differences in these associations for ASD in the context of intellectual disability, epilepsy, chromosomal abnormalities, and congenital malformations.

    METHODS: Individuals born between 1985 and 2009 living in Sweden on their seventh birthday were linked to their biological parents in order to identify different types of relatives. We retrieved information on all the disorders considered from the National Patient Register. Logistic regression was used to estimate the familial association between ASD and other neurodevelopmental and psychiatric disorders in the different groups of relatives. Structural equation modeling was used to estimate phenotypic (rp ) and genetic associations (rg ), as well as the contribution of genetic influences to rp .

    RESULTS: The study included 2,398,608 individuals. Among relatives of individuals diagnosed with ASD, there was an increased risk of the disorders considered, compared to relatives of individuals who were not diagnosed with ASD. Stronger associations were detected for ASD without any additional diagnosis of intellectual disability, epilepsy, chromosomal abnormalities, and congenital malformations. The strongest genetic correlation was estimated between ASD and other neurodevelopmental disorders (rg  = 0.73; 95% CI = 0.66-0.79). Moderate genetic correlations were estimated for anxiety disorders (rg  = 0.47; 95% CI = 0.33-0.61), depression (rg  = 0.52; 95% CI = 0.37-0.66), and intentional self-harm (rg  = 0.54; 95% CI = 0.36-0.71).

    CONCLUSIONS: ASD shows familial and genetic association not only with other neurodevelopmental disorders, but also with other psychiatric disorders, such as anxiety, depression, and intentional self-harm. Family history of ASD comorbid with intellectual disability, epilepsy, congenital malformations, or chromosomal abnormalities is less related to other psychiatric disorders, potentially suggesting a different etiology for this subgroup of patients.

  • 13.
    Ginsberg, Ylva
    et al.
    Karolinska Institutet, Stockholm, Sweden.
    D'Onofrio, Brian M.
    Karolinska Institutet, Stockholm, Sweden; Indiana University, Bloomington IN, USA.
    Rickert, Martin E.
    Indiana University, Bloomington IN, USA.
    Class, Quetzal A.
    University of Illinois, Chicago IL, USA.
    Rosenqvist, Mina A.
    Karolinska Institutet, Stockholm, Sweden.
    Almqvist, Catarina
    Karolinska Institutet, Stockholm, Sweden; Astrid Lindgren Children′s Hospital, Karolinska University Hospital, Stockholm, Sweden.
    Lichtenstein, Paul
    Karolinska Institutet, Stockholm, Sweden.
    Larsson, Henrik
    Örebro University, School of Medical Sciences. Karolinska Institutet, Stockholm, Sweden.
    Maternal infection requiring hospitalization during pregnancy and attention-deficit hyperactivity disorder in offspring: a quasi-experimental family-based study2019In: Journal of Child Psychology and Psychiatry, ISSN 0021-9630, E-ISSN 1469-7610, Vol. 60, no 2, p. 160-168Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Maternal infection during pregnancy (IDP) has been associated with increased risk of attention-deficit/hyperactivity disorder (ADHD) in offspring. However, infection is associated with social adversity, poor living conditions and other background familial factors. As such, there is a need to rule out whether the observed association between maternal IDP and ADHD might be attributed to such confounding.

    METHODS: This nationwide population-based cohort study using a family-based, quasi-experimental design included 1,066,956 individuals born in Sweden between 1992 and 2002. Data on maternal IDP (bacterial or viral) requiring hospitalization and ADHD diagnosis in offspring were gathered from Swedish National Registers, with individuals followed up through the end of 2009. Ordinary and stratified Cox regression models were used for estimation of hazard ratios (HRs) and several measured covariates were considered. Cousin- and sibling-comparisons accounted for unmeasured genetic and environmental factors shared by cousins and siblings.

    RESULTS: In the entire population, maternal IDP was associated with ADHD in offspring (HR = 2.31, 95% CI = 2.04-2.61). This association was attenuated when accounting for measured covariates (HR = 1.86, 95% CI = 1.65-2.10). The association was further attenuated when adjusting for unmeasured factors shared between cousins (HR = 1.52, 95% CI = 1.12-2.07). Finally, the association was fully attenuated in sibling comparisons (HR = 1.03, 95% CI = 0.76-1.41).

    CONCLUSIONS: This study suggests that the association between maternal IDP and offspring ADHD is largely due to unmeasured familial confounding. Our results underscore the importance of adjusting for unobserved familial risk factors when exploring risk factors for ADHD.

  • 14.
    Halldner, Linda
    et al.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Karolinska Institutet Center of Neurodevelopmental Disorders (KIND), Karolinska Institutet, Stockholm, Sweden.
    Tillander, Annika
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Lundholm, Cecilia
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Boman, Marcus
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Långström, Niklas
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Larsson, Henrik
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Lichtenstein, Paul
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Relative immaturity and ADHD: findings from nationwide registers, parent- and self-reports2014In: Journal of Child Psychology and Psychiatry, ISSN 0021-9630, E-ISSN 1469-7610, Vol. 55, no 8, p. 897-904Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: We addressed if immaturity relative to peers reflected in birth month increases the likelihood of ADHD diagnosis and treatment.

    METHODS: We linked nationwide Patient and Prescribed Drug Registers and used prospective cohort and nested case-control designs to study 6-69 year-old individuals in Sweden from July 2005 to December 2009 (Cohort 1). Cohort 1 included 56,263 individuals diagnosed with ADHD or ever used prescribed ADHD-specific medication. Complementary population-representative cohorts provided DSM-IV ADHD symptom ratings; parent-reported for 10,760 9-year-old twins born 1995-2000 from the CATSS study (Cohort 2) and self-reported for 6,970 adult twins age 20-47 years born 1959-1970 from the STAGE study (Cohort 3). We calculated odds ratios (OR:s) for ADHD across age for individuals born in November/December compared to January/February (Cohort 1). ADHD symptoms in Cohorts 2 and 3 were studied as a function of calendar birth month.

    RESULTS: ADHD diagnoses and medication treatment were both significantly more common in individuals born in November/December versus January/February; peaking at ages 6 (OR: 1.8; 95% CI: 1.5-2.2) and 7 years (OR: 1.6; 95% CI: 1.3-1.8) in the Patient and Prescribed Drug Registers, respectively. We found no corresponding differences in parent- or self-reported ADHD symptoms by calendar birth month.

    CONCLUSION: Relative immaturity compared to class mates might contribute to ADHD diagnosis and pharmacotherapy despite absence of parallel findings in reported ADHD symptom loads by relative immaturity. Increased clinical awareness of this phenomenon may be warranted to decrease risk for imprecise diagnostics and treatment. We speculate that flexibility regarding age at school start according to individual maturity could reduce developmentally inappropriate demands on children and improve the precision of ADHD diagnostic practice and pharmacological treatment.

  • 15.
    Hedman, Anna
    et al.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Breithaupt, Lauren
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Department of Psychology, George Mason University, Fairfax VA, USA.
    Hübel, Christopher
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Social, Genetic & Developmental Psychiatry Centre, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK.
    Thornton, Laura M.
    Department of Psychiatry, University of North Carolina aDepartment of Psychiatry, University of North Carolina, Chapel Hill NC, USAt Chapel Hill, Chapel Hill NC, USA.
    Tillander, Annika
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Department of Computer and Information Science, Linköping University, Linköping, Sweden.
    Norring, Claes
    Department of Clinical Neuroscience, Centre for Psychiatry Research, Karolinska Institutet, Stockholm, Sweden; Stockholm Health Care Services, Stockholm County Council, Stockholm, Sweden.
    Birgegård, Andreas
    Department of Clinical Neuroscience, Centre for Psychiatry Research, Karolinska Institutet, Stockholm, Sweden; Stockholm Health Care Services, Stockholm County Council, Stockholm, Sweden.
    Larsson, Henrik
    Örebro University, School of Medical Sciences. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Ludvigsson, Jonas F.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Department of Pediatrics, Örebro University Hospital, Örebro, Sweden.
    Sävendahl, Lars
    Department of Women's and Children's Health, Karolinska Institutet, Stockholm, 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.
    Bulik, Cynthia M.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; University of North Carolina at Chapel Hill, Chapel Hill NC, USA.
    Bidirectional relationship between eating disorders and autoimmune diseases2019In: Journal of Child Psychology and Psychiatry, ISSN 0021-9630, E-ISSN 1469-7610, Vol. 60, no 7, p. 803-812Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Immune system dysfunction may be associated with eating disorders (ED) and could have implications for detection, risk assessment, and treatment of both autoimmune diseases and EDs. However, questions regarding the nature of the relationship between these two disease entities remain. We evaluated the strength of associations for the bidirectional relationships between EDs and autoimmune diseases.

