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  • 1.
    Asherson, Philip
    et al.
    MRC SGDP Centre, Institute of Psychiatry Psychology and Neuroscience, King’s College London, London, United Kingdom.
    Larsson, Henrik
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Family, twin, and adoption studies of childhood onset psychiatric and neurodevelopmental disorders2016In: American Journal of Medical Genetics Part B: Neuropsychiatric Genetics, ISSN 1552-4841, E-ISSN 1552-485X, Vol. 171, no 7, p. 923-924Article in journal (Refereed)
  • 2.
    Baker, J. H.
    et al.
    Virginia Institute for Psychiatric and Behavioral Genetics, Department of Psychiatry, Medical College of Virginia of Virginia Commonwealth University, Richmond, USA; Department of Psychology, Virginia Commonwealth University, Richmond, USA.
    Maes, H. H.
    Virginia Institute for Psychiatric and Behavioral Genetics, Department of Psychiatry, Medical College of Virginia of Virginia Commonwealth University, Richmond, USA; Department of Human Genetics, Virginia Commonwealth University, Richmond, USA; Massey Cancer Center, Virginia Commonwealth University, Richmond, USA.
    Larsson, Henrik
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Lichtenstein, P.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Kendler, K. S.
    Virginia Institute for Psychiatric and Behavioral Genetics, Department of Psychiatry, Medical College of Virginia of Virginia Commonwealth University, Richmond, USA; Department of Human Genetics, Virginia Commonwealth University, Richmond, USA; Department of Psychiatry, Virginia Commonwealth University, Richmond, USA.
    Sex differences and developmental stability in genetic and environmental influences on psychoactive substance consumption from early adolescence to young adulthood2011In: Psychological Medicine, ISSN 0033-2917, E-ISSN 1469-8978, Vol. 41, no 9, p. 1907-1916Article in journal (Refereed)
    Abstract [en]

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

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

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

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

  • 3.
    Baker, Jessica H.
    et al.
    Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
    Brosof, Leigh C.
    Department of Psychological and Brain Sciences, University of Louisville, Louisville, Kentucky, USA.
    Munn-Chernoff, Melissa A.
    Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
    Lichtenstein, Paul
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Larsson, Henrik
    Örebro University, School of Medical Sciences. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Maes, Hermine H.
    Department of Genetics, Virginia Commonwealth University, Richmond, Virginia, USA.
    Kendler, Kenneth S.
    Department of Psychiatry, Virginia Commonwealth University, Richmond, Virginia, USA.
    Associations Between Alcohol Involvement and Drive for Thinness and Body Dissatisfaction in Adolescent Twins: A Bivariate Twin Study2018In: Alcoholism: Clinical and Experimental Research, ISSN 0145-6008, E-ISSN 1530-0277, Vol. 42, no 11, p. 2214-2223Article in journal (Refereed)
    Abstract [en]

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

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

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

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

  • 4.
    Baker, Jessica H.
    et al.
    Department of Psychiatry, University of North Carolina, Chapel Hill, United States.
    Munn-Chernoff, Melissa A.
    Department of Psychiatry, University of North Carolina, Chapel Hill, United States.
    Lichtenstein, Paul
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Larsson, Henrik
    Örebro University, School of Medical Sciences. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Maes, Hermine
    Department of Genetics, VA Commonwealth University, Richmond, United States.
    Kendler, Kenneth S.
    Department of Psychiatry, VA Commonwealth University, Richmond, United States.
    Shared Familial Risk Between Bulimic Symptoms and Alcohol Involvement During Adolescence2017In: Journal of Abnormal Psychology, ISSN 0021-843X, E-ISSN 1939-1846, Vol. 126, no 5, p. 506-518Article in journal (Refereed)
    Abstract [en]

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

  • 5.
    Beckman, K.
    et al.
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden; St Goran Hosp, Stockholm City Council, Stockholm, Sweden.
    Mittendorfer-Rutz, E.
    Department of Clinical Neuroscience, Insurance Medicine, Karolinska Institutet, Stockholm, Sweden.
    Lichtenstein, P.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Larsson, Henrik
    Örebro University, School of Medical Sciences. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Almqvist, C
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Astrid Lindgren Children’s Hospital, Karolinska University Hospital, Stockholm, Sweden.
    Runeson, B.
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden; St Goran Hosp, Stockholm City Council, Stockholm, Sweden.
    Dahlin, M.
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden; St Goran Hosp, Stockholm City Council, Stockholm, Sweden.
    Mental illness and suicide after self-harm among young adults: long-term follow-up of self-harm patients, admitted to hospital care, in a national cohort2016In: Psychological Medicine, ISSN 0033-2917, E-ISSN 1469-8978, Vol. 46, no 16, p. 3397-3405Article in journal (Refereed)
    Abstract [en]

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

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

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

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

  • 6.
    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 and Allied Disciplines, 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.

  • 7.
    Bergman, Olle
    et al.
    Department of Pharmacology, University of Gothenburg, Gothenburg, Sweden.
    Westberg, Lars
    Department of Pharmacology, University of Gothenburg, Gothenburg, Sweden.
    Lichtenstein, Paul
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Eriksson, Elias
    Department of Pharmacology, University of Gothenburg, Gothenburg, Sweden.
    Larsson, Henrik
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Center of Neurodevelopmental Disorders, Karolinska Institutet, Stockholm, Sweden.
    Study on the possible association of brain-derived neurotrophic factor polymorphism with the developmental course of symptoms of attention deficit and hyperactivity2011In: International Journal of Neuropsychopharmacology, ISSN 1461-1457, E-ISSN 1469-5111, Vol. 14, no 10, p. 1367-1376Article in journal (Refereed)
    Abstract [en]

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

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

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

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

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

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

  • 9.
    Borg, J.
    et al.
    Department of Clinical Neuroscience, Center for Psychiatry Research, Karolinska Institutet, Stockholm, Sweden; Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Cervenka, S.
    Department of Clinical Neuroscience, Center for Psychiatry Research, Karolinska Institutet, Stockholm, Sweden.
    Kuja-Halkola, R
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden .
    Matheson, G. J.
    Department of Clinical Neuroscience, Center for Psychiatry Research, Karolinska Institutet, Stockholm, Sweden.
    Jönsson, E. G.
    Department of Clinical Neuroscience, Center for Psychiatry Research, Karolinska Institutet, Stockholm, Sweden; NORMENT, KG Jebsen Centre for Psychosis Research, Institute of Clinical Medicine, Psychiatry Section, University of Oslo, Oslo, Norway.
    Lichtenstein, P.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Henningsson, S.
    Danish Research Centre for Magnetic Resonance, Copenhagen University Hospital, Hvidovre, Denmark.
    Ichimiya, T.
    Department of Clinical Neuroscience, Center for Psychiatry Research, Karolinska Institutet, Stockholm, Sweden; Department of Neuropsychiatry, Nippon Medical School, Tokyo, Japan.
    Larsson, Henrik
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Stenkrona, P.
    Department of Clinical Neuroscience, Center for Psychiatry Research, Karolinska Institutet, Stockholm, Sweden.
    Halldin, C.
    Department of Clinical Neuroscience, Center for Psychiatry Research, Karolinska Institutet, Stockholm, Sweden.
    Farde, L.
    Department of Clinical Neuroscience, Center for Psychiatry Research, Karolinska Institutet, Stockholm, Sweden; AstraZeneca Translational Science Center, Karolinska Institutet, Stockholm, Sweden.
    Contribution of non-genetic factors to dopamine and serotonin receptor availability in the adult human brain2016In: Molecular Psychiatry, ISSN 1359-4184, E-ISSN 1476-5578, Vol. 21, no 8, p. 1077-1084Article in journal (Refereed)
    Abstract [en]

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

  • 10.
    Bramson, L. M.
    et al.
    Indiana University, Bloomington, United States .
    Rickert, M. E.
    Indiana University, Bloomington, United States.
    Class, Q. A.
    University of Chicago, Chicago, United States .
    Sariaslan, A.
    University of Oxford, Oxford, United Kingdom .
    Almqvist, C.
    Karolinska Institutet, Stockholm, Sweden .
    Larsson, Henrik
    Karolinska Institutet, Stockholm, Sweden.
    Lichtenstein, P.
    Karolinska Institutet, Stockholm, Sweden .
    D'Onofrio, B. M.
    Indiana University, Bloomington, United States.
    The association between childhood relocations and subsequent risk of suicide attempt, psychiatric problems, and low academic achievement2016In: Psychological Medicine, ISSN 0033-2917, E-ISSN 1469-8978, Vol. 46, no 5, p. 969-979Article in journal (Refereed)
    Abstract [en]

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

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

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

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

  • 11.
    Brander, Gustaf
    et al.
    Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Pérez-Vigil, Ana
    Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Larsson, Henrik
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Mataix-Cols, David
    Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden; Stockholm Health Care Services, Stockholm County Council, Stockholm, Sweden.
    Systematic review of environmental risk factors for Obsessive-Compulsive Disorder: A proposed roadmap from association to causation2016In: Neuroscience and Biobehavioral Reviews, ISSN 0149-7634, E-ISSN 1873-7528, Vol. 65, p. 36-62Article, review/survey (Refereed)
    Abstract [en]

