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  • 1.
    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.

  • 2.
    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.

  • 3.
    Choque Olsson, Nora
    et al.
    Center of Neurodevelopmental Disorders (KIND), Neuropsychiatry Unit, Karolinska Institutet, Stockholm, Sweden; Child and Adolescent Psychiatry, Center for Psychiatry Research, Stockholm County Council, Stockholm, Sweden.
    Flygare, Oskar
    Center of Neurodevelopmental Disorders (KIND), Neuropsychiatry Unit, Karolinska Institutet, Stockholm, Sweden; Child and Adolescent Psychiatry, Center for Psychiatry Research, Stockholm County Council, Stockholm, Sweden.
    Coco, Christina
    Center of Neurodevelopmental Disorders (KIND), Neuropsychiatry Unit, Karolinska Institutet, Stockholm, Sweden; Child and Adolescent Psychiatry, Center for Psychiatry Research, Stockholm County Council, Stockholm, Sweden.
    Görling, Anders
    Center of Neurodevelopmental Disorders (KIND), Neuropsychiatry Unit, Karolinska Institutet, Stockholm, Sweden; Child and Adolescent Psychiatry, Center for Psychiatry Research, Stockholm County Council, Stockholm, Sweden.
    Råde, Anna
    Center of Neurodevelopmental Disorders (KIND), Neuropsychiatry Unit, Karolinska Institutet, Stockholm, Sweden; Child and Adolescent Psychiatry, Center for Psychiatry Research, Stockholm County Council, Stockholm, Sweden.
    Chen, Qi
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Lindstedt, Katarina
    Örebro University, School of Medical Sciences. University Health Care Research Center, Region Örebro County, Örebro, sweden.
    Berggren, Steve
    Center of Neurodevelopmental Disorders (KIND), Neuropsychiatry Unit, Karolinska Institutet, Stockholm, Sweden; Child and Adolescent Psychiatry, Center for Psychiatry Research, Stockholm County Council, Stockholm, Sweden.
    Serlachius, Eva
    Child- and adolescent Psychiatry, Stockholm County Council, Stockholm, Sweden.
    Jonsson, Ulf
    Center of Neurodevelopmental Disorders (KIND), Neuropsychiatry Unit, Karolinska Institutet, Stockholm, Sweden; Child and Adolescent Psychiatry, Center for Psychiatry Research, Stockholm County Council, Stockholm, Sweden.
    Tammimies, Kristiina
    Center of Neurodevelopmental Disorders (KIND), Neuropsychiatry Unit, Karolinska Institutet, Stockholm, Sweden; Child and Adolescent Psychiatry, Center for Psychiatry Research, Stockholm County Council, Stockholm, Sweden.
    Kjellin, Lars
    University Health Care Research Center, Region Örebro County, Örebro, Sweden.
    Bölte, Sven
    Center of Neurodevelopmental Disorders (KIND), Neuropsychiatry Unit, Karolinska Institutet, Stockholm, Sweden; Child and Adolescent Psychiatry, Center for Psychiatry Research, Stockholm County Council, Stockholm, Sweden.
    Social Skills Training for Children and Adolescents With Autism Spectrum Disorder: A Randomized Controlled Trial2017In: Journal of the American Academy of Child and Adolescent Psychiatry, ISSN 0890-8567, E-ISSN 1527-5418, Vol. 56, no 7, p. 585-592, article id S0890-8567(17)30202-2Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: Social skills group training (SSGT) for children and adolescents with autism spectrum disorder (ASD) is widely applied, but effectiveness in real-world practice has not yet been properly evaluated. This study sought to bridge this gap.