    METHODS: In this nationwide population-based study, Swedish registers were linked to establish a cohort of more than 2.5 million individuals born in Sweden between January 1, 1979 and December 31, 2005 and followed up until December 2013. Cox proportional hazard regression models were used to investigate: (a) subsequent risk of EDs in individuals with autoimmune diseases; and (b) subsequent risk of autoimmune diseases in individuals with EDs.

    RESULTS: We observed a strong, bidirectional relationship between the two illness classes indicating that diagnosis in one illness class increased the risk of the other. In women, the diagnoses of autoimmune disease increased subsequent hazards of anorexia nervosa (AN), bulimia nervosa (BN), and other eating disorders (OED). Similarly, AN, BN, and OED increased subsequent hazards of autoimmune diseases.Gastrointestinal-related autoimmune diseases such as, celiac disease and Crohn's disease showed a bidirectional relationship with AN and OED. Psoriasis showed a bidirectional relationship with OED. The previous occurence of type 1 diabetes increased the risk for AN, BN, and OED. In men, we did not observe a bidirectional pattern, but prior autoimmune arthritis increased the risk for OED.

    CONCLUSIONS: The interactions between EDs and autoimmune diseases support the previously reported associations. The bidirectional risk pattern observed in women suggests either a shared mechanism or a third mediating variable contributing to the association of these illnesses.

  • 16.
    Kerr, Margaret
    et al.
    Örebro University, School of Law, Psychology and Social Work.
    van Zalk, Maarten
    Örebro University, School of Law, Psychology and Social Work.
    Stattin, Håkan
    Örebro University, School of Law, Psychology and Social Work.
    Psychopathic traits moderate peer influence on adolescent delinquency2012In: Journal of Child Psychology and Psychiatry, ISSN 0021-9630, E-ISSN 1469-7610, Vol. 53, no 8, p. 826-835Article in journal (Refereed)
    Abstract [en]

    Background: Peer influence on adolescent delinquency is well established, but little is known about moderators of peer influence. In this study, we examined adolescents (targets) and their peers psychopathic personality traits as moderators of peer influence on delinquency in peer networks. We used three separate dimensions of the psychopathic personality: grandiose-manipulative traits, callous-unemotional traits, and impulsive-irresponsible traits. Methods: We used a peer network approach with five waves of longitudinal data from 847 adolescents in one community. Peer nominations were not limited to the school context, thus allowing us to capture all potentially important peers. In addition, peers reported on their own delinquency, thus allowing us to avoid problems of false consensus or projection that arise when individuals report on their peers delinquency. We used simulation investigation for empirical network analyses (SIENA), which is the only program currently available that can be used to study peer influence effects in peer networks of multiple relationships while controlling for selection effects. Results: Targets and peers callous-unemotional and grandiose-manipulative traits uniquely moderated peer influence on delinquency. Relative to those with low levels, targets who were high on these traits were less influenced by peers delinquency, and peers who were high on these traits were more influential on targets delinquency. Selection effects were found for impulsive-irresponsible traits, but these traits did not moderate peer influence on delinquency. Conclusions: As the first study to look at moderating effects of psychopathic traits on peer influence, this study advances knowledge about peer influence on delinquency and about psychopathic traits in adolescents. In addition, the study contributes to the literature by looking at unique effects of the three dimensions of psychopathy and taking a peer network approach, in which network effects, self-selection, and other selection effects are controlled when examining influence and moderators of influence.

  • 17.
    Kuja-Halkola, Ralf
    et al.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Lichtenstein, Paul
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    D'Onofrio, Brian M
    Department of Psychological and Brain Sciences, Indiana University, Bloomington IN, USA.
    Larsson, Henrik
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Codevelopment of ADHD and externalizing behavior from childhood to adulthood2015In: Journal of Child Psychology and Psychiatry, ISSN 0021-9630, E-ISSN 1469-7610, Vol. 56, no 6, p. 640-647Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Attention-Deficit/Hyperactivity Disorder (ADHD) frequently co-occurs with externalizing disorders, but a clear understanding of the etiologic underpinnings is hampered by the limited understanding of the codevelopment of the traits from childhood into early adulthood.

    METHODS: Using a birth cohort of 2600 twins, the Swedish Twin study of Child and Adolescent Development study, assessed at ages 8-9, 13-14, 16-17, and 19-20, we investigated the codevelopment of ADHD and externalizing behavior from childhood to adulthood. The analyses examined ADHD-like and externalizing traits, as rated by twins and their parents using the Attention Problems scale and Externalizing scale of the Child Behavior Checklist, and estimated cross-lagged effects (one trait at one time-point predicting the other at the next). The covariation between the traits were decomposed into stable (effects carried over from the prior time-points) and innovative (new effects for each time-point) sources; each source was further decomposed into additive genetics, shared and nonshared environment.

    RESULTS: The analysis suggested that externalizing traits in middle childhood (age 8-9) predicted ADHD-like traits in early adolescence (age 13-14), whereas the reverse association was nonsignificant. In contrast, ADHD-like traits in lateadolescence (age 16-17) predicted externalizing traits in early adulthood (age 19-20). The correlation between ADHD-like and externalizing traits increased over time. At all time-points, innovative sources contributed substantially to maintained comorbidity. Genetic effects explained 67% of the covariation at each time-point; importantly, nearly 50% of these effects were innovative.

    CONCLUSIONS: This study challenges the belief that ADHD generally precedes externalizing behaviors; rather, change in the etiologic factors across the development is the rule. The effects were due to both new genetic and environmental factors emerging up to young adulthood. Clinicians and researchers needs to consider complex etiologic and developmental models for the comorbidity between ADHD and externalizing behaviors.

  • 18.
    Larsson, Henrik
    Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden.
    Commentary: How can family-based quasi-experimental designs and national registers be used to address confounding in risk factor studies of psychopathology? A reflection on Obel et al. (2016)2016In: Journal of Child Psychology and Psychiatry, ISSN 0021-9630, E-ISSN 1469-7610, Vol. 57, no 4, p. 538-539Article in journal (Refereed)
    Abstract [en]

    Standard observational studies have reported a robust correlation between maternal smoking during pregnancy and risk of ADHD in offspring. In the accompanying article, Obel et al. used sibling-comparisons to explore the extent to which unmeasured familial confounding explains this association. This commentary highlights three important implications of the study. At a general level, Obel et al. illustrates how (1) family-based quasi-experimental designs and (2) national registers can be used to address confounding in risk factor studies of psychopathology. At a more specific level, the study suggests that maternal smoking during pregnancy is probably not a causal risk factor for ADHD.

  • 19.
    Larsson, Henrik
    Örebro University, School of Medical Sciences. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Commentary: Important design features to consider in observational research on the long-term outcomes of ADHD - reflections on Sibley et al. (2017) and Swanson et al. (2017)2017In: Journal of Child Psychology and Psychiatry, ISSN 0021-9630, E-ISSN 1469-7610, Vol. 58, no 6, p. 679-681Article in journal (Refereed)
    Abstract [en]

    In this issue of the Journal, Sibley etal. (2017) presented some important insights into how different assessment approaches influence the apparent persistence of ADHD into adulthood, while Swanson etal. (2017) presented interesting results regarding the long-term benefits (adult symptom reduction) and costs (adult height suppression) associated with the treatment of ADHD with stimulant medication. This commentary highlights that (a) future studies that attempt to explore the occurrence and predictors of persisting and remitting developmental trajectories of ADHD, as well as late-onset ADHD, need to be based on thorough assessment of ADHD in adulthood using a combination of self-ratings and other informants (parents), and that (b) observational studies of the long-term benefits and risk associated with ADHD medications will play an important role in future research and clinical guidelines.