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

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

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

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

  • 12.
    Brander, Gustaf
    et al.
    Department of Clinical Neuroscience, Centre for Psychiatry Research, Karolinska Institutet, Stockholm, Sweden.
    Rydell, Mina
    Department of Clinical Neuroscience, Centre for Psychiatry Research, Karolinska Institutet, Stockholm, Sweden.
    Kuja-Halkola, Ralf
    Department of Clinical Neuroscience, Centre for Psychiatry Research, Karolinska Institutet, Stockholm, Sweden.
    Fernández de la Cruz, Lorena
    Department of Clinical Neuroscience, Centre for Psychiatry Research, Karolinska Institutet, Stockholm, Sweden.
    Lichtenstein, Paul S.
    Department of Clinical Neuroscience, Centre for Psychiatry Research, Karolinska Institutet, Stockholm, Sweden.
    Serlachius, Eva
    Department of Clinical Neuroscience, Centre for Psychiatry Research, Karolinska Institutet, Stockholm, Sweden.
    Rück, Christian
    Department of Clinical Neuroscience, Centre for Psychiatry Research, Karolinska Institutet, Stockholm, Sweden.
    Almqvist, Catarina
    Department of Clinical Neuroscience, Centre for Psychiatry Research, Karolinska Institutet, Stockholm, Sweden.
    D'Onofrio, Brian M.
    Department of Clinical Neuroscience, Centre for Psychiatry Research, Karolinska Institutet, Stockholm, Sweden.
    Larsson, Henrik
    Örebro University, School of Medical Sciences. Department of Clinical Neuroscience, Centre for Psychiatry Research, Karolinska Institutet, Stockholm, Sweden.
    Mataix-Cols, David
    Department of Clinical Neuroscience, Centre for Psychiatry Research, Karolinska Institutet, Stockholm, Sweden.
    Perinatal risk factors in Tourette's and chronic tic disorders: a total population sibling comparison study2018In: Molecular Psychiatry, ISSN 1359-4184, E-ISSN 1476-5578, Vol. 23, no 5, p. 1189-1197Article in journal (Refereed)
    Abstract [en]

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

  • 13.
    Brander, Gustaf
    et al.
    Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Rydell, Mina
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden .
    Kuja-Halkola, Ralf
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden .
    Fernández de la Cruz, Lorena
    Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Lichtenstein, Paul
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Serlachius, Eva
    Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden; Stockholm Health Care Services, Stockholm County Council, Stockholm, Sweden .
    Rück, Christian
    Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden; Stockholm Health Care Services, Stockholm County Council, Stockholm, Sweden.
    Almqvist, Catarina
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Astrid Lindgren Children’s Hospital, Karolinska University Hospital, Stockholm, Sweden .
    D'Onofrio, Brian M.
    Department of Psychological and Brain Sciences, Indiana University, Bloomington IN, USA.
    Larsson, Henrik
    Örebro University, School of Medical Sciences. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden .
    Mataix-Cols, David
    Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden; Stockholm Health Care Services, Stockholm County Council, Stockholm, Sweden.
    Association of Perinatal Risk Factors With Obsessive-Compulsive Disorder: A Population-Based Birth Cohort, Sibling Control Study2016In: JAMA psychiatry, ISSN 2168-6238, E-ISSN 2168-622X, Vol. 73, no 11, p. 1135-1144Article in journal (Refereed)
    Abstract [en]

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

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

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

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

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

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

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

  • 14.
    Brew, Bronwyn K.
    et al.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Gong, Tong
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Williams, Dylan M.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Larsson, Henrik
    Örebro University, School of Medical Sciences. Deptartment of Medicine, Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; School of Medical Sciences, Örebro University, Örebro, Sweden.
    Almqvist, Catarina
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Pediatric Allergy and Pulmonology Unit, Astrid Lindgren Children’s Hospital, Karolinska University Hospital, Stockholm, Sweden.
    Using fathers as a negative control exposure to test the Developmental Origins of Health and Disease Hypothesis: A case study on maternal distress and offspring asthma using Swedish register data2017In: Scandinavian Journal of Public Health, ISSN 1403-4948, E-ISSN 1651-1905, Vol. 45, no 17, p. 36-40Article in journal (Refereed)
    Abstract [en]

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

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

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

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

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

  • 15.
    Brew, Bronwyn K.
    et al.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Lundholm, Cecilia
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Gong, Tong
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Woolcock Institute of Medical Research, University of Sydney, Sydney, Australia.
    Larsson, Henrik
    Örebro University, School of Medical Sciences. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Almqvist, Catarina
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet; Sweden Pediatric Allergy and Pulmonology Unit,t Astrid Lindgren Children's Hospital, Karolinska University Hospital, Stockholm, Sweden.
    The familial aggregation of atopic diseases and depression or anxiety in children2018In: Clinical and Experimental Allergy, ISSN 0954-7894, E-ISSN 1365-2222, Vol. 48, no 6, p. 703-711Article in journal (Refereed)
    Abstract [en]

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

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

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

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

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

  • 16.
    Brew, Bronwyn K.
    et al.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Lundholm, Cecilia
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Viktorin, Alexander
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York NY, USA.
    Lichtenstein, Paul
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Larsson, Henrik
    Örebro University, School of Medical Sciences. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Almqvist, Catarina
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; School of Medical Sciences, Örebro University, Örebro, Sweden.
    Longitudinal depression or anxiety in mothers and offspring asthma: a Swedish population-based study2018In: International Journal of Epidemiology, ISSN 0300-5771, E-ISSN 1464-3685, Vol. 47, no 1, p. 166-174Article in journal (Refereed)
    Abstract [en]

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

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

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

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

  • 17.
    Brikell, I.
    et al.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Ghirardi, L.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Chang, Z.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    D'Onofrio, B. M.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Department of Psychological and Brain Sciences, Indiana University, Bloomington, USA.
    Kuja-Halkola, R.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Larsson, Henrik
    Örebro University, School of Medical Sciences. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    ADHD medications and the risk of epileptic seizures: a pharmacoepidemiological study using nationwide register data2017In: European Neuropsychopharmacology, ISSN 0924-977X, E-ISSN 1873-7862, Vol. 27, no Suppl. 4, p. S1113-S1114Article in journal (Other academic)
    Abstract [en]

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

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

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

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

    References

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

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

  • 18.
    Brikell, Isabell
    et al.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Ghirardi, Laura
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    D'Onofrio, Brian M.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Department of Psychological and Brain Sciences, Indiana University, Bloomington, United States.
    Dunn, David W.
    Department of Psychiatry, Riley Child and Adolescent Psychiatry Clinic, Indiana University School of Medicine, Indiana University Health Physicians, Indianapolis Indiana, United States.
    Almqvist, Catarina
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Astrid Lindgren Children's Hospital, Karolinska University Hospital, Stockholm, Sweden.
    Dalsgaard, Søren
    National Centre for Register-Based Research, Department of Economics, Aarhus University, Aarhus, Denmark; The Lundbeck Foundation Initiative for Integrative Psychiatric Research, Aarhus University, Aarhus, Denmark; Department for Child and Adolescent Psychiatry, Hospital of Telemark, Kragerø, Norway.
    Kuja-Halkola, Ralf
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Larsson, Henrik
    Örebro University, School of Medical Sciences. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Familial Liability to Epilepsy and Attention-Deficit/Hyperactivity Disorder: A Nationwide Cohort Study2018In: Biological Psychiatry, ISSN 0006-3223, E-ISSN 1873-2402, Vol. 83, no 2, p. 173-180Article in journal (Refereed)
    Abstract [en]

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

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

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

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

  • 19.
    Brikell, Isabell
    et al.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Kuja-Halkola, Ralf
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Larsson, Henrik
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Heritability of attention-deficit hyperactivity disorder in adults2015In: American Journal of Medical Genetics Part B: Neuropsychiatric Genetics, ISSN 1552-4841, E-ISSN 1552-485X, Vol. 168, no 6, p. 406-413Article, review/survey (Refereed)
    Abstract [en]

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

  • 20.
    Brikell, Isabell
    et al.
    Karolinska Institutet, Stockholm, Sweden.
    Kuja-Halkola, Ralf
    Karolinska Institutet, Stockholm, Sweden.
    Larsson, Jan-Olov
    Karolinska Institutet, Stockholm, Sweden.
    Lahey, Benjamin B.
    University of Chicago, Chicago, USA .
    Kuntsi, Jonna
    MRC Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, United Kingdom.
    Lichtenstein, Paul
    Karolinska Institutet, Stockholm, Sweden.
    Rydelius, Per-Anders
    Karolinska Institutet, Stockholm, Sweden; Center for Research on Child and Adolescent Mental Health, Karlstad University, Karlstad, Sweden.
    Larsson, Henrik
    Örebro University, School of Medical Sciences. Karolinska Institutet, Stockholm, Sweden.
    Relative Immaturity in Childhood and Attention-Deficit/Hyperactivity Disorder Symptoms From Childhood to Early Adulthood: Exploring Genetic and Environmental Overlap Across Development2016In: Journal of the American Academy of Child and Adolescent Psychiatry, ISSN 0890-8567, E-ISSN 1527-5418, Vol. 55, no 10, p. 886-895Article in journal (Refereed)
    Abstract [en]

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

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

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

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

  • 21.
    Brikell, Isabell
    et al.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Larsson, Henrik
    Örebro University, School of Medical Sciences. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Lu, Yi
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Statistical Genetics, Genetics and Computational Biology Department, QIMR Berghofer Medical Research Institute, Brisbane QLD, Australia.
    Pettersson, Erik
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Chen, Qi
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Kuja-Halkola, Ralf
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Karlsson, Robert
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Lahey, Benjamin B.
    Department of Public Health Sciences, University of Chicago, Chicago IL, USA.
    Lichtenstein, Paul
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Martin, Joanna
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, UK.
    The contribution of common genetic risk variants for ADHD to a general factor of childhood psychopathology2018In: Molecular Psychiatry, ISSN 1359-4184, E-ISSN 1476-5578Article in journal (Refereed)
    Abstract [en]

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

  • 22.
    Burt, S. Alexandra
    et al.
    Department of Psychology, Michigan State University, East Lansing, United States .
    Larsson, Henrik
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Lichtenstein, Paul
    Department of Medical Epidemiology, Karolinska Institutet, Stockholm, Sweden.
    Klump, Kelly L
    Department of Psychology, Michigan State University, East Lansing, United States.
    Additional evidence against shared environmental contributions to attention-deficit/hyperactivity problems2012In: Behavior Genetics, ISSN 0001-8244, E-ISSN 1573-3297, Vol. 42, no 5, p. 711-721Article in journal (Refereed)
    Abstract [en]

    A recent meta-analysis "Burt (Psychol Bull 135:608-637, 2009)" indicated that shared environmental influences (C) do not contribute to Attention-Deficit/Hyperactivity Disorder (ADHD). Unfortunately, the meta-analysis relied almost exclusively on classical twin studies. Although useful in many ways, some of the assumptions of the classical twin model (e.g., dominant genetic and shared environmental influences do not simultaneously influence the phenotype) can artifactually decrease estimates of C. There is thus a need to confirm that dominant genetic influences are not suppressing estimates of C on ADHD. The current study sought to do just this via the use of a nuclear twin family model, which allows researchers to simultaneously model and estimate dominant genetic and shared environmental influences. We examined two independent samples of child twins: 312 pairs from the Michigan State University Twin Registry and 854 pairs from the PrE School Twin Study in Sweden. Shared environmental influences were found to be statistically indistinguishable from zero and to account for less than 5 % of the variance. We conclude that the presence of dominant genetic influences does not account for the absence of C on ADHD.