    METHOD: This 12-week pragmatic randomized controlled trial of SSGT compared to standard care alone was conducted at 13 child and adolescent psychiatry outpatient units in Sweden. Twelve sessions of manualized SSGT ("KONTAKT") were delivered by regular clinical staff. Participants (N = 296; 88 females and 208 males) were children (n = 172) and adolescents (n = 124) aged 8 to 17 years with ASD without intellectual disability. The primary outcome was the Social Responsiveness Scale rating by parents and blinded teachers. Secondary outcomes included parent- and teacher-rated adaptive behaviors, trainer-rated global functioning and clinical severity, and self-reported child and caregiver stress. Assessments were made at baseline, posttreatment, and 3-month follow-up. Moderator analyses were conducted for age and gender.

    RESULTS: Significant treatment effects on the primary outcome were limited to parent ratings for the adolescent subgroup (posttreatment: -8.3; 95% CI = -14.2 to -1.9; p = .012, effect size [ES] = 0.32; follow-up: -8.6; 95% CI = -15.4 to -1.8; p = .015, ES = 0.33) and females (posttreatment: -8.9; 95% CI = -16.2 to -1.6; p = .019, ES = 0.40). Secondary outcomes indicated moderate effects on adaptive functioning and clinical severity.

    CONCLUSION: SSGT for children and adolescents with ASD in regular mental health services is feasible and safe. However, the modest and inconsistent effects underscore the importance of continued efforts to improve SSGT beyond current standards.

    CLINICAL TRIAL REGISTRATION INFORMATION: Social Skills Group Training ("KONTAKT") for Children and Adolescent With High-functioning Autism Spectrum Disorders; https://clinicaltrials.gov/; NCT01854346.

  • 4.
    Faraone, Stephen V.
    et al.
    State University of New York Upstate Medical University, Syracuse, USA; K.G. Jebsen Centre for Research on Neuropsychiatric Disorders, University of Bergen, Bergen, Norway.
    Ghirardi, Laura
    Karolinska Institutet, Stockholm, Sweden.
    Kuja-Halkola, Ralf
    Karolinska Institutet, Stockholm, Sweden.
    Lichtenstein, Paul
    Karolinska Institutet, Stockholm, Sweden.
    Larsson, Henrik
    Örebro University, School of Medical Sciences.
    The Familial Co-Aggregation of Attention-Deficit/Hyperactivity Disorder and Intellectual Disability: A Register-Based Family Study2017In: Journal of the American Academy of Child and Adolescent Psychiatry, ISSN 0890-8567, E-ISSN 1527-5418, Vol. 56, no 2, p. 167-174.e1Article in journal (Refereed)
    Abstract [en]

    Objective: Although many studies document an association between attention-deficit/hyperactivity disorder (ADHD) and intellectual disability (ID), little is known about the etiology of this comorbidity and how it should be addressed in clinical settings. We sought to clarify this issue.

    Method: All individuals born in Sweden between 1987 and 2006 (n = 2,049,587) were identified using the Medical Birth Register (MBR). From this we selected 7 cohorts of relatives: 1,899,654 parent-offspring pairs, 4,180 monozygotic twin pairs, 12,655 dizygotic twin pairs, 914,848 full sibling pairs, 136,962 maternal half-sibling pairs, 134,502 paternal half-sibling pairs, and 2,790,164 full cousin pairs. We used within-individual and within-family analyses to assess the association between ADHD and ID.

    Results: Individuals with ID were at increased risk for ADHD compared to those without ID, and relatives of participants with ID were at increased risk of ADHD compared with relatives of those without ID. The magnitude of this association was positively associated with the fraction of the genome shared by the relative pair and was lower for severe compared with mild and moderate ID. Model-fitting analyses demonstrated that 91% of the correlation between the liabilities of ADHD and ID was attributable to genetic factors.

    Conclusion: These data provide evidence that nearly all of the comorbidity between ADHD and ID can be attributed to genetic factors, which has implications for diagnostic practice.