  • 20.
    Larsson, Henrik
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Commentary: Psychopathic traits enhance adolescents' influence on others and make them less easily influenced by others?--reflections on Kerr et al. (2012)2012In: Journal of Child Psychology and Psychiatry, ISSN 0021-9630, E-ISSN 1469-7610, Vol. 53, no 8, p. 836-837Article in journal (Refereed)
  • 21.
    Larsson, Henrik
    et al.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Center for Neurodevelopmental Disorders, Karolinska Institutet Stockholm, Sweden.
    Anckarsäter, Henrik
    Department of Forensic Psychiatry, Institute of Neuroscience and Physiology, Sahlgren’s Academy, University of Gothenburg, Gothenburg, Sweden.
    Råstam, Maria
    Division of Child and Adolescent Psychiatry, Department of Clinical Sciences, Lund University, Lund, Sweden.
    Chang, Zheng
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Lichtenstein, Paul
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Childhood attention-deficit hyperactivity disorder as an extreme of a continuous trait: a quantitative genetic study of 8,500 twin pairs2012In: Journal of Child Psychology and Psychiatry, ISSN 0021-9630, E-ISSN 1469-7610, Vol. 53, no 1, p. 73-80Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Although the clinical utility of categorically defined attention-deficit hyperactivity disorder (ADHD) is well established, there is also strong evidence supporting the notion of ADHD as an extreme of a continuous trait. Nevertheless, the question of whether the etiology is the same for different levels of DSM-IV ADHD symptoms remains to be investigated. The aim of this study was to assess genetic links between the extreme and the subthreshold range of ADHD symptoms.

    METHOD: Parents of all Swedish 9- and 12-year-old twins born between 1992 and 2000 were interviewed for DSM-IV ADHD symptoms and associated conditions. Two validated cutoff values were used for screening and assigning research diagnoses. Response rate was 80%. Twin methods were applied to investigate the extent to which ADHD is etiologically distinct from subthreshold variations in ADHD symptoms.

    RESULTS: Extremes analyses indicated a strong genetic link between the extreme and the subthreshold variation, with almost identical group heritability estimates around .60 for the diagnostic (prevalence 1.78%) and screening (prevalence 9.75%) criteria of ADHD.

    CONCLUSION: A strong genetic link between the extreme and the subthreshold variation of DSM-IV based assessments of ADHD symptoms was found. The data suggest that ADHD is best viewed as the quantitative extreme of genetic and environmental factors operating dimensionally throughout the distribution of ADHD symptoms, indicating that the same etiologic factors are involved in the full range of symptoms of inattention, hyperactivity and impulsivity.

  • 22.
    Larsson, Henrik
    et al.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Center for Neurodevelopmental Disorders, Karolinska Institutet, Stockholm, Sweden.
    Dilshad, Rezin
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Lichtenstein, Paul
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Barker, Edward D
    Department of Developmental Science, Birkbeck College, University of London, London, UK.
    Developmental trajectories of DSM-IV symptoms of attention-deficit/hyperactivity disorder: genetic effects, family risk and associated psychopathology2011In: Journal of Child Psychology and Psychiatry, ISSN 0021-9630, E-ISSN 1469-7610, Vol. 52, no 9, p. 954-963Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: DSM-IV specifies three ADHD subtypes; the combined, the hyperactive-impulsive and the inattentive. Little is known about the developmental relationships underlying these subtypes. The objective of this study was to describe the development of parent-reported hyperactivity-impulsivity and inattention symptoms from childhood to adolescence and to study their associations with genetic factors, family risk, and later adjustment problems in early adulthood.

    METHOD: Data in this study comes from 1,450 twin pairs participating in a population-based, longitudinal twin study. Developmental trajectories were defined using parent-ratings of hyperactivity-impulsivity and inattention symptoms at age 8-9, 13-14, and 16-17. Twin methods were used to explore genetic influences on trajectories. Family risk measures included low socioeconomic status, large family size and divorce. Self-ratings of externalizing and internalizing problems in early adulthood were used to examine adjustment problems related to the different trajectory combinations.

    RESULTS: We found two hyperactivity-impulsivity trajectories (low, high/decreasing) and two inattention trajectories (low, high/increasing). Twin modeling revealed a substantial genetic component underlying both the hyperactivity-impulsivity and the inattention trajectory. Joint trajectory analyses identified four groups of adolescents with distinct developmental patterns of hyperactivity-impulsivity and inattention: a low/low group, a primarily hyperactive, a primarily inattentive and a combined (high/high) trajectory type. These trajectory combinations showed discriminant relations to adjustment problems in early adulthood. The hyperactive, inattentive and combined trajectory subtypes were associated with higher rates of family risk environments compared to the low/low group.

    CONCLUSION: Study results showed that for those on a high trajectory, hyperactivity decreased whereas inattention increased. The combinations of these trajectories lend developmental insight into how children shift from (i) a combined to inattentive subtype, and (ii) a hyperactive-impulsive to a combined subtype. This study suggests that ADHD subtypes cannot be viewed as discrete and stable categories.

  • 23.
    Larsson, Henrik
    et al.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Sariaslan, Amir
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Långström, Niklas
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    D'Onofrio, Brian
    Department of Psychological and Brain Sciences, Indiana University, Bloomington IN, USA.
    Lichtenstein, Paul
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Family income in early childhood and subsequent attention deficit/hyperactivity disorder: a quasi-experimental study2014In: Journal of Child Psychology and Psychiatry, ISSN 0021-9630, E-ISSN 1469-7610, Vol. 55, no 5, p. 428-435Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Studies have found negative associations between socioeconomic position and attention deficit/hyperactivity disorder (ADHD), but it remains unclear if this association is causal. The aim of this study was to determine the extent to which the association between family income in early childhood and subsequent ADHD depends on measured and unmeasured selection factors.

    METHODS: A total of 811,803 individuals born in Sweden between 1992 and 2000 were included in this nationwide population-based cohort study. Diagnosis of ADHD was assessed via the Swedish national Patient Register and the Swedish Prescribed Drug Register. Annual family income during offspring's first 5 years in life was collected prospectively from the Swedish Integrated Database for Labour Market Research and divided into quartiles by (lower) family disposable income. We predicted ADHD from family income while controlling for covariates and also comparing differently exposed cousins and siblings to control for unmeasured familial confounding.

    RESULTS: The crude analyses suggested that children exposed to lower income levels were at increased risk for ADHD (HRQ uartile1  = 2.52; 95% CI, 2.42-2.63; HRQ uartile2  = 1.52; 95% CI, 1.45-1.58; HRQ uartile3  = 1.20; 95% CI, 1.14-1.15). This dose-dependent association decreased after adjustment for measured covariates (HRQ uartile1  = 2.09; 95% CI, 2.00-2.19; HRQ uartile2  = 1.36; 95% CI, 1.30-1.42; HRQ uartile3  = 1.13; 95% CI, 1.08-1.18). Although the association was attenuated in cousin comparisons (HRQ uartile1  = 1.61; 95% CI, 1.40-1.84; HRQ uartile2  = 1.28; 95% CI, 1.12-1.45; HRQ uartile3  = 1.14; 95% CI, 1.01-1.28) and sibling comparison models (HRQ uartile1  = 1.37; 95% CI, 1.07-1.75; HRQ uartile2  = 1.37; 95% CI, 1.12-1.68; HRQ uartile3  = 1.23; 95% CI, 1.04-1.45), it remained statistically significant across all levels of decreased disposable family income.

    CONCLUSIONS: Our results indicated that low family income in early childhood was associated with increased likelihood of ADHD. The link remained even after controlling for unmeasured selection factors, highlighting family income in early childhood as a marker of causal factors for ADHD.