  • 23.
    Butwicka, Agnieszka
    et al.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden;.
    Lichtenstein, Paul
    Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden .
    Frisén, Louise
    Child and Adolescent Psychiatry Research Center, Stockholm, Sweden; Department of Clinical Neuroscience, Karolinska Institute, Stockholm, Sweden.
    Almqvist, Catarina
    Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden; Child and Adolescent Psychiatry Research Center, Stockholm, Sweden.
    Larsson, Henrik
    Örebro University, School of Medical Sciences. Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden.
    Ludvigsson, Jonas F.
    Örebro University, School of Medical Sciences. Örebro University Hospital. Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden; Department of Pediatrics, Örebro University Hospital, Örebro, Sweden; Division of Epidemiology and Public Health, School of Medicine, University of Nottingham, Nottingham, United Kingdom; Department of Medicine, Columbia University College of Physicians and Surgeons, New York NY, United States.
    Celiac disease is associated with childhood psychiatric disorders: A Population-Based Study2017In: Journal of Pediatrics, ISSN 0022-3476, E-ISSN 1097-6833, Vol. 184, p. 87-93.e1, article id S0022-3476(17)30153-1Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES: To determine the risk of future childhood psychiatric disorders in celiac disease, assess the association between previous psychiatric disorders and celiac disease in children, and investigate the risk of childhood psychiatric disorders in siblings of celiac disease probands.

    STUDY DESIGN: This was a nationwide registry-based matched cohort study in Sweden with 10 903 children (aged <18 years) with celiac disease and 12 710 of their siblings. We assessed the risk of childhood psychiatric disorders (any psychiatric disorder, psychotic disorder, mood disorder, anxiety disorder, eating disorder, psychoactive substance misuse, behavioral disorder, attention-deficit hyperactivity disorder [ADHD], autism spectrum disorder [ASD], and intellectual disability). HRs of future psychiatric disorders in children with celiac disease and their siblings was estimated by Cox regression. The association between previous diagnosis of a psychiatric disorder and current celiac disease was assessed using logistic regression.

    RESULTS: Compared with the general population, children with celiac disease had a 1.4-fold greater risk of future psychiatric disorders. Childhood celiac disease was identified as a risk factor for mood disorders, anxiety disorders, eating disorders, behavioral disorders, ADHD, ASD, and intellectual disability. In addition, a previous diagnosis of a mood, eating, or behavioral disorder was more common before the diagnosis of celiac disease. In contrast, siblings of celiac disease probands were at no increased risk of any of the investigated psychiatric disorders.

    CONCLUSIONS: Children with celiac disease are at increased risk for most psychiatric disorders, apparently owing to the biological and/or psychological effects of celiac disease.

  • 24.
    Butwicka, Agnieszka
    et al.
    Department of Medical Epidemiology and Biostatistics, MEB, Karolinska Institutet, Stockholm, Sweden; Department of Child Psychiatry, Medical University of Warsaw, Warsaw, Poland.
    Långström, Niklas
    Department of Medical Epidemiology and Biostatistics, MEB, Karolinska Institutet, Stockholm, Sweden; Department of Neuroscience, Uppsala University, Uppsala, Sweden.
    Larsson, Henrik
    Örebro University, School of Medical Sciences. Department of Medical Epidemiology and Biostatistics, MEB, Karolinska Institutet, Stockholm, Sweden.
    Lundström, Sebastian
    Department of Neuroscience, Uppsala University, Uppsala, Sweden; Centre for Ethics, Law and Mental Health (CELAM), University of Gothenburg, Mölndal, Sweden; Gillberg Neuropsychiatry Centre, University of Gothenburg, Gothenburg, Sweden.
    Serlachius, Eva
    Department of Clinical Neuroscience, Centre for Psychiatric Research, Karolinska Institutet, Stockholm, Sweden; Child and Adolescent Psychiatry, Stockholm County Council, Stockholm, Sweden.
    Almqvist, Catarina
    Department of Medical Epidemiology and Biostatistics, MEB, Karolinska Institutet, Stockholm, Sweden; Lung and Allergy Unit, Astrid Lindgren Children’s Hospital, Stockholm, Sweden.
    Frisén, Louise
    Department of Clinical Neuroscience, Centre for Psychiatric Research, Karolinska Institutet, Stockholm, Sweden; Child and Adolescent Psychiatry, Stockholm County Council, Stockholm, Sweden.
    Lichtenstein, Paul
    Department of Medical Epidemiology and Biostatistics, MEB, Karolinska Institutet, Stockholm, Sweden.
    Increased Risk for Substance Use-Related Problems in Autism Spectrum Disorders: A Population-Based Cohort Study2017In: Journal of autism and developmental disorders, ISSN 0162-3257, E-ISSN 1573-3432, Vol. 47, no 1, p. 80-89Article in journal (Refereed)
    Abstract [en]

    Despite limited and ambiguous empirical data, substance use-related problems have been assumed to be rare among patients with autism spectrum disorders (ASD). Using Swedish population-based registers we identified 26,986 individuals diagnosed with ASD during 1973-2009, and their 96,557 non-ASD relatives. ASD, without diagnosed comorbidity of attention deficit hyperactivity disorder (ADHD) or intellectual disability, was related to a doubled risk of substance use-related problems. The risk of substance use-related problems was the highest among individuals with ASD and ADHD. Further, risks of substance use-related problems were increased among full siblings of ASD probands, half-siblings and parents. We conclude that ASD is a risk factor for substance use-related problems. The elevated risks among relatives of probands with ASD suggest shared familial (genetic and/or shared environmental) liability.

  • 25.
    Capusan, A. J.
    et al.
    Department of Psychiatry and Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
    Kuja-Halkola, R.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Bendtsen, P.
    Department of Medical specialist and Department of Medical and Health Sciences, Linköpings University, Motala, Sweden.
    Viding, E.
    Developmental Risk and Resilience Unit, University College London, London, UK.
    McCrory, E.
    Developmental Risk and Resilience Unit, University College London, London, UK.
    Marteinsdottir, I.
    Department of Clinical and Experimental Medicine, Center for Social and Affective Neuroscience (CSAN), Linköping University, Linköping, Sweden.
    Larsson, Henrik
    Örebro University, School of Medical Sciences. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Childhood maltreatment and attention deficit hyperactivity disorder symptoms in adults: a large twin study2016In: Psychological Medicine, ISSN 0033-2917, E-ISSN 1469-8978, Vol. 46, no 12, p. 2637-2646Article in journal (Refereed)
    Abstract [en]

    Background: Childhood maltreatment (CM) has been associated with increased risk of attention deficit hyperactivity disorder (ADHD) in children and adults. It is, however, unclear whether this association is causal or due to familial confounding.

    Method: Data from 18 168 adult twins, aged 20-46 years, were drawn from the population-based Swedish twin registry. Retrospective self-ratings of CM (emotional and physical neglect, physical and sexual abuse and witnessing family violence), and self-ratings for DSM-IV ADHD symptoms in adulthood were analysed. Possible familial confounding was investigated using a within twin-pair design based on monozygotic (MZ) and dizygotic (DZ) twins.

    Results: CM was significantly associated with increased levels of ADHD symptom scores in adults [regression coefficient: 0.40 standard deviations, 95% confidence interval (CI) 0.37-0.43]. Within twin-pair analyses showed attenuated but significant estimates within DZ (0.29, 95% CI 0.21-0.36) and MZ (0.18, 95% CI 0.10-0.25) twin pairs. Similar results emerged for hyperactive/impulsive and inattentive ADHD symptom scores separately in association with CM. We conducted sensitivity analyses for early maltreatment, before age 7, and for abuse and neglect separately, and found similarly reduced estimates in DZ and MZ pairs. Re-traumatization after age 7 did not significantly influence results.

    Conclusions: CM was significantly associated with increased ADHD symptoms in adults. Associations were partly due to familial confounding, but also consistent with a causal interpretation. Our findings support cognitive neuroscience studies investigating neural pathways through which exposure to CM may influence ADHD. Clinicians treating adults with ADHD should be aware of the association with maltreatment.

  • 26.
    Capusan, A. J.
    et al.
    Department of Psychiatry and Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden; Department of Clinical and Experimental Medicine, Center for Social and Affective Neuroscience (CSAN), Linköping University, Linköping, Sweden.
    Yao, S.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Kuja-Halkola, R.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Bulik, C. M.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, USA; Department of Nutrition, University of North Carolina at Chapel Hill, Chapel Hill, USA.
    Thornton, L. M.
    Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, USA.
    Bendtsen, P.
    Department of Medical Specialist and Department of Medical and Health Sciences, Linköping University, Motala, Sweden.
    Marteinsdottir, I.
    Department of Clinical and Experimental Medicine, Center for Social and Affective Neuroscience (CSAN), Linköping University, Linköping, Sweden.
    Thorsell, A.
    Department of Clinical and Experimental Medicine, Center for Social and Affective Neuroscience (CSAN), Linköping University, Linköping, Sweden.
    Larsson, Henrik
    Örebro University, School of Medical Sciences. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Genetic and environmental aspects in the association between attention-deficit hyperactivity disorder symptoms and binge-eating behavior in adults: a twin study2017In: Psychological Medicine, ISSN 0033-2917, E-ISSN 1469-8978, Vol. 47, no 16, p. 2866-2878Article in journal (Refereed)
    Abstract [en]

    Background: Prior research demonstrated that attention-deficit hyperactivity disorder (ADHD) is associated with binge-eating behavior, binge-eating disorder (BED), and bulimia nervosa (BN). The aim of this study was to investigate these associations in an adult twin population, and to determine the extent to which ADHD symptoms and binge-eating behavior share genetic and environmental factors.