  • 5.
    Ghirardi, Laura
    et al.
    Karolinska Institutet, Stockholm, Sweden.
    Larsson, Henrik
    Örebro University, School of Medical Sciences. Karolinska Institutet, Stockholm, Sweden.
    Chang, Zheng
    Karolinska Institutet, Stockholm, Sweden.
    Chen, Qi
    School of Public Health, Indiana University, Bloomington, IN, USA.
    Quinn, Patrick D.
    School of Public Health, Indiana University, Bloomington, IN, USA.
    Hur, Kwan
    Center for Health Statistics, University of Chicago, IL, USA.
    Gibbons, Robert D.
    Center for Health Statistics, University of Chicago, IL, USA.
    D'Onofrio, Brian M.
    Karolinska Institutet, Stockholm, Sweden; Indiana University, Bloomington, IN, USA.
    Attention-Deficit/Hyperactivity Disorder Medication and Unintentional Injuries in Children and Adolescents.2019In: Journal of the American Academy of Child and Adolescent Psychiatry, ISSN 0890-8567, E-ISSN 1527-5418Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: Our objective was to determine whether ADHD medication is associated with a decreased risk of unintentional injuries in children and adolescents in the United States across sexes, age groups and injury types.

    METHOD: We used de-identified inpatient, outpatient, and filled prescription claims data from the Truven Health MarketScan® Research Databases. Individuals were followed from January 1, 2005, date of first ADHD diagnosis or medication prescription, or age 6, whichever occurred last, until December 31, 2014, first healthcare insurance disenrollment, or the first year at which their age was recorded as 19, whichever occurred first. A person was considered on ADHD medication during a given month if a prescription was filled in that month. The outcome was defined as emergency department visits for injuries, including traumatic brain injuries, with unintentional causes. Odds of having the outcome were compared between medicated and un-medicated months at the population-level and in within-individual analyses using logistic regression.

    RESULTS: Among 1 968 146 individuals diagnosed with ADHD or receiving ADHD medication, 87 154 had at least one event. At the population-level, medication use was associated a lower risk of injuries, both in boys (OR= 0.85; 95% CI: 0.84-0.86) and girls (OR=0.87; 95% CI: 0.85-0.89). Similar results were obtained from within-individual analysis among male (OR= 0.72; 95% CI: 0.70-0.74) and female (OR= 0.72; 95% CI: 0.69-0.75) children, and among male (OR= 0.64; 95% CI: 0.60-0.67) and female (OR= 0.65; 95% CI: 0.60-0.71) adolescents. Similar results were found for traumatic brain injuries.

    CONCLUSION: ADHD medication use was associated with a reduction of different types of unintentional injuries in children and adolescents of both sexes.

  • 6.
    Hultman, Christina
    et al.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Department of Neuroscience Psychiatry, Ulleråker, University of Uppsala, Sweden; Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Torrång, Anna
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Sweden .
    Tuvblad, Catherine
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Sweden .
    Cnattingius, Sven
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Sweden .
    Larsson, Jan-Olov
    Department of Child and Adolescent Psychiatry, Karolinska University Hospital, Stockholm, Sweden .
    Lichtenstein, Paul
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Sweden .
    Birth weight and attention-deficit/hyperactivity symptoms in childhood and early adolescence: a prospective Swedish twin study2007In: Journal of the American Academy of Child and Adolescent Psychiatry, ISSN 0890-8567, E-ISSN 1527-5418, Vol. 46, no 3, p. 370-377Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: To determine whether low birth weight increases the risk of attention-deficit/hyperactivity disorder (ADHD) in childhood and early adolescence.

    METHOD: In a population-based sample of 1,480 twin pairs born in the period 1985-1986 ascertained from the Swedish Twin Registry, birth weight was collected prospectively through the Medical Birth Registry. ADHD symptoms were measured with a 14-item checklist covering DSM-III-R criteria (parental rating) at age 8 to 9 years and 13 to 14 years. We used both a dichotomous approach for birth weight (>400 g or 15% weight difference) and ADHD (eight or more symptoms) and continuous measures to investigate between- and within-twin pair effects.