  • 24.
    Leone, Marica
    et al.
    Janssen Pharmaceutical Companies of Johnson & Johnson, Solna, Sweden; Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Solna, Sweden.
    Kuja-Halkola, Ralf
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Solna, Sweden.
    Lagerberg, Tyra
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Solna, Sweden.
    Bjureberg, Johan
    Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm Health Care Services, Region Stockholm, Stockholm, Sweden.
    Butwicka, Agnieszka
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Solna, Sweden; Child and Adolescent Psychiatry Stockholm, Stockholm Health Care Services, Region Stockholm, Stockholm, Sweden; Department of Child Psychiatry, Medical University of Warsaw, Warsaw, Poland; Department of Biostatistics and Translational Medicine, Medical University of Lodz, Lodz, Poland.
    Chang, Zheng
    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.
    D'Onofrio, Brian M.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Solna, Sweden; Department of Psychological and Brain Sciences, Indiana University, Bloomington, IN, USA.
    Leval, Amy
    Janssen Pharmaceutical Companies of Johnson & Johnson, Solna, Sweden; Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Solna, Sweden.
    Bergen, Sarah E.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Solna, Sweden.
    Melatonin use and the risk of self-harm and unintentional injuries in youths with and without psychiatric disorders2023In: Journal of Child Psychology and Psychiatry, ISSN 0021-9630, E-ISSN 1469-7610, Vol. 64, no 7, p. 1027-1036Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Sleep disorders in youth have been associated with increased risks of injury, including suicidal behavior. This study investigated whether melatonin, which is the most common medication for sleep disturbances in youth in Sweden, is associated with a decreased risk of injury.

    METHODS: This population-based cohort study included 25,575 youths who initiated melatonin treatment between ages 6 and 18. Poisson regression was used to estimate rate of injuries in the year prior to and following melatonin treatment initiation. A within-individual design was used to estimate relative risks by comparing injury risk in the last unmedicated month with injury risks in the 12 months after medication initiation. Analyses were stratified by sex, injury type, psychiatric comorbidities and age at melatonin-treatment initiation.

    RESULTS: While body injuries, falls and transport accident rates were comparable in the year before and after melatonin-treatment initiation, the risk of self-harm was highest in the months immediately prior to medication, and decreased thereafter. This was particularly prominent among adolescents with depression and/or anxiety, with females displaying greater absolute risks than males. Compared to the last unmedicated month, the 12 months post medication initiation had decreased relative risks for self-harm, with an IRR [95% CI] in the month following melatonin-treatment initiation of 0.46 [0.27-0.76] among adolescent females with psychiatric disorders, after excluding antidepressant users.

    CONCLUSIONS: Decreased risk of intentional self-harm was observed following melatonin-treatment initiation among females with depression and anxiety, suggesting that sleep interventions could be considered in an effort to reduce risk of self-harm in this population.

  • 25.
    Lichtenstein, Paul
    et al.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Martin, Cederlöf
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Lundström, Sebastian
    Centre for Ethics, Law and Mental Health (CELAM), University of Gothenburg, Gothenburg, Sweden; Gillberg Neuropsychiatry Centre, University of Gothenburg, Gothenburg, Sweden.
    D'Onofrio, Brian M.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Department of Psychological and Brain Sciences, Indiana University, Bloomington, IN, USA .
    Anckarsäter, Henrik
    Centre for Ethics, Law and Mental Health (CELAM), University of Gothenburg, Gothenburg, Sweden.
    Larsson, Henrik
    Örebro University, School of Medical Sciences.
    Pettersson, Erik
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Associations between conduct problems in childhood and adverse outcomes in emerging adulthood: a longitudinal Swedish nationwide twin cohort2020In: Journal of Child Psychology and Psychiatry, ISSN 0021-9630, E-ISSN 1469-7610, Vol. 61, no 7, p. 798-806Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: We examined whether childhood conduct problems predicted a wide range of adverse outcomes in emerging adulthood and whether the association with internalizing problems remained after adjusting for general comorbidity and externalizing problems.

    METHODS: Participants were 18,649 twins from the Child and Adolescent Twin Study in Sweden. At age 9/12, parents rated their children on eight conduct problems. Adverse outcomes were retrieved from national registers in emerging adulthood (median follow-up time = 9.2 years), including diagnoses of six psychiatric disorders, prescriptions of antidepressants, suicide attempts, criminality, high school ineligibility, and social welfare recipiency. We estimated risk for the separate outcomes and examined if conduct problems predicted an internalizing factor above and beyond a general comorbidity and an externalizing factor. We used twin analyses to estimate genetic and environmental contributions to these associations.

    RESULTS:  On the average, each additional conduct symptom in childhood was associated with a 32% increased risk of the adverse outcomes in emerging adulthood (mean hazard ratio = 1.32; range = 1.16, 1.56). A latent childhood conduct problems factor predicted the internalizing factor in emerging adulthood (beta(boys) = .24, standard error, SE = 0.03; beta(girls) = .17, SE = 0.03), above and beyond its association with the externalizing (beta(boys) = 0.21, SE = 0.04; beta(girls) = 0.17, SE = 0.05) and general factors (beta(boys) = 0.45, SE = 0.03; beta(girls) = 0.34, SE = 0.04). These associations were differentially influenced by genetic and environmental factors.

    CONCLUSIONS: It is important to monitor boys and girls with conduct problems not only for future externalizing problems, but also for future internalizing problems. Prevention of specific outcomes, however, might require interventions at different levels.

  • 26.
    Lichtenstein, Paul
    et al.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Tideman, Magnus
    School of Health and Social Science, Halmstad University, Halmstad, Sweden.
    Sullivan, Patrick F.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; UNC Center for Psychiatric Genomics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
    Serlachius, Eva
    Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet and Stockholm Health Care Service, Region Stockholm, Stockholm, Sweden.
    Larsson, Henrik
    Örebro University, School of Medical Sciences. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Kuja-Halkola, Ralf
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Butwicka, Agnieszka
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Health Child and Adolescent Psychiatry Stockholm, Stockholm Health Care Services, Region Stockholm, Stockholm, Sweden; Department of Child Psychiatry, Medical University of Warsaw, Warsaw, Poland; Department of Biostatistics and Translational Medicine, Medical University of Lodz, Lodz, Poland.
    Familial risk and heritability of intellectual disability: a population-based cohort study in Sweden2022In: Journal of Child Psychology and Psychiatry, ISSN 0021-9630, E-ISSN 1469-7610, Vol. 63, no 9, p. 1092-1102Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Intellectual disability (ID) aggregates in families, but factors affecting individual risk and heritability estimates remain unknown.

    METHODS: A population-based family cohort study of 4,165,785 individuals born 1973-2013 in Sweden, including 37,787 ID individuals and their relatives. The relative risks (RR) of ID with 95% confidence intervals (95% CI) were obtained from stratified Cox proportional-hazards models. Relatives of ID individuals were compared to relatives of unaffected individuals. Structural equation modeling was used to estimate heritability.

    RESULTS: Relatives of ID individuals were at increased risk of ID compared to individuals with unaffected relatives. The RR of ID among relatives increased proportionally to the degree of genetic relatedness with ID probands; 256.70(95% CI 161.30-408.53) for monozygotic twins, 16.47(13.32-20.38) for parents, 14.88(12.19-18.16) for children, 7.04(4.67-10.61) for dizygotic twins, 8.38(7.97-8.83) for full siblings, 4.56(4.02-5.16) for maternal, 2.90(2.49-3.37) for paternal half-siblings, 3.03(2.61-3.50) for nephews/nieces, 2.84(2.45-3.29) for uncles/aunts, and 2.04(1.91-2.20) for cousins. Lower RRs were observed for siblings of probands with chromosomal abnormalities (RR 5.53, 4.74-6.46) and more severe ID (mild RR 9.15, 8.55-9.78, moderate RR 8.13, 7.28-9.08, severe RR 6.80, 5.74-8.07, and profound RR 5.88, 4.52-7.65). Male sex of relative and maternal line of relationship with proband was related to higher risk (RR 1.33, 1.25-1.41 for brothers vs. sisters and RR 1.49, 1.34-1.68 for maternal vs. paternal half-siblings). ID was substantially heritable with 0.95(95% CI 0.93-0.98) of the variance in liability attributed to genetic influences.

    CONCLUSIONS: The risk estimates will benefit researchers, clinicians, families in understanding the risk of ID in the family and the whole population. The higher risk of ID related to male sex and maternal linage will be of value for planning and interpreting etiological studies in ID.