    Methods: We used self-reports of current ADHD symptoms and lifetime binge-eating behavior and associated characteristics from a sample of over 18 000 adult twins aged 20-46 years, from the population-based Swedish Twin Registry. Mixed-effects logistic regression was used to examine the association between ADHD and lifetime binge-eating behavior, BED, and BN. Structural equation modeling was used in 13 773 female twins to determine the relative contribution of genetic and environmental factors to the association between ADHD symptoms and binge-eating behavior in female adult twins.

    Results: ADHD symptoms were significantly associated with lifetime binge-eating behavior, BED, and BN. The heritability estimate for current ADHD symptoms was 0.42 [95% confidence interval (CI) 0.41-0.44], and for lifetime binge-eating behavior 0.65 (95% CI 0.54-0.74). The genetic correlation was estimated as 0.35 (95% CI 0.25-0.46) and the covariance between ADHD and binge-eating behavior was primarily explained by genetic factors (91%). Non-shared environmental factors explained the remaining part of the covariance.

    Conclusions: The association between adult ADHD symptoms and binge-eating behavior in females is largely explained by shared genetic risk factors.

  • 27.
    Capusan, Andrea J.
    et al.
    Division of Psychiatry, Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
    Bendtsen, Preben
    Department of Specialist Medicine, Motala, Sweden; Department of Medical and Health Sciences, Division of Community Medicine Linköping University, Linköping, Sweden.
    Marteinsdottir, Ina
    Division of Psychiatry, Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
    Kuja-Halkola, Ralf
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Larsson, Henrik
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Genetic and environmental contributions to the association between attention deficit hyperactivity disorder and alcohol dependence in adulthood: A large population-based twin study2015In: American Journal of Medical Genetics Part B: Neuropsychiatric Genetics, ISSN 1552-4841, E-ISSN 1552-485X, Vol. 168, no 6, p. 414-422Article in journal (Refereed)
    Abstract [en]

    Previous research indicates that attention deficit hyperactivity disorder (ADHD) frequently co-occurs with alcohol dependence; however, the extent to which shared genetic risk factors underpin this association remains unclear. The aim of this study is to investigate the relative importance of genetic, shared, and nonshared environmental factors for the overlap between ADHD and alcohol dependence in adults. Almost 18,000 adult twins aged 20-45 years, from more than 12,000 twin pairs (5,420 complete pairs), from the population-representative Swedish Twin Registry, were included. Self-ratings were used to assess symptoms of ADHD and alcohol dependence. Twin analysis was used to determine the role of additive genetic (A), shared (C), and nonshared environmental (E) factors. As a result, we found a significant association between ADHD and alcohol dependence (odds ratio 3.58; 95% confidence interval, 2.85-4.49). Twin analysis suggested that shared genetic risk factors explained 64% of the overlap between ADHD and alcohol dependence. Nonshared environmental factors accounted for the remaining 36%, whereas the contribution of shared environmental factors was minimal. We found no support for statistically significant sex differences in the overlap between ADHD and alcohol dependence. In conclusion the overlap between ADHD and alcohol dependence in adulthood was largely explained by shared genetic risk factors. This is an important step toward understanding the underlying nature of the risk of alcohol dependence in patients with ADHD and suggests that individuals with ADHD and their family members are important targets for alcohol prevention and treatment.

  • 28.
    Capusan, Andrea J.
    et al.
    Department of Psychiatry and Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
    Bendtsen, Preben
    Department of Medical Specialist and Department of Medicine and Health Sciences, Linköping University, Motala, Sweden.
    Marteinsdottir, Ina
    Centre for Social and Affective Neuroscience, Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
    Larsson, Henrik
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Comorbidity of Adult ADHD and Its Subtypes With Substance Use Disorder in a Large Population-Based Epidemiological Study2016In: Journal of Attention Disorders, ISSN 1087-0547, E-ISSN 1557-1246Article in journal (Refereed)
    Abstract [en]

    Objective: The objective of the study is to explore the role and possible substance preference in ADHD and subtypes in substance use disorder (SUD).

    Method: Using self-report data on ADHD Diagnostic and Statistical Manual of Mental Disorders (4th ed.; DSM-IV) symptoms and SUD (alcohol, illicit drugs, and nicotine) in 18,167 Swedish twins, aged 20 to 45 years, we obtained odds ratios (OR) from mixed effect logistic regression, controlling for age, sex, education, and nonindependence of twin data.

    Results: Increased ADHD symptoms were significantly associated with increased odds for all SUD. ORs ranged between 1.33 for regular nicotine (95% confidence interval [CI] = [1.12, 1.59]); 2.54 for multiple drug use (95% CI = [2.00, 3.23]), and 3.58 for alcohol dependence (95% CI = [2.86, 4.49]).

    Conclusion: ADHD symptoms and subtypes in the population are associated with increased risks for all SUD outcomes, with no difference between ADHD subtypes, no substance preference, and no sex differences for the comorbidity. Clinicians need to consider ADHD evaluation and treatment as part of management of SUD in adults.

  • 29.
    Carulla-Roig, Marta
    et al.
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden; Department of Child and Adolescent Psychiatry, Sant Joan de Déu Hospital, Barcelona, Spain .
    Isomura, Kayoko
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden; Stockholm Health Care Services, Stockholm County Council, Stockholm, Sweden .
    Pérez-Vigil, Ana
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden .
    Larsson, Henrik
    Örebro University, School of Medical Sciences. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden .
    Hellner, Clara
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden; Stockholm Health Care Services, Stockholm County Council, Stockholm, Sweden.
    Mataix-Cols, David
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden; Stockholm Health Care Services, Stockholm County Council, Stockholm, Sweden.
    Fernández de la Cruz, Lorena
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Pharmacoepidemiology of Tourette and Chronic Tic Disorders in Sweden 2005-20132018In: Journal of child and adolescent psychopharmacology, ISSN 1044-5463, E-ISSN 1557-8992Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Monitoring "real world" dispensation patterns over time is important to build the evidence base for safe and efficient use of psychotropic drugs. In this study, we aimed to comprehensively examine the patterns of psychotropic drug dispensations in patients with Tourette and chronic tic disorders (TD/CTD) in Sweden between 2005 and 2013.

    METHODS: A cohort of 6979 TD/CTD patients was identified through the Swedish National Patient Register. Their drug dispensation patterns, collected in the Swedish Prescribed Drug Register, were examined between July 1, 2005 and December 31, 2013. Frequencies of drug dispensations were further stratified by gender and comorbidities. Additionally, differences in the patterns of dispensation in children and adolescents versus adults in the last year of the follow-up were examined, as well as the time trends of the dispensations over the 8-year study period.

    RESULTS: A total of 5299 (75.9%) TD/CTD patients were dispensed at least one drug during the study period. The most frequently dispensed medications were attention-deficit/hyperactivity disorder (ADHD) drugs (53.8%), antidepressants (50.7%), hypnotics/sedatives (41.7%), and antipsychotics (41.5%). Most of the medicated patients (72.1%) were dispensed more than one drug during the study period. Patterns of dispensation varied according to patient's gender, associated comorbidities, and age group. Dispensation of quetiapine and aripiprazole, antiadrenergics, ADHD drugs, antiepileptics, and hypnotics/sedatives and anxiolytics (particularly the nonbenzodiazepine types) significantly increased over time, whereas dispensation of antidepressants, typical antipsychotics, and benzodiazepine-based anxiolytics significantly decreased over the study period.

    CONCLUSIONS: Long-term monitoring of these drug dispensation patterns and the study of both their beneficial and adverse effects is warranted.

  • 30.
    Cederlöf, M.
    et al.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden.
    Karlsson, R.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden.
    Larsson, Henrik
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Almqvist, C.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden; Lung and Allergy Unit, Astrid Lindgren Children’s Hospital, Karolinska University Hospital, Stockholm, Sweden.
    Magnusson, P. K. E.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden.
    Nordlind, K.
    Department of Medicine, Karolinska Institute, Stockholm, Sweden.
    Landén, M.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden; Institute of Neuroscience and Physiology, University of Gothenburg, Gothenburg, Sweden.
    Lichtenstein, P.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden.
    Intellectual disability and cognitive ability in Darier disease: Swedish nation-wide study2015In: British Journal of Dermatology, ISSN 0007-0963, E-ISSN 1365-2133, Vol. 173, no 1, p. 155-158Article in journal (Refereed)
    Abstract [en]

    Background: Darier disease is an autosomal dominant skin disorder caused by mutations in the ATP2A2 gene. Anecdotal reports suggest a relationship between Darier disease and intellectual disabilities, but these reports are based on small clinical samples and limited by absence of control populations.

    Objectives: To examine the risk of intellectual disability and subclinical impairments in cognitive ability in Darier disease.

    Methods: We conducted a matched cohort study based on Swedish Population-, Patient- and Conscript Registers. The risk of being diagnosed with intellectual disability was estimated in 770 individuals with Darier disease, compared with matched comparison individuals without Darier disease. Associations were examined with risk ratios from conditional logistic regressions. In addition, we analysed test-based cognitive ability data (i.e. IQ data) from the Swedish conscript examination, for a subset of patients without diagnosed intellectual disability.

    Results: Individuals with Darier disease had a sixfold increased risk of being diagnosed with intellectual disability (risk ratio 6.2, 95% confidence interval 3.1-12.4). For conscripted individuals with Darier disease but no diagnosed intellectual disability, mean cognitive ability scores were about half a standard deviation lower than for comparison subjects.

    Conclusions: Darier disease is associated with intellectual disability and subclinical impairments in cognitive ability. The Darier-causing mutations merit further attention in molecular genetic research on intellectual disability and cognitive ability.