  • 27.
    Lundström, Sebastian
    et al.
    Gillberg Neuropsychiatry Centre, Institute of Neuroscience and Physiology, University of Gothenburg, Gothenburg, Sweden; Center for Ethics, Law and Mental health (CELAM), Institute of Neuroscience and Physiology, University of Gothenburg, Gothenburg, Sweden.
    Taylor, Mark
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Larsson, Henrik
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Lichtenstein, Paul
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Kuja-Halkola, Ralf
    Gillberg, Christopher
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Perceived child impairment and the 'autism epidemic'2022In: Journal of Child Psychology and Psychiatry, ISSN 0021-9630, E-ISSN 1469-7610, Vol. 63, no 5, p. 591-598Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The prevalence of diagnosed Autism Spectrum Disorder (ASD) has increased substantially across the world. Much - or even most - prevalence increase seems to reflect changes in diagnostic practice and ascertainment. A key part of ASD assessment is to document that the relevant symptoms are associated with clinical impairment. The aim of the present study is to capitalize on a nationwide longitudinal study spanning 15 consecutive birth year cohorts in order to investigate whether there has been a secular change in how parents perceive the impairment and suffering conferred by autism symptomatology in their children.

    METHODS: Data came from the Child and Adolescent Twin Study in Sweden (27,240 individuals), where parents had reported on their child's ASD symptoms and impairment. Impairment due to ASD symptoms was regressed on an ASD symptom score across time. This was done for five 3-year birth cohorts (1995-1997, 1998-2000, 2001-2003, 2004-2006, and 2007-2009).

    RESULTS: Reported impairment increased with consecutively later birth cohorts. This was evident across all levels of autism symptomatology. At clinically relevant levels of symptomatology, parents of those born 2007-2009 reported a 23% higher degree of impairment as compared with parents of those born in 1995-1997. The relative difference, however, was even greater at levels that previously would have been considered below the diagnostic threshold.

    DISCUSSION: The results presented here contribute to the notion of a growing diffuseness in the conceptualization of the ASD diagnosis by adding the element of secular changes in the parental perception of the consequences of ASD symptom expression.

  • 28.
    Martin, Joanna
    et al.
    Department of Medical Epidemiology & Biostatistics, Karolinska Institutet, Stockholm, Sweden; MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, UK.
    Taylor, Mark J.
    Department of Medical Epidemiology & Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Rydell, Mina
    Department of Medical Epidemiology & Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Riglin, Lucy
    MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, UK.
    Eyre, Olga
    MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, UK.
    Lu, Yi
    Department of Medical Epidemiology & Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Lundström, Sebastian
    Institute of Neuroscience and Physiology, Gillberg Neuropsychiatry Centre, Centre for Ethics Law and Mental Health, University of Gothenburg, Gothenburg, Sweden.
    Larsson, Henrik
    Örebro University, School of Medical Sciences. Department of Medical Epidemiology & Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Thapar, Anita
    MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, UK.
    Lichtenstein, Paul
    Department of Medical Epidemiology & Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Sex-specific manifestation of genetic risk for attention deficit hyperactivity disorder in the general population2018In: Journal of Child Psychology and Psychiatry, ISSN 0021-9630, E-ISSN 1469-7610, Vol. 59, no 8, p. 908-916Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Attention deficit hyperactivity disorder (ADHD) is more commonly diagnosed in males than in females. A growing body of research suggests that females with ADHD might be underdiagnosed or receive alternative diagnoses, such as anxiety or depression. Other lines of reasoning suggest that females might be protected from developing ADHD, requiring a higher burden of genetic risk to manifest the disorder.

    METHODS: We tested these two hypotheses, using common variant genetic data from two population-based cohorts. First, we tested whether females and males diagnosed with anxiety or depression differ in terms of their genetic risk for ADHD, assessed as polygenic risk scores (PRS). Second, we tested whether females and males with ADHD differed in ADHD genetic risk burden. We used three different diagnostic definitions: registry-based clinical diagnoses, screening-based research diagnoses and algorithm-based research diagnoses, to investigate possible referral biases.

    RESULTS: In individuals with a registry-based clinical diagnosis of anxiety or depression, females had higher ADHD PRS than males [OR(CI) = 1.39 (1.12-1.73)] but there was no sex difference for screening-based [OR(CI) = 1.15 (0.94-1.42)] or algorithm-based [OR(CI) = 1.04 (0.89-1.21)] diagnoses. There was also no sex difference in ADHD PRS in individuals with ADHD diagnoses that were registry-based [OR(CI) = 1.04 (0.84-1.30)], screening-based [OR(CI) = 0.96 (0.85-1.08)] or algorithm-based [OR(CI) = 1.15 (0.78-1.68)].

    CONCLUSIONS: This study provides genetic evidence that ADHD risk may be more likely to manifest or be diagnosed as anxiety or depression in females than in males. Contrary to some earlier studies, the results do not support increased ADHD genetic risk in females with ADHD as compared to affected males.

  • 29.
    Martini, Miriam I.
    et al.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Butwicka, Agnieszka
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Division of Mental Health Services, R&D Department, Akershus University Hospital, Lørenskog, Norway; Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway; Department of Biostatistics and Translational Medicine, Medical University of Lodz, Lodz, Poland.
    Du Rietz, Ebba
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Kanina, Aleksandra
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Rosenqvist, Mina A.
    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.
    Lichtenstein, Paul
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Taylor, Mark J.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Age effects on autism heritability and etiological stability of autistic traits2024In: Journal of Child Psychology and Psychiatry, ISSN 0021-9630, E-ISSN 1469-7610Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Autism and autistic traits onset in childhood but persist into adulthood. Little is known about how genetic and environmental factors influence autism and autistic traits into adulthood. We aimed to determine age effects on the heritability of clinically diagnosed autism and the etiological stability of autistic traits from childhood to adulthood using twin methods.

    METHODS: From 23,849 twin pairs in the Swedish Twin Register born between 1959 and 2010, we identified 485 individuals (1.01%, 31.5% female) with a clinical autism diagnosis. We estimated and compared the relative contribution of genetic, shared, and nonshared environmental influences to autism in childhood and adulthood. We further used multivariate twin analysis with four measurement points among 1,348 twin pairs in the longitudinal Twin Study of Child and Adolescent Development to assess the phenotypic and etiological stability of autistic traits - measured with three scales from the Child Behavior Checklist - from childhood to adulthood.

    RESULTS: Autism heritability was comparable from childhood, (96% [95% CI, 76-99%]) to adulthood (87% [67-96%]). Autistic traits were moderately stable (phenotypic correlation = 0.35-0.61) from childhood to adulthood, and their heritability varied between 52 and 71%. We observed stable as well as newly emerging genetic influences on autistic traits from ages 8-9 to 19-20, and unique nonshared environmental influences at each age.

    CONCLUSIONS: Genetic factors are important for autism and autistic traits in adulthood and separate genetic studies in adults are warranted.

  • 30.
    Munoz, Luna C.
    et al.
    Örebro University, Department of Behavioural, Social and Legal Sciences.
    Frick, Paul J.
    Kimonis, Eva R.
    Aucoin, Katherine J.
    Verbal ability and delinquency: testing the moderating role of psychopathic traits2008In: Journal of Child Psychology and Psychiatry, ISSN 0021-9630, E-ISSN 1469-7610, Vol. 49, no 4, p. 414-421Article in journal (Refereed)
    Abstract [en]

    Background Impaired verbal abilities are one of the most consistent risk factors for serious antisocial and delinquent behavior. However, individuals with psychopathic traits often show serious antisocial behavior, despite showing no impairment in their verbal abilities. Thus, the aim of the current study was to examine whether psychopathy moderates the relationship between verbal abilities and delinquent behavior in a sample of detained youth. Methods The sample included 100 detained adolescent boys who were assessed on self-reported delinquent acts and psychopathic traits, as well as their age at first offense based on official records. Participants also completed a competitive computer task involving two levels of provocation, during which skin conductance was measured. A standard measure of receptive vocabulary was individually administered. Results As predicted, there was a significant interaction between callous-unemotional (CU) traits (a critical dimension of psychopathy) and verbal ability when predicting violent delinquency. Individuals who were high on CU traits with higher scores on the measure of verbal abilities reported the greatest violent delinquency. These individuals also showed the lowest level of skin conductance reactivity during the provocation task. Conclusions The results suggest CU traits are an important moderator of the relation between verbal abilities and violent delinquency.

  • 31.
    O'Reilly, Lauren M.
    et al.
    Department of Psychological and Brain Sciences, Indiana University, Bloomington, IN, USA.
    Pettersson, Erik
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Donahue, Kelly
    Indiana University School of Medicine, Indianapolis, IN, USA.
    Quinn, Patrick D.
    Department of Applied Health Science, School of Public Health, Indiana University, Bloomington, IN, USA.
    Klonsky, E. David
    Department of Psychology, University of British Columbia, Vancouver, BC, Canada.
    Lundström, Sebastian
    Department of Psychiatry and Neurochemistry, University of Gothenburg, Gothenburg, Sweden.
    Larsson, Henrik
    Örebro University, School of Medical Sciences. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Lichtenstein, Paul
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Swede.
    D'Onofrio, Brian M
    Department of Psychological and Brain Sciences, Indiana University, Bloomington, IN, USA; Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Swede.
    Sexual orientation and adolescent suicide attempt and self-harm: a co-twin control study2021In: Journal of Child Psychology and Psychiatry, ISSN 0021-9630, E-ISSN 1469-7610, Vol. 62, no 7, p. 834-841Article, review/survey (Refereed)
    Abstract [en]

    BACKGROUND: Research has demonstrated that individuals who identify as a sexual minority (e.g., gay/lesbian, bisexual) are at increased risk for suicidality-related outcomes. However, previous research is primarily limited by the lack of adjustment for unmeasured (i.e., genetic and environmental) confounding factors and previous psychopathology.

    METHODS: Using the Child and Adolescent Twin Study in Sweden, we employed a co-twin control design to examine the extent to which the association between sexual orientation and adolescent suicide attempt and self-harm (SA/SH) was independent of genetic and environmental factors shared by twins, as well as measured symptoms of childhood psychopathology.

    RESULTS: Adolescents who identified as a sexual minority (i.e., gay/lesbian, bisexual, or other sexual orientation) were at two-fold increased odds for SA/SH (OR, 2.01 [95% confidence interval, 1.63-2.49) compared to heterosexual adolescents. When adjusting for all genetic and shared environmental factors that make twins similar and for measured childhood psychopathology, the association remained positive but attenuated to OR, 1.55 (1.11-2.16).

    CONCLUSIONS: Identifying as a sexual minority was associated with approximately 50% increased odds of SA/SH in adolescence after adjusting for unmeasured genetic and environmental factors shared by twins and for childhood psychopathology. The results support that environmental factors specifically associated with identifying as a sexual minority likely increase risk for SA/SH. Our findings highlight the need to monitor suicidality risk among this group.

  • 32.
    Pagani, Linda
    et al.
    University of Montreal.
    Tremblay, Richard E.
    University of Montreal.
    Vitaro, Frank
    University of Montreal.
    Kerr, Margaret
    University of Montreal.
    McDuff, Pierre
    University of Montreal.
    The impact of family transition on the development of delinquency in adolescent boys: a 9-year longitudinal study1998In: Journal of Child Psychology and Psychiatry, ISSN 0021-9630, E-ISSN 1469-7610, Vol. 39, no 4, p. 489-499Article in journal (Refereed)
    Abstract [en]

    Examined prospectively the impact of family transition on deviant development in a sample of 427 French-Canadian boys participating in a longitudinal study from kindergarten onwards. During the course of the study some boys experienced family transition. The boys were grouped by developmental period and number of marital transitions they experienced: divorced between ages 6-11; divorced between ages 12-15; remarried between ages 6-11; and remarried between ages 12-15. From ages 11-15 the author's assessed boys' delinquency and their family processes (parental supervision, punishment, and communication) annually. The results suggest that boys who experienced remarriage between ages 12-15 are at greater risk for delinquency. In particular, they showed evidence of comparatively more theft and fighting at earlier ages than their peers from families that had remained intact. At similar points in development, they perceived less expressive parent-child relationships. Finally, these boys also perceived less monitoring by their parents, both overall and at different points in adolescence.

  • 33.
    Pettersson, Erik
    et al.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Sjölander, Arvid
    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.
    Anckarsäter, Henrik
    Institute of Neuroscience and Physiology, University of Gothenburg, Gothenburg, Sweden.
    D'Onofrio, Brian M.
    Department of Psychological and Brain Sciences, Indiana University, Bloomington, USA.
    Lichtenstein, Paul
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Larsson, Henrik
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Birth weight as an independent predictor of ADHD symptoms: a within-twin pair analysis2015In: Journal of Child Psychology and Psychiatry, ISSN 0021-9630, E-ISSN 1469-7610, Vol. 56, no 4, p. 453-459Article in journal (Refereed)
    Abstract [en]

    Background Studies have found an association between low birth weight and ADHD, but the nature of this relation is unclear. First, it is uncertain whether birth weight is associated with both of the ADHD dimensions, inattentiveness and hyperactivity-impulsivity. Second, it remains uncertain whether the association between birth weight and ADHD symptom severity is confounded by familial factors.

    Method: Parents of all Swedish 9- and 12-year-old twins born between 1992 and 2000 were interviewed for DSM-IV inattentive and hyperactive-impulsive ADHD symptoms by the Autism - Tics, AD/HD and other Comorbidities (A-TAC) inventory (N = 21,775 twins). Birth weight was collected prospectively through the Medical Birth Registry. We used a within-twin pair design to control for genetic and shared environmental factors.

    Results: Reduced birth weight was significantly associated with a mean increase in total ADHD (β = -.42; 95% CI: -.53, -.30), inattentive (β = -.26; 95% CI: -.33, -.19), and hyperactive-impulsive (β = -.16; 95% CI: -.22, -.10) symptom severity. These results imply that a change of one kilogram of birth weight corresponded to parents rating their child nearly one unit higher (going from "no" to "yes, to some extent" on a given symptom) on the total ADHD scale. These associations remained within pairs of MZ and DZ twins, and were also present when restricting the analyses to full term births.

    Conclusions: There is an independent association between low birth weight and all forms of ADHD symptoms, even after controlling for all environmental and genetic confounds shared within twin pairs. These results indicate that fetal growth restriction (as reflected in birth weight differences within twin pairs) and/or the environmental factors which influence it is in the casual pathway leading to ADHD.

  • 34.
    Rosenqvist, Mina A.
    et al.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Sjölander, Arvid
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Ystrom, Eivind
    Department of Mental Disorders, Norwegian Institute of Public Health, Oslo, Norway; Department of Psychology, University of Oslo, Oslo, Norway; School of Pharmacy, University of Oslo, Oslo, Norway.
    Larsson, Henrik
    Örebro University, School of Medical Sciences. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Reichborn-Kjennerud, Ted
    Department of Mental Disorders, Norwegian Institute of Public Health, Oslo, Norway; Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
    Adverse family life events during pregnancy and ADHD symptoms in five-year-old offspring2019In: Journal of Child Psychology and Psychiatry, ISSN 0021-9630, E-ISSN 1469-7610, Vol. 60, no 6, p. 665-675Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Prenatal exposure to maternal adverse life events has been associated with offspring ADHD, but the role of familial confounding is unclear. We aimed to clarify if adverse life events during pregnancy are related to ADHD symptoms in offspring, taking shared familial factors into account.

    METHOD: Data were collected on 34,751 children (including 6,427 siblings) participating in the population-based Norwegian Mother and Child Cohort Study. During pregnancy, mothers reported whether they had experienced specific life events. We assessed ADHD symptoms in five-year-old children with the Conners' Parent Rating Scale-Revised: short form. We modeled the associations between life events and mean ADHD scores with ordinary linear regression in the full cohort, and with fixed-effect linear regression in sibling comparisons to adjust for familial confounding.

    RESULTS: Children exposed to adverse life events had higher ADHD scores at age 5, with the strongest effect observed for financial problems (mean differences 0.10 [95% CI: 0.09, 0.11] in adjusted model), and the weakest for having lost someone close (0.02 [95% CI 0.01, 0.04] in adjusted model). Comparing exposure-discordant siblings resulted in attenuated estimates that were no longer statistically significant (e.g. mean difference for financial problems -0.03 [95% CI -0.07, 0.02]). ADHD scores increased if the mother had experienced the event as painful or difficult, and with the number of events, whereas sibling-comparison analyses resulted in estimates attenuated toward the null.