  • 31.
    Cederlöf, Martin
    et al.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden .
    Bergen, Sarah E.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Larsson, Henrik
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Landén, Mikael
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Institute of Neuroscience and Physiology, University of Gothenburg, Gothenburg, Sweden .
    Lichtenstein, Paul
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Acute intermittent porphyria: comorbidity and shared familial risks with schizophrenia and bipolar disorder in Sweden2015In: British Journal of Psychiatry, ISSN 0007-1250, E-ISSN 1472-1465, Vol. 207, no 6, p. 556-557Article in journal (Refereed)
    Abstract [en]

    Acute intermittent porphyria (AIP) has been associated with schizophrenia in some studies, but prior research is limited by the absence of comparison populations. Here, we linked Swedish registers to examine the risk of schizophrenia and bipolar disorder in 717 individuals diagnosed with AIP and their first-degree relatives, compared with matched individuals without AIP and their first-degree relatives. Individuals with AIP had a fourfold increased risk of schizophrenia or bipolar disorder. Similarly, relatives of individuals with AIP had double the risk of schizophrenia or bipolar disorder, suggesting that these associations may be as a result of common genetic influences.

  • 32.
    Cederlöf, Martin
    et al.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Bergen, Sarah E.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Långström, Niklas
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Swedish Prison and Probation Service R andD, Norrköping, Sweden.
    Larsson, Henrik
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Boman, Marcus
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Craddock, Nick
    Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, United Kingdom .
    Östberg, Per
    Division of Speech and Language Pathology, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Huddinge, Sweden; Department of Speech-Language Pathology, Karolinska University Hospital, Huddinge, Sweden .
    Lundström, Sebastian
    Centre for Ethics, Law and Mental Health (CELAM), University of Gothenburg, Gothenburg, Sweden; Gillberg Neuropsychiatry Centre, University of Gothenburg, Gothenburg, Sweden .
    Sjölander, Arvid
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Nordlind, Klas
    Department of Medicine, Karolinska Institutet, Stockholm, Sweden .
    Landén, Mikael
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Institute of Neuroscience and Physiology, University of Gothenburg, Gothenburg, Sweden .
    Lichtenstein, Paul
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    The association between Darier disease, bipolar disorder, and schizophrenia revisited: a population-based family study2015In: Bipolar Disorders, ISSN 1398-5647, E-ISSN 1399-5618, Vol. 17, no 3, p. 340-344Article in journal (Refereed)
    Abstract [en]

    Objectives: Darier disease is an autosomal dominant skin disorder caused by mutations in the ATPase, Ca++ transporting, cardiac muscle, slow twitch 2 (ATP2A2) gene and previously reported to cosegregate with bipolar disorder and schizophrenia in occasional pedigrees. It is, however, unknown whether these associations exist also in the general population, and the objective of this study was to examine this question.

    Methods: We compared a national sample of individuals with Darier disease and their first-degree relatives with matched unexposed individuals from the general population and their first-degree relatives, respectively. To examine risks for bipolar disorder and schizophrenia, risk ratios and 95% confidence intervals (CIs) were estimated using conditional logistic regressions.

    Results: Individuals with Darier disease had a 4.3 times higher risk of being diagnosed with bipolar disorder (95% CI: 2.6-7.3) and a 2.3 times higher risk of being diagnosed with schizophrenia (95% CI: 1.1-5.2) than matched individuals from the general population. Relatives of individuals with Darier disease had a 1.6 times higher risk of having bipolar disorder (95% CI: 1.1-2.5) than relatives of matched individuals from the general population, but no increased risk of schizophrenia (risk ratio = 0.8, 95% CI: 0.4-1.8).

    Conclusions: The association between Darier disease and bipolar disorder is manifest also in the population, and our data suggest that genetic variability within the ATP2A2 gene that causes Darier disease also confers susceptibility for bipolar disorder. The Darier-causing mutations merit additional attention in molecular genetic research on bipolar disorder.

  • 33.
    Cederlöf, Martin
    et al.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Kuja-Halkola, Ralf
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Larsson, Henrik
    Örebro University, School of Medical Sciences. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Sjölander, Arvid
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Östberg, Per
    Division of Speech and Language Pathology, Department of Clinical Science, Intervention and Technology, 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, Gothenburg, Sweden.
    Kelleher, Ian
    Department of Psychiatry, Royal College of Surgeons in Ireland, Dublin, Ireland.
    Lichtenstein, Paul
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    A longitudinal study of adolescent psychotic experiences and later development of substance use disorder and suicidal behavior2017In: Schizophrenia Research, ISSN 0920-9964, E-ISSN 1573-2509, Vol. 181, p. 13-16Article in journal (Refereed)
    Abstract [en]

    Introduction: Psychotic experiences are associated with later substance use disorder and suicidal behavior, but individual psychotic experiences have not been examined in a longitudinal data set. Also, the potential dose-response relationship between these phenomena remains unknown.

    Method: Cohort study including 9242 adolescents who participated in The Child and Adolescent Twin Study in Sweden (CATSS). At ages 15 and/or 18, seven psychotic experiences (auditory and visual hallucinations, and five delusions) were assessed via questionnaires. Outcomes at follow-up were physician-assigned diagnoses of substance use disorder and suicide attempts ascertained from the Swedish Patient Register. Associations were estimated with Cox regressions and expressed as hazard ratios.

    Results: All psychotic experiences were associated with later substance use disorder and/or suicide attempts, with hazard ratios ranging from 1.6 to 3.0. A dose-response relationship was observed between psychotic experiences and later substance use disorder, and suicide attempt.

    Discussion: Auditory and visual hallucinations as well as delusions in adolescence are associated with later development of substance use disorder and suicide attempt, and there is a dose-response relationship between the load of psychotic experiences and these adverse outcomes. Clinicians should assess subclinical hallucinations as well as delusions in psychiatric evaluations of adolescents.

  • 34.
    Cederlöf, Martin
    et al.
    Department Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Larsson, Henrik
    Department Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Lichtenstein, Paul
    Department Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Almqvist, Catarina
    Department Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Astrid Lindgren Children's Hospital, Karolinska University Hospital, Stockholm, Sweden.
    Serlachius, Eva
    Centre for Psychiatry Research, Stockholm Health Care Services, Stockholm County Council, Stockholm, Sweden; Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Ludvigsson, Jonas F.
    Örebro University, School of Medical Sciences. Department Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Division of Epidemiology and Public Health, School of Medicine, University of Nottingham, Nottingham, United Kingdom; Department of Medicine, Columbia University College of Physicians and Surgeons, New York, United States.
    Nationwide population-based cohort study of psychiatric disorders in individuals with Ehlers-Danlos syndrome or hypermobility syndrome and their siblings2016In: BMC Psychiatry, ISSN 1471-244X, E-ISSN 1471-244X, Vol. 16, article id 207Article in journal (Refereed)
    Abstract [en]

    Background: To assess the risk of psychiatric disorders in Ehlers-Danlos syndrome (EDS) and hypermobility syndrome.

    Methods: Nationwide population-based matched cohort study. EDS, hypermobility syndrome and psychiatric disorders were identified through Swedish national registries. Individuals with EDS (n = 1,771) were matched with comparison individuals (n = 17,710). Further, siblings to individuals with EDS who did not have an EDS diagnosis themselves were compared with matched comparison siblings. Using conditional logistic regression, risk of autism spectrum disorder (ASD), bipolar disorder, attention deficit hyperactivity disorder (ADHD), depression, attempted suicide, suicide and schizophrenia were estimated. The same analyses were conducted in individuals with hypermobility syndrome (n = 10,019) and their siblings.

    Results: EDS was associated with ASD: risk ratio (RR) 7.4, 95 % confidence interval (95 % CI) 5.2-10.7; bipolar disorder: RR 2.7, CI 1.5-4.7; ADHD: RR 5.6, CI 4.2-7.4; depression: RR 3.4, 95 % CI 2.9-4.1; and attempted suicide: RR 2.1, 95 % CI 1.7-2.7, but not with suicide or schizophrenia. EDS siblings were at increased risk of ADHD: RR 2.1, 95 % CI 1.4-3.3; depression: RR 1.5, 95 % CI 1.1-1.8; and suicide attempt: RR 1.8, 95 % CI 1.4-2.3. Similar results were observed for individuals with hypermobility syndrome and their siblings.

    Conclusions: Individuals with EDS and hypermobility syndrome are at increased risks of being diagnosed with psychiatric disorders. These risk increases may have a genetic and/or early environmental background as suggested by evidence showing that siblings to patients have elevated risks of certain psychiatric disorders.

  • 35.
    Cederlöf, Martin
    et al.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Lichtenstein, Paul
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Larsson, Henrik
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Boman, Marcus
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Rück, Christian
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Landén, Mikael
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Institute of Neuroscience and Physiology, University of Gothenburg, Gothenburg, Sweden.
    Mataix-Cols, David
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Obsessive-Compulsive Disorder, Psychosis, and Bipolarity: A Longitudinal Cohort and Multigenerational Family Study2015In: Schizophrenia Bulletin, ISSN 0586-7614, E-ISSN 1745-1701, Vol. 41, no 5, p. 1076-1083Article in journal (Refereed)
    Abstract [en]

    Obsessive-compulsive disorder (OCD) often co-occurs with psychotic and bipolar disorders; this comorbidity complicates the clinical management of these conditions. In this population-based longitudinal and multigenerational family study, we examined the patterns of comorbidity, longitudinal risks, and shared familial risks between these disorders. Participants were individuals with a diagnosis of OCD (n = 19,814), schizophrenia (n = 58,336), bipolar disorder (n = 48,180), and schizoaffective disorder (n = 14,904) included in the Swedish Patient Register between January 1969 and December 2009; their first-, second-, and third-degree relatives; and population-matched (1:10 ratio) unaffected comparison individuals and their relatives. The Swedish Prescribed Drug Register was used to control for the potential effect of medication in the longitudinal analyses. Individuals with OCD had a 12-fold increased risk of having a comorbid diagnosis of schizophrenia and a 13-fold increased risk of bipolar disorder and schizoaffective disorder. Longitudinal analyses showed that individuals first diagnosed with OCD had an increased risk for later diagnosis of all other disorders, and vice versa. The risk of bipolar disorder was reduced, but not eliminated, when the use of selective serotonin reuptake inhibitors was adjusted for. OCD-unaffected first-, second-, and third-degree relatives of probands with OCD had a significantly increased risk for all 3 disorders; the magnitude of this risk decreased as the genetic distance increased. We conclude that OCD is etiologically related to both schizophrenia spectrum and bipolar disorders. The results have implications for current gene-searching efforts and for clinical practice.