    CONCLUSIONS: These results suggest that the association between adverse life events during pregnancy and offspring ADHD symptoms is largely explained by familial factors.

  • 35.
    Rydell, Mina
    et al.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Lundström, Sebastian
    Gillberg Neuropsychiatry Centre, University of Gothenburg, Gothenburg, Sweden; Centre for Ethics, Law and Mental Health (CELAM), University of Gothenburg, Gothenburg, Sweden.
    Gillberg, Christopher
    Gillberg Neuropsychiatry Centre, University of Gothenburg, Gothenburg, Sweden.
    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.
    Has the attention deficit hyperactivity disorder phenotype become more common in children between 2004 and 2014?: Trends over 10 years from a Swedish general population sample2018In: Journal of Child Psychology and Psychiatry, ISSN 0021-9630, E-ISSN 1469-7610, Vol. 59, no 8, p. 863-871Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Studies have reported increases in clinically diagnosed and treated attention deficit hyperactivity disorder (ADHD) during the last decade, but it is unclear if this reflects an increase in the underlying ADHD phenotype. We aimed to clarify if there has been an increase in the prevalence of ADHD-like traits in the general population from 2004 to 2014.

    METHOD: Data were collected from 9-year-old twins (19,271), participating in the population-based Child and Adolescent Twin Study in Sweden between 2004 and 2014. We assessed lifetime ADHD symptoms using the Autism-Tics, ADHD and other Comorbidities inventory. Research proxies for diagnostic-level ADHD and subthreshold ADHD were derived from this scale. We modeled the lifetime prevalence of diagnostic-level and subthreshold ADHD with logistic regression, and assessed mean ADHD scores each year with linear regression. Lifetime prevalence of clinically diagnosed ADHD was retrieved from the National Patient Register and modeled with logistic regression.

    RESULTS: The prevalence of diagnostic-level ADHD based on parent ratings did not differ significantly over time from 2004 to 2014 (OR 1.37; 95% CI: 0.77-2.45; p-value .233). Both subthreshold ADHD and mean ADHD scores increased significantly over time (both p-values <.001). Clinically diagnosed ADHD increased more than fivefold from 2004 to 2014 (OR 5.27, 95% CI: 1.85-14.96).

    CONCLUSIONS: We found no evidence of an increase in ADHD-like traits at the extreme end of the distribution from 2004 to 2014, but small increases in normal and subthreshold variations of ADHD-like traits were observed. This suggests that the increased rates of clinically diagnosed ADHD might reflect changes in diagnostic and treatment practices of ADHD, administrative changes in reporting diagnoses, greater awareness of ADHD, better access to healthcare, or current overdiagnosis, rather than an increase in the ADHD phenotype.

  • 36.
    Skoglund, Charlotte
    et al.
    Department of Clinical Neuroscience, Karolinska Institute, Stockholm, Sweden.
    Chen, Qi
    Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden.
    D'Onofrio, Brian M
    Department of Psychological and Brain Sciences, Indiana University, Bloomington IN, United States.
    Lichtenstein, Paul
    Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden.
    Larsson, Henrik
    Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden.
    Familial confounding of the association between maternal smoking during pregnancy and ADHD in offspring2014In: Journal of Child Psychology and Psychiatry, ISSN 0021-9630, E-ISSN 1469-7610, Vol. 55, no 1, p. 61-8Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Maternal Smoking During Pregnancy (SDP) has consistently been associated with increased risk of attention-deficit/hyperactivity disorder (ADHD) in offspring, but recent studies indicate that this association might be due to unmeasured familial confounding.

    METHODS: A total of 813,030 individuals born in Sweden between 1992 and 2000 were included in this nationwide population-based cohort study. Data on maternal SDP and ADHD diagnosis were obtained from national registers and patients were followed up from the age of 3 to the end of 2009. Hazard Ratios (HRs) were estimated using stratified Cox regression models. Cousin and sibling data were used to control for unmeasured familial confounding.

    RESULTS: At the population level maternal SDP predicted ADHD in offspring (HR(ModerateSDP) = 1.89; HR(HighSDP)= 2.50). This estimate gradually attenuated toward the null when adjusting for measured confounders (HR(ModerateSDP)= 1.62; HR(HighSDP)= 2.04), unmeasured confounders shared within the extended family (i.e., cousin comparison) (HR(ModerateSDP)= 1.45; HR(HighSDP)= 1.69), and unmeasured confounders within the nuclear family (i.e., sibling comparison) (HR(ModerateSDP)= 0.88; HR(HighSDP)= 0.84).

    CONCLUSIONS: Our results suggest that the association between maternal SDP and offspring ADHD are due to unmeasured familial confounding.

  • 37.
    Taylor, Mark J.
    et al.
    Department of Medical Epidemiology & Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Larsson, Henrik
    Örebro University, School of Medical Sciences. Department of Medical Epidemiology & Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Gillberg, Christopher
    Gillberg Neuropsychiatry Centre, University of Gothenburg, Gothenburg, Sweden.
    Lichtenstein, Paul
    Department of Medical Epidemiology & Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Lundström, Sebastian
    Gillberg Neuropsychiatry Centre, University of Gothenburg, Gothenburg, Sweden; Sweden Centre for Ethics, Law and Mental Health, University of Gothenburg, Gothenburg, Sweden.
    Investigating the childhood symptom profile of community-based individuals diagnosed with attention-deficit/hyperactivity disorder as adults2019In: Journal of Child Psychology and Psychiatry, ISSN 0021-9630, E-ISSN 1469-7610, Vol. 60, no 3, p. 259-266Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) is currently defined as a disorder with onset during childhood. Although ADHD occurs in adults as well as children, recent debate has focused on whether adult ADHD represents a continuation of a child-onset disorder or if ADHD may, in at least some cases, have an adult onset. We therefore aimed to test the hypothesis of adult-onset ADHD using a sample born relatively recently (1992-1999) in order to minimize confounding by secular changes in diagnostic practices.

    METHODS: We identified 74 individuals with a community diagnosis of ADHD first assigned during adulthood. We also identified individuals with childhood (N = 194) and adolescent (N = 394) community diagnoses of ADHD. These groups were compared with a comparison group (N = 14,474) on their childhood ADHD and neuropsychiatric symptoms, and rate of other psychiatric diagnoses during childhood.

    RESULTS: Having an adulthood community diagnosis of ADHD was associated with a mean increase in childhood ADHD symptoms of approximately three times that of the comparison group. Individuals with an adult community diagnosis of ADHD also displayed more autistic traits, motor problems, learning difficulties, tics, and oppositional behavior. Forty two percent of these individuals, compared with 1% of comparison cases, had a psychiatric diagnosis other than ADHD as children. In post-hoc analyses of 21 ADHD cases showing few or no ADHD symptoms in childhood, we were unable to detect any other childhood symptomatology in only nine cases, of whom six were female.

    CONCLUSIONS: Our results indicate that alternative explanations for data that appear to show adult onset ADHD, such as sex biases in diagnostic practices, need rigorous testing before adult onset ADHD can be accepted as a valid clinical construct.

  • 38.
    Taylor, Mark J.
    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.
    Lundström, Sebastian
    Gillberg Neuropsychiatry Centre, University of Gothenburg, Gothenburg, Sweden; Sweden Centre for Ethics, Law and Mental Health, University of Gothenburg, Gothenburg, Sweden.
    Lichtenstein, Paul
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Butwicka, Agnieszka
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Department ofChild Psychiatry, Medical University of Warsaw, Warsaw, Poland; Child and Adolescent Psychiatry, Stockholm Health Care Services, Stockholm County Council, Stockholm, Sweden.
    Etiological links between autism and difficulties in initiating and maintaining sleep: a familial co-aggregation and twin study2022In: Journal of Child Psychology and Psychiatry, ISSN 0021-9630, E-ISSN 1469-7610, Vol. 63, no 3, p. 315-323Article in journal (Refereed)
    Abstract [en]

    Background: Difficulties initiating and maintaining sleep (DIMS) are frequent features of autism, yet little is known about why these conditions co-occur. One possibility is that they share etiological factors, yet this hypothesis remains to be tested using quantitative genetic designs. We thus investigated etiological links between autism and DIMS using familial co-aggregation and twin methods.