  • 36.
    Cederlöf, Martin
    et al.
    Medical Research Council Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology & Neuroscience, King's College, London, United Kingdom.
    Maughan, Barbara
    Medical Research Council Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology & Neuroscience, King's College, London, United Kingdom.
    Larsson, Henrik
    Örebro University, School of Medical Sciences. 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 of America.
    Plomin, Robert
    Medical Research Council Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology & Neuroscience, King's College, London, United Kingdom.
    Reading problems and major mental disorders: co-occurrences and familial overlaps in a Swedish nationwide cohort2017In: Journal of Psychiatric Research, ISSN 0022-3956, E-ISSN 1879-1379, Vol. 91, p. 124-129Article in journal (Refereed)
    Abstract [en]

    Reading problems often co-occur with ADHD and conduct disorder. However, the patterns of co-occurrence and familial overlap between reading problems and other psychiatric disorders have not been systematically explored. We conducted a register-based cohort study including 8719 individuals with reading problems and their siblings, along with matched comparison individuals. Conditional logistic regressions estimated risks for ADHD, autism, obsessive-compulsive disorder, anorexia nervosa, schizophrenia, bipolar disorder, depression, substance use disorder, and violent/non-violent criminality in individuals with reading problems and their siblings. Diagnoses of psychiatric disorders were physician-assigned and ascertained from the Swedish National Patient Register, and crime convictions from the Swedish National Crime Register. We found that individuals with reading problems had excess risks for all psychiatric disorders (except anorexia nervosa) and criminality, with risk ratios between 1.34 and 4.91. Siblings of individuals with reading problems showed excess risks for ADHD, autism, schizophrenia, bipolar disorder, depression, substance use disorder, and non-violent criminality, with risk ratios between 1.14 and 1.70. In summary, individuals with reading problems had increased risks of virtually all psychiatric disorders, and criminality. The origin of most of these overlaps was familial, in that siblings of individuals with reading problems also had elevated risks of ADHD, autism, schizophrenia, bipolar disorder, depression, substance use disorder, and non-violent criminality. These findings have implications for gene-searching efforts, and suggest that health care practitioners should be alert for signs of psychiatric disorders in families where reading problems exist.

  • 37.
    Cederlöf, Martin
    et al.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Ohlsson Gotby, Agnes
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Larsson, Henrik
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Serlachius, Eva
    Department of Clinical Neuroscience, Centre for Psychiatric Research and Education, 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; R&D Unit, Swedish Prison and Probation Service, Norrköping, Sweden.
    Landén, Mikael
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Institute of Neuroscience and Physiology, University of Gothenburg, Gothenburg, Sweden.
    Lichtenstein, Paul
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Klinefelter syndrome and risk of psychosis, autism and ADHD2014In: Journal of Psychiatric Research, ISSN 0022-3956, E-ISSN 1879-1379, Vol. 48, no 1, p. 128-130Article in journal (Refereed)
    Abstract [en]

    Background: Schizophrenia, bipolar disorder, autism spectrum disorders and ADHD might be overrepresented in Klinefelter syndrome, but previous investigations have yielded inconclusive results.

    Methods: We compared a national sample of 860 Klinefelter patients in Sweden with 86 000 matched population controls. To assess the risks of schizophrenia, bipolar disorder, autism spectrum disorder and ADHD in Klinefelter patients, we estimated odds ratios and 95% confidence intervals using conditional logistic regressions.

    Results: Klinefelter patients had almost four times higher risks of schizophrenia, odds ratio (OR) = 3.6, 95% confidence interval (CI) 2.0-6.7 and bipolar disorder (OR = 3.8, CI 1.8-7.6) and about six times higher risk of autism spectrum disorder (OR = 6.2, CI 4.0-9.4) and ADHD (OR = 5.6, CI 4.0-7.8).

    Conclusions: The risk of psychosis, autism and ADHD is increased in Klinefelter patients. These findings indicate an X chromosome-related factor in the etiology of the studied psychiatric disorders, and may also have implications for treatment of patients with Klinefelter syndrome.

  • 38.
    Cederlöf, Martin
    et al.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Pettersson, Erik
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Sariaslan, Amir
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Larsson, Henrik
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Östberg, Per
    Division of Speech and Language Pathology, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden; Department of Speech and Language Pathology, Karolinska University Hospital, Stockholm, Sweden.
    Kelleher, Ian
    Department of Psychiatry, Royal College of Surgeons in Ireland, Dublin, Ireland.
    Långström, Niklas
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; R&D unit, Swedish Prison and Probation Service, Stockholm, Sweden.
    Gumpert, Clara Hellner
    Centre for Psychiatry Research & Education, Department of Clinical Neuroscience, Karolinska Institutet & Stockholm County Council, 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.
    Lichtenstein, Paul
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    The association between childhood autistic traits and adolescent psychotic experiences is explained by general neuropsychiatric problems.2016In: American Journal of Medical Genetics Part B: Neuropsychiatric Genetics, ISSN 1552-4841, E-ISSN 1552-485X, Vol. 171, no 2, p. 153-159Article in journal (Refereed)
    Abstract [en]

    Studies suggest associations between childhood autistic traits and adolescent psychotic experiences. However, recent research suggests that a general neuropsychiatric problems factor predicts adverse outcomes better than specific diagnostic entities. To examine if the alleged association between autistic traits and psychotic experiences could rather be explained by a general neuropsychiatric problems factor comprising symptoms of ADHD, tic disorder, developmental coordination disorder, and learning disorder, we conducted a prospective cohort study based on the Child and Adolescent Twin Study in Sweden. In addition, we examined the genetic and environmental influences on the associations. A total of 9,282 twins with data on childhood autistic traits and other neuropsychiatric problems, and follow-up data on psychotic experiences at ages 15 and/or 18 years were included. First, psychotic experiences were regressed on autistic traits and second, the general neuropsychiatric problems factor was added to the model. Auditory hallucinations were analyzed separately from the other psychotic experiences. Finally, twin analyses were employed to disentangle genetic from environmental influences in the observed associations. Replicating prior research, significant associations were found between autistic traits in childhood and auditory hallucinations at ages 15 and 18. However, after controlling for the general neuropsychiatric problems factor, the associations between autistic traits and auditory hallucinations disappeared, whereas the association between the general neuropsychiatric problems factor and auditory hallucinations persisted after controlling for autistic traits. Twin analyses revealed that the association between the general neuropsychiatric problems factor and auditory hallucinations was driven by shared genetic influences. .

  • 39.
    Cederlöf, Martin
    et al.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Thornton, Laura M.
    Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
    Baker, Jessica
    Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, NC, 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.
    Rück, Christian
    Department of Clinical Neuroscience, Centre for Psychiatric Research and Education, Karolinska Institutet and Stockholm County Council, Stockholm, Sweden.
    Bulik, Cynthia M.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Department of Nutrition, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
    Mataix-Cols, David
    Department of Clinical Neuroscience, Centre for Psychiatric Research and Education, Karolinska Institutet and Stockholm County Council, Stockholm, Sweden.
    Etiological overlap between obsessive-compulsive disorder and anorexia nervosa: a longitudinal cohort, multigenerational family and twin study2015In: World Psychiatry, ISSN 1723-8617, E-ISSN 2051-5545, Vol. 14, no 3, p. 333-338Article in journal (Refereed)
    Abstract [en]

    Obsessive-compulsive disorder (OCD) often co-occurs with anorexia nervosa (AN), a comorbid profile that complicates the clinical management of both conditions. This population-based study aimed to examine patterns of comorbidity, longitudinal risks, shared familial risks and shared genetic factors between OCD and AN at the population level. Participants were individuals with a diagnosis of OCD (N=19,814) or AN (N=8,462) in the Swedish National Patient Register between January 1992 and December 2009; their first-, second- and third-degree relatives; and population-matched (1:10 ratio) unaffected comparison individuals and their relatives. Female twins from the population-based Swedish Twin Register (N=8,550) were also included. Females with OCD had a 16-fold increased risk of having a comorbid diagnosis of AN, whereas males with OCD had a 37-fold increased risk. Longitudinal analyses showed that individuals first diagnosed with OCD had an increased risk for a later diagnosis of AN (risk ratio, RR=3.6), whereas individuals first diagnosed with AN had an even greater risk for a later diagnosis of OCD (RR=9.6). These longitudinal risks were about twice as high for males than for females. First- and second-degree relatives of probands with OCD had an increased risk for AN, and the magnitude of this risk tended to increase with the degree of genetic relatedness. Bivariate twin models revealed a moderate but significant degree of genetic overlap between self-reported OCD and AN diagnoses (ra =0.52, 95% CI: 0.26-0.81), but most of the genetic variance was disorder-specific. The moderately high genetic correlation supports the idea that this frequently observed comorbid pattern is at least in part due to shared genetic factors, though disorder-specific factors are more important. These results have implications for current gene-searching efforts and for clinical practice.

  • 40.
    Chang, Zheng
    et al.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    D'Onofrio, Brian M.
    Department of Psychological and Brain Sciences, Indiana University, Bloomington, USA.
    Quinn, Patrick D.
    Department of Psychological and Brain Sciences, Indiana University, Bloomington, USA.
    Lichtenstein, Paul
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Larsson, Henrik
    Örebro University, School of Medical Sciences. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Medication for Attention-Deficit/Hyperactivity Disorder and Risk for Depression: A Nationwide Longitudinal Cohort Study2016In: Biological Psychiatry, ISSN 0006-3223, E-ISSN 1873-2402, Vol. 80, no 12, p. 916-922Article in journal (Refereed)
    Abstract [en]

    Background: Attention-deficit/hyperactivity disorder (ADHD) is associated with high rates of psychiatric comorbidity, including depression. However, it is unclear whether ADHD medication increases or decreases the risk for depression.

    Methods: We studied all individuals with a diagnosis of ADHD born between 1960 and 1998 in Sweden (N = 38,752). We obtained data for prescription of ADHD medication, diagnosis of depression and other psychiatric disorders, and sociodemographic factors from population-based registers. The association between ADHD medication and depression was estimated with Cox proportional hazards regression.

    Results: After adjustment for sociodemographic and clinical confounders, ADHD medication was associated with a reduced long-term risk (i.e., 3 years later) for depression (hazard ratio = 0.58; 95% confidence interval, 0.51-0.67). The risk was lower for longer duration of ADHD medication. Also, ADHD medication was associated with reduced rates of concurrent depression; within-individual analysis suggested that occurrence of depression was 20% less common during periods when patients received ADHD medication compared with periods when they did not (hazard ratio = 0.80; 95% confidence interval, 0.70-0.92).

    Conclusions Our study suggests that ADHD medication does not increase the risk of later depression; rather, medication was associated with a reduced risk for subsequent and concurrent depression.

  • 41.
    Chang, Zheng
    et al.
    Department of Psychiatry, Warneford Hospital, University of Oxford, Oxford, UK; 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.
    Fazel, Seena
    Department of Psychiatry, Warneford Hospital, University of Oxford, Oxford, UK.
    Psychiatric disorders and violent reoffending: a national cohort study of convicted prisoners in Sweden2015In: Lancet psychiatry, ISSN 2215-0374, E-ISSN 2215-0366, Vol. 2, no 10, p. 891-900Article in journal (Refereed)
    Abstract [en]

    Background Reoffending and presence of psychiatric disorders are common in prisoners worldwide. However, whether psychiatric disorders are risk factors for reoffending is still unknown. We aimed to examine the association between psychiatric disorders, including substance use disorder, and violent reoffending.

    Methods: We did a longitudinal cohort study of 47,326 prisoners who were imprisoned since Jan 1, 2000, and released before Dec 31, 2009, in Sweden. We obtained data for diagnosed psychiatric disorders from both inpatient and outpatient registers, and sociodemographic and criminological factors from other population-based registers. We calculated hazard ratios (HRs) for violent reoffending with Cox regression. To control for potential familial confounding, we compared sibling prisoners with and without psychiatric disorders. We calculated population attributable fraction to assess the population effect.

    Findings: Diagnosed psychiatric disorders were associated with an increased hazard of violent reoffending in male (adjusted HR 1·63 [95% CI 1·57-1·70]) and female (2·02 [1·54-2·63]) prisoners, and these associations were independent of measured sociodemographic and criminological factors, and, in men, remained substantial after adjustment for unmeasured familial factors (2·01 [1·66-2·43]). However, findings differed between individual diagnoses and sex. We found some evidence of stronger effects on violent reoffending of alcohol and drug use disorders and bipolar disorder than of other psychiatric disorders. Alcohol use disorder seemed to have a greater effect in women than in men (women 2·08 [1·66-2·60]; men 1·63 [1·56-1·71]). The overall effects of psychiatric disorders did not differ with severity of crime. The hazard of violent reoffending increased in a stepwise way with the number of diagnosed psychiatric disorders. Assuming causality, up to 20% (95% CI 19-22) of violent reoffending in men and 40% (27-52) in women was attributable to the diagnosed psychiatric disorders that we investigated.

    Interpretation Certain psychiatric disorders are associated with a substantially increased hazard of violent reoffending. Because these disorders are prevalent and mostly treatable, improvements to prison mental health services could counteract the cycle of reoffending and improve both public health and safety. National violence prevention strategies should consider the role of prison health.

    Funding: Wellcome Trust, Swedish Research Council, and Swedish Research Council for Health, Working Life and Welfare.

  • 42.
    Chang, Zheng
    et al.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden .
    Lichtenstein, Paul
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Asherson, Philip J.
    Institute of Psychiatry, King's College London, London, United Kingdom .
    Larsson, Henrik
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Center of Neurodevelopmental Disorders, Karolinska Institutet, Stockholm, Sweden .
    Developmental twin study of attention problems: high heritabilities throughout development.2013In: JAMA psychiatry, ISSN 2168-6238, E-ISSN 2168-622X, Vol. 70, no 3, p. 311-318Article in journal (Refereed)
    Abstract [en]

    Context: The genetic and environmental link between attention-deficit/hyperactivity disorder in childhood and the adult manifestation of the disorder is poorly understood because of a lack of longitudinal studies with cross-informant data.

    Objective: To explore the relative contribution of genetic and environmental influences on symptoms of attention problems from childhood to early adulthood.

    Design: Analysis was conducted using longitudinal structural equation modeling with multiple informants.

    Setting The Swedish Twin Study of Child and Adolescent Development.

    Participants: One thousand four hundred eighty twin pairs were prospectively followed up from childhood to young adulthood.

    Main outcome measures: Symptoms were obtained using parent and self-ratings of the Attention Problems Scale at ages 8 to 9, 13 to 14, 16 to 17, and 19 to 20 years.

    Results: The best-fitting model revealed high heritability of attention problems as indexed by parent and self-ratings from childhood to early adulthood (h² = 0.77-0.82). Genetic effects operating at age 8 to 9 years continued, explaining 41%, 34%, and 24% of the total variance at ages 13 to 14, 16 to 17, and 19 to 20 years. Moreover, new sets of genetic risk factors emerged at ages 13 to 14, 16 to 17, and 19 to 20 years.

    Conclusions: The shared view of self- and informant-rated attention problems is highly heritable in childhood, adolescence, and early adulthood, suggesting that the previous reports of low heritability for attention-deficit/hyperactivity disorder in adults are best explained by rater effects. Both genetic stability and genetic innovation were present throughout this developmental stage, suggesting that attention problems are a developmentally complex phenotype characterized by both continuity and change across the life span.

  • 43.
    Chang, Zheng
    et al.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Department of Psychiatry, University of Oxford, Oxford, UK.
    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, USA.
    Almqvist, Catarina
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Astrid Lindgren Children’s Hospital, Karolinska University Hospital, 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.
    Larsson, Henrik
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Maternal age at childbirth and risk for ADHD in offspring: a population-based cohort study2014In: International Journal of Epidemiology, ISSN 0300-5771, E-ISSN 1464-3685, Vol. 43, no 6, p. 1815-1824Article in journal (Refereed)
    Abstract [en]

    Background: Women who give birth at younger ages (e.g. teenage mothers) are more likely to have children who exhibit behaviour problems, such as attention-deficit/hyperactivity disorder (ADHD). However, it is not clear whether young maternal age is causally associated with poor offspring outcomes or confounded by familial factors.

    Methods: The association between early maternal age at childbirth and offspring ADHD was studied using data from Swedish national registers. The sample included all children born in Sweden between 1988 and 2003 (N = 1 495 543), including 30 674 children with ADHD. We used sibling- and cousin-comparisons to control for unmeasured genetic and environmental confounding. Further, we used a children-of-siblings model to quantify the genetic and environmental contribution to the association between maternal age and offspring ADHD.

    Results: Maternal age at first birth (MAFB) was associated with offspring ADHD. Teenage childbirth (<20 years) was associated with 78% increased risk of ADHD. The association attenuated in cousin-comparison, suggesting unmeasured familial confounding. The children-of-siblings model indicated that the association between MAFB and ADHD was mainly explained by genetic confounding.

    Conclusions: All children born to mothers who bore their first child early in their reproductive lives were at increased risk of ADHD. The association was mainly explained by genetic factors transmitted from mothers to their offspring that contribute to both age at childbirth and ADHD in offspring. Our results highlight the importance of using family-based designs to understand how early life circumstances affect child development.

  • 44.
    Chang, Zheng
    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, United States .
    Sjölander, Arvid
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Larsson, Henrik
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Serious transport accidents in adults with attention-deficit/hyperactivity disorder and the effect of medication: a population-based study2014In: JAMA psychiatry, ISSN 2168-6238, E-ISSN 2168-622X, Vol. 71, no 3, p. 319-325Article in journal (Refereed)
    Abstract [en]

    Importance: Studies have shown that attention-deficit/hyperactivity disorder (ADHD) is associated with transport accidents, but the magnitude of the association remains unclear. Most important, it is also unclear whether ADHD medication reduces this risk.

    Objectives: To estimate the association between ADHD and the risk of serious transport accidents and to explore the extent to which ADHD medication influences this risk among patients with ADHD.

    Design, setting and participants: In total, 17,408 patients with a diagnosis of ADHD were observed from January 1, 2006, through December 31, 2009, for serious transport accidents documented in Swedish national registers. The association between ADHD and accidents was estimated with Cox proportional hazards regression. To study the effect of ADHD medication, we used stratified Cox regression to compare the risk of accidents during the medication period with the risk during the nonmedication period within the same patients.

    Main outcomes and measures: Serious transport accident, identified as an emergency hospital visit or death due to transport accident.

    Results: Compared with individuals without ADHD, male patients with ADHD (adjusted hazard ratio, 1.47; 95% CI, 1.32-1.63) and female patients with ADHD (1.45; 1.24-1.71) had an increased risk of serious transport accidents. In male patients with ADHD, medication was associated with a 58% risk reduction (hazard ratio, 0.42; 95% CI, 0.23-0.75), but there was no statistically significant association in female patients. Estimates of the population-attributable fractions suggested that 41% to 49% of the accidents in male patients with ADHD could have been avoided if they had been receiving treatment during the entire follow-up.

    Conclusions and relevance: Attention-deficit/hyperactivity disorder is associated with an increased risk of serious transport accidents, and this risk seems to be possibly reduced by ADHD medication, at least among male patients. This should lead to increased awareness among clinicians and patients of the association between serious transport accidents and ADHD medication.

  • 45.
    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 and Allied Disciplines, 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.