    Methods: Twins, siblings, half-siblings, and cousins of 50,097 individuals with autism were identified from Swedish population registries. Their risk of DIMS, defined through diagnoses of insomnia and/or melatonin prescriptions, was then estimated. Twin analyses conducted on 15,279 child and adolescent twin pairs investigated etiological links between DIMS and ASD.

    Results: 22.8% of autistic individuals had DIMS. Monozygotic co-twins of individuals with autism were most at risk of DIMS compared to the reference group (OR = 6.6 [2.5-17.4]), followed by dizygotic co-twins (OR = 2.6 [1.5-4.5]) and full siblings (OR = 2.5 [2.4-2.6]). Half-siblings and cousins of individuals with autism were least likely to have DIMS relative to the reference group (OR range = 1.3-1.5). Twin analyses estimated a correlation of 0.57 (0.53-0.61) between autism and DIMS, with a genetic correlation of 0.62 (0.60-0.68). These overlapping genetic factors explained 94% of the covariance between these conditions. Autistic traits also showed genetic overlap with DIMS.

    Conclusions: Our results suggest that shared genetic mechanisms underlie autism and DIMS, which may lead them to co-occur. Untangling the etiological overlap between these conditions has potential to assist in understanding the etiology of each condition, as well as their associated outcomes.

  • 39.
    Taylor, Mark J.
    et al.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Martin, Joanna
    MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, UK.
    Butwicka, Agnieszka
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Department of Child Psychiatry, Medical University of Warsaw, Warsaw, Poland; Child and Adolescent Psychiatry, Stockholm Health Care Service, Region Stockholm, Sweden.
    Lichtenstein, Paul
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    D'Onofrio, Brian
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Department of Psychological and Brain Science, Indiana University, Bloomington, IN, USA.
    Lundström, Sebastian
    Gillberg Neuropsychiatry Centre, Centre for Ethics, Law and Mental Health, University of Gothenburg, Gothenburg, Sweden.
    Larsson, Henrik
    Örebro University, School of Medical Sciences. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Rosenqvist, Mina A.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    A twin study of genetic and environmental contributions to attention-deficit/hyperactivity disorder over time2023In: Journal of Child Psychology and Psychiatry, ISSN 0021-9630, E-ISSN 1469-7610, Vol. 64, no 11, p. 1608-1616Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) is an increasingly commonly diagnosed neurodevelopmental condition. One possibility is that this reflects a genuine increase in the prevalence of ADHD due to secular environmental changes, yet this hypothesis remains untested. We therefore investigated whether the genetic and environmental variance underlying ADHD, and traits of ADHD, has changed over time.

    METHODS: We identified twins born from 1982 to 2008 from the Swedish Twin Registry (STR). We linked the STR with the Swedish National Patient Register and Prescribed Drug Register to identify diagnoses of ADHD and prescriptions of ADHD medication for these twins. We also utilized data collected from participants in the Child and Adolescent Twin Study in Sweden (CATSS), born from 1992 to 2008. Their parents completed a structured ADHD screening tool, which was used to measure traits of ADHD and assign broad screening diagnoses of ADHD. We used the classical twin design to test whether the degree to which variation in these measures was influenced by genetic and environmental variation changed over time.

    RESULTS: We included 22,678 twin pairs from the STR and 15,036 pairs from CATSS. The heritability of ADHD in the STR ranged from 66% to 86% over time, although these fluctuations were not statistically significant. We observed a modest increase in variance in ADHD traits, from 0.98 to 1.09. This was driven by small increases in the underlying genetic and environmental variance, with heritability estimated as 64%-65%. No statistically significant changes in variance in screening diagnoses were observed.

    CONCLUSIONS: The relative contribution of genetic and environmental factors to ADHD has remained stable over time, despite its increasing prevalence. Thus, changes in the underlying etiology of ADHD over time are unlikely to explain the increase in ADHD diagnoses.

  • 40.
    Tuvblad, Catherine
    et al.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Sweden.
    Grann, Martin
    The Centre for Violence Prevention, Karolinska Institutet, Sweden.
    Paul, Lichtenstein
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Sweden.
    Heritability for adolescent antisocial behavior differs with socioeconomic status: gene–environment interaction2006In: Journal of Child Psychology and Psychiatry, ISSN 0021-9630, E-ISSN 1469-7610, Vol. 47, no 7, p. 734-743Article in journal (Refereed)
    Abstract [en]

    Background: Socioeconomic status is often assumed to be of importance for the development of antisocial behavior, yet it explains only a fraction of the variance. One explanation for this paradox could be that socioeconomic status moderates the influence of genetic and environmental effects on antisocial behavior.

    Method: TCHAD is a Swedis h longitudinal population-based twin study that contains 1,480 twin pairs born 1985-1986. The present study included 1,133 twin pairs, aged 16-17 years. Antisocial behavior was measured through self-report. Family socioeconomic status was assessed by parentalreported education and occupational status. Neighborhood socioeconomic conditions were assessed using five aggregated level variables: ethnic diversity, basic educational level, unemployment level, buying power, and crime-rate. We used structural equation modeling to test whether socioeconomic status interacted with latent genetic and environmental effects for antisocial behavior.

    Results: Gen etic influences on antisocial behavior were more important in adolescents in socioeconomically more advantaged environments, whereas the shared environment was higher in adolescents in socioeconomically less advantaged environments. Heritability for antisocial behavior was higher in girls than in boys, irrespective of socioeconomic background.

    Conclusions: Our results suggest that differe nt intervention policies should be considered in different socioeconomic areas. In socioeconomically advantaged areas, it might be more fruitful to focus on individually based preventions and treatments. In socioeconomically disadvantaged areas, intervention and prevention policies might be more effective on a community level, to account for shared environmental risk factors.

  • 41.
    Zhang-James, Yanli
    et al.
    Department of Psychiatry and Behavioral Sciences, SUNY Upstate Medical University, Syracuse NY, USA.
    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.
    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.
    Faraone, Stephen V.
    Department of Psychiatry and Behavioral Sciences, SUNY Upstate Medical University, Syracuse NY, USA; Department of Neuroscience and Physiology, SUNY Upstate Medical University, Syracuse NY, USA.
    Machine-Learning prediction of comorbid substance use disorders in ADHD youth using Swedish registry data2020In: Journal of Child Psychology and Psychiatry, ISSN 0021-9630, E-ISSN 1469-7610, Vol. 61, no 12, p. 1370-1379Article in journal (Refereed)
    Abstract [en]

    Background: Children with attention-deficit/hyperactivity disorder (ADHD) have a high risk for substance use disorders (SUDs). Early identification of at-risk youth would help allocate scarce resources for prevention programs.

    Methods: Psychiatric and somatic diagnoses, family history of these disorders, measures of socioeconomic distress, and information about birth complications were obtained from the national registers in Sweden for 19,787 children with ADHD born between 1989 and 1993. We trained (a) a cross-sectional random forest (RF) model using data available by age 17 to predict SUD diagnosis between ages 18 and 19; and (b) a longitudinal recurrent neural network (RNN) model with the Long Short-Term Memory (LSTM) architecture to predict new diagnoses at each age.

    Results: The area under the receiver operating characteristic curve (AUC) was 0.73(95%CI 0.70-0.76) for the random forest model (RF). Removing prior diagnosis from the predictors, the RF model was still able to achieve significant AUCs when predicting all SUD diagnoses (0.69, 95%CI 0.66-0.72) or new diagnoses (0.67, 95%CI: 0.64, 0.71) during age 18-19. For the model predicting new diagnoses, model calibration was good with a low Brier score of 0.086. Longitudinal LSTM model was able to predict later SUD risks at as early as 2 years age, 10 years before the earliest diagnosis. The average AUC from longitudinal models predicting new diagnoses 1, 2, 5 and 10 years in the future was 0.63.

    Conclusions: Population registry data can be used to predict at-risk comorbid SUDs in individuals with ADHD. Such predictions can be made many years prior to age of the onset, and their SUD risks can be monitored using longitudinal models over years during child development. Nevertheless, more work is needed to create prediction models based on electronic health records or linked population registers that are sufficiently accurate for use in the clinic.

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