  • 46.
    Chang, Zheng
    et al.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden .
    Lichtenstein, Paul
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Larsson, Henrik
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Center of Neurodevelopmental Disorders, Karolinska Institutet, Stockholm, Sweden .
    The effects of childhood ADHD symptoms on early-onset substance use: a Swedish twin study2012In: Journal of Abnormal Child Psychology, ISSN 0091-0627, E-ISSN 1573-2835, Vol. 40, no 3, p. 319-325Article in journal (Refereed)
    Abstract [en]

    Research has documented that children and adolescents with attention-deficit/hyperactivity disorder (ADHD) are at increased risk of substance use problems. Few studies, however, have focused on early-onset substance use. This study therefore investigated how the two symptom dimensions of ADHD (hyperactivity/impulsivity and inattention) are associated with early-onset substance use, the role of persistent ADHD for the association, and to what extent the association is influenced by genetic and environmental factors. Twins (1,480 pairs) in the Swedish Twin Study of Child and Adolescent Development were followed from childhood to adolescence. ADHD symptoms were measured at age 8-9 and age 13-14 via parent-report, whereas substance use was assessed at age 13-14 via self-report. Results revealed that hyperactive/impulsive symptoms predicted early-onset "sometimes" tobacco use (adjusted odds ratios, 1.12, for one symptom count), controlling for inattentive symptoms and conduct problem behaviors. There is no independent effect of inattentive symptoms on early-onset substance use. Children with persistent hyperactivity/impulsivity (defined as scoring above the 75th percentile at both time points) had a pronounced risk of both early-onset tobacco and alcohol use (adjusted odds ratios from 1.86 to 3.35, compared to the reference group). The associations between hyperactivity/impulsivity and early-onset substance use were primarily influenced by genetic factors. Our results indicated that hyperactivity/impulsivity, but not inattention, is an important early predictor for early-onset substance use, and a shared genetic susceptibility is suggested to explain this association.

  • 47.
    Chang, Zheng
    et al.
    Department of Psychiatry, Warneford Hospital, University of Oxford, Oxford, United Kingdom; Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Lichtenstein, Paul
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Larsson, Henrik
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Fazel, Seena
    Department of Psychiatry, Warneford Hospital, University of Oxford, Oxford, United Kingdom.
    Substance use disorders, psychiatric disorders, and mortality after release from prison: a nationwide longitudinal cohort study2015In: Lancet psychiatry, ISSN 2215-0374, E-ISSN 2215-0366, Vol. 2, no 5, p. 422-430Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: High mortality rates have been reported in people released from prison compared with the general population. However, few studies have investigated potential risk factors associated with these high rates, especially psychiatric determinants. We aimed to investigate the association between psychiatric disorders and mortality in people released from prison in Sweden.

    METHODS: We studied all people who were imprisoned since Jan 1, 2000, and released before Dec 31, 2009, in Sweden for risks of all-cause and external-cause (accidents, suicide, homicide) mortality after prison release. We obtained data for substance use disorders and other psychiatric disorders, and criminological and sociodemographic factors from population-based registers. We calculated hazard ratios (HRs) by Cox regression, and then used them to calculate population attributable fractions for post-release mortality. To control for potential familial confounding, we compared individuals in the study with siblings who were also released from prison, but without psychiatric disorders. We tested whether any independent risk factors improved the prediction of mortality beyond age, sex, and criminal history.

    FINDINGS: We identified 47,326 individuals who were imprisoned. During a median follow-up time of 5·1 years (IQR 2·6-7·5), we recorded 2874 (6%) deaths after release from prison. The overall all-cause mortality rate was 1205 deaths per 100,000 person-years. Substance use disorders significantly increased the rate of all-cause mortality (alcohol use: adjusted HR 1·62, 95% CI 1·48-1·77; drug use: 1·67, 1·53-1·83), and the association was independent of sociodemographic, criminological, and familial factors. We identified no strong evidence that other psychiatric disorders increased mortality after we controlled for potential confounders. In people released from prison, 925 (34%) of all-cause deaths in men and 85 (50%) in women were potentially attributable to substance use disorders. Substance use disorders were also an independent determinant of external-cause mortality, with population attributable fraction estimates at 42% in men and 70% in women. Substance use disorders significantly improved the prediction of external-cause mortality, in addition to sociodemographic and criminological factors.

    INTERPRETATION: Interventions to address substance use disorders could substantially decrease the burden of excess mortality in people released from prison, but might need to be provided beyond the immediate period after release.

  • 48.
    Chang, Zheng
    et al.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Department of Psychiatry, Warneford Hospital, University of Oxford, Oxford, England.
    Lichtenstein, Paul
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Långström, Niklas
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Department of Neuroscience, Uppsala University, Uppsala, Sweden.
    Larsson, Henrik
    Örebro University, School of Medical Sciences. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Fazel, Seena
    Department of Psychiatry, Warneford Hospital, University of Oxford, Oxford, England.
    Association Between Prescription of Major Psychotropic Medications and Violent Reoffending After Prison Release2016In: Journal of the American Medical Association (JAMA), ISSN 0098-7484, E-ISSN 1538-3598, Vol. 316, no 17, p. 1798-1807Article in journal (Refereed)
    Abstract [en]

    Importance: Individuals released from prison have high rates of violent reoffending, and there is uncertainty about whether pharmacological treatments reduce reoffending risk.

    Objective: To investigate the associations between major classes of psychotropic medications and violent reoffending.

    Design, Setting, and Participants: This cohort study included all released prisoners in Sweden from July 1, 2005, to December 31, 2010, through linkage of population-based registers. Rates of violent reoffending during medicated periods were compared with rates during nonmedicated periods using within-individual analyses. Follow-up ended December 31, 2013.

    Exposures: Periods with or without dispensed prescription of psychotropic medications (antipsychotics, antidepressants, psychostimulants, drugs used in addictive disorders, and antiepileptic drugs) after prison release. Prison-based psychological treatments were investigated as a secondary exposure.

    Main Outcomes and Measures: Violent crime after release from prison.

    Results: The cohort included 22 275 released prisoners (mean [SD] age, 38 [13] years; 91.9% male). During follow-up (median, 4.6 years; interquartile range, 3.0-6.4 years), 4031 individuals (18.1%) had 5653 violent reoffenses. The within-individual hazard ratio (HR) associated with dispensed antipsychotics was 0.58 (95% CI, 0.39-0.88), based on 100 events in 1596 person-years during medicated periods and 1044 events in 11 026 person-years during nonmedicated periods, equating to a risk difference of 39.7 (95% CI, 11.3-57.7) fewer violent reoffenses per 1000 person-years. The within-individual HR associated with dispensed psychostimulants was 0.62 (95% CI, 0.40-0.98), based on 94 events in 1648 person-years during medicated periods and 513 events in 4553 person-years during nonmedicated periods, equating to a risk difference of 42.8 (95% CI, 2.2-67.6) fewer violent reoffenses per 1000 person-years. The within-individual HR associated with dispensed drugs for addictive disorders was 0.48 (95% CI, 0.23-0.97), based on 46 events in 1168 person-years during medicated periods and 1103 events in 15 725 person-years during nonmedicated periods, equating to a risk difference of 36.4 (95% CI, 2.1-54.0) fewer violent reoffenses per 1000 person-years. In contrast, antidepressants and antiepileptics were not significantly associated with violent reoffending rates (HR = 1.09 [95% CI, 0.83-1.43] and 1.14 [95% CI, 0.79-1.65], respectively). The most common prison-based program was psychological treatments for substance abuse, associated with an HR of 0.75 (95% CI, 0.63-0.89), which equated to a risk difference of 23.2 (95% CI, 10.3-34.1) fewer violent reoffenses per 1000 person-years.

    Conclusions and Relevance: Among released prisoners in Sweden, rates of violent reoffending were lower during periods when individiduals were dispensed antipsychotics, psychostimulants, and drugs for addictive disorders, compared with periods in which they were not dispensed these medications. Further research is needed to understand the causal nature of this association.

  • 49.
    Chang, Zheng
    et al.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Center for Health Statistics, University of Chicago, Chicago IL, United States.
    Quinn, Patrick D.
    Center for Health Statistics, University of Chicago, Chicago IL, United States; Department of Psychological and Brain Sciences, Indiana University, Bloomington, United States.
    Hur, Kwan
    Center for Health Statistics, University of Chicago, Chicago IL, United States.
    Gibbons, Robert D.
    Center for Health Statistics, University of Chicago, Chicago IL, United States.
    Sjolander, Arvid
    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.
    D'Onofrio, Brian M.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Department of Psychological and Brain Sciences, Indiana University, Bloomington, United States.
    Association Between Medication Use for Attention-Deficit/Hyperactivity Disorder and Risk of Motor Vehicle Crashes2017In: JAMA psychiatry, ISSN 2168-6238, E-ISSN 2168-622X, Vol. 74, no 6, p. 597-603Article in journal (Refereed)
    Abstract [en]

    IMPORTANCE: Motor vehicle crashes (MVCs) are a major public health problem. Research has demonstrated that individuals with attention-deficit/hyperactivity disorder (ADHD) are more likely to experience MVCs, but the effect of ADHD medication treatment on the risk of MVCs remains unclear.

    OBJECTIVE: To explore associations between ADHD medication use and risk of MVCs in a large cohort of patients with ADHD.

    DESIGN, SETTING, AND PARTICIPANTS: For this study, a US national cohort of patients with ADHD (n = 2 319 450) was identified from commercial health insurance claims between January 1, 2005, and December 31, 2014, and followed up for emergency department visits for MVCs. The study used within-individual analyses to compare the risk of MVCs during months in which patients received ADHD medication with the risk of MVCs during months in which they did not receive ADHD medication.

    EXPOSURES: Dispensed prescription of ADHD medications.

    MAIN OUTCOMES AND MEASURES: Emergency department visits for MVCs.

    RESULTS: Among 2 319 450 patients identified with ADHD, the mean (SD) age was 32.5 (12.8) years, and 51.7% were female. In the within-individual analyses, male patients with ADHD had a 38%(odds ratio, 0.62; 95% CI, 0.56-0.67) lower risk of MVCs in months when receiving ADHD medication compared with months when not receiving medication, and female patients had a 42%(odds ratio, 0.58; 95% CI, 0.53-0.62) lower risk of MVCs in months when receiving ADHD medication. Similar reductions were found across all age groups, across multiple sensitivity analyses, and when considering the long-term association between ADHD medication use and MVCs. Estimates of the population-attributable fraction suggested that up to 22.1% of the MVCs in patients with ADHD could have been avoided if they had received medication during the entire follow-up.

    CONCLUSIONS AND RELEVANCE: Among patients with ADHD, rates of MVCs were lower during periods when they received ADHD medication. Considering the high prevalence of ADHD and its association with MVCs, these findings warrant attention to this prevalent and preventable cause of mortality and morbidity.

  • 50.
    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 and Allied Disciplines, 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.

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