    RESULTS: Our results showed that low birth weight was a risk factor for symptoms of ADHD and the associations did not diminish when we controlled for genetic influence. The lighter twin in birth weight-discordant pairs had on average 13% higher ADHD symptom score at age 8 to 9 years (p = .006) and 12% higher ADHD score at age 13 to 14 years (p = .018) compared with the heavier twin. The genetic correlations suggest modest or no genetic overlap between birth weight and ADHD.

    CONCLUSIONS: The hypothesis that low birth weight is associated with the development of ADHD symptoms was supported in this prospective twin study. Fetal growth restriction seems to represent a modest but fairly consistent environmental influence on the development of ADHD symptoms.

  • 7.
    Jangmo, Andreas
    et al.
    Karolinska Institutet, Stockholm, Sweden.
    Stålhandske, Amanda
    Karolinska Institutet, Stockholm, Sweden; Child and Adolescent Clinic, Stockholm County Council, Stockholm, Sweden.
    Chang, Zheng
    Karolinska Institutet, Stockholm, Sweden.
    Chen, Qi
    Karolinska Institutet, Stockholm, Sweden.
    Almqvist, Catarina
    Karolinska Institutet, Stockholm, Sweden; Astrid Lindgren Children's Hospital, Karolinska University Hospital, Stockholm, Sweden.
    Feldman, Inna
    Uppsala University, Uppsala, Sweden.
    Bulik, Cynthia M.
    Karolinska Institutet, Stockholm, Sweden; University of North Carolina at Chapel Hill, NC, USA.
    Lichtenstein, Paul
    Karolinska Institutet, Stockholm, Sweden.
    D'Onofrio, Brian
    Karolinska Institutet, Stockholm, Sweden; Indiana University, Bloomington, IN, USA.
    Kuja-Halkola, Ralf
    Karolinska Institutet, Stockholm, Sweden.
    Larsson, Henrik
    Örebro University, School of Medical Sciences. Karolinska Institutet, Stockholm, Sweden.
    Attention-Deficit/Hyperactivity Disorder, School Performance, and Effect of Medication2019In: Journal of the American Academy of Child and Adolescent Psychiatry, ISSN 0890-8567, E-ISSN 1527-5418, Vol. 58, no 4, p. 423-432Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: Individuals with attention-deficit/hyperactivity disorder (ADHD) are at increased risk for poor school performance, and pharmacological treatment of ADHD may have beneficial effects on school performance. Conclusions from previous research have been limited by small sample sizes, outcome measures, and treatment follow-up. The current study analyzed school performance in students with ADHD compared to students without ADHD, and the association between pharmacological treatment of ADHD and school performance.

    METHOD: A linkage of Swedish national registers covering 657,720 students graduating from year 9 of compulsory school provided measures of school performance, electronically recorded dispensations of ADHD medication, and potentially confounding background factors such as parental socioeconomic status. Primary measures of school performance included student eligibility to upper secondary school and grade point sum.

    RESULTS: ADHD was associated with substantially lower school performance independent of socioeconomic background factors. Treatment with ADHD medication for 3 months was positively associated with all primary outcomes, including a decreased risk of no eligibility to upper secondary school, odds ratio = 0.80, 95% confidence interval (CI) = 0.76-0.84, and a higher grade point sum (range, 0.0-320.0) of 9.35 points, 95% CI = 7.88-10.82; standardized coefficient = 0.20.

    CONCLUSION: ADHD has a substantial negative impact on school performance, whereas pharmacological treatment for ADHD is associated with higher levels in several measures of school performance. Our findings emphasize the importance of detection and treatment of ADHD at an early stage to reduce the negative impact on school performance.

  • 8.
    Larsson, Henrik
    et al.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Lichtenstein, Paul
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Larsson, Jan-Olov
    Department of Women and Child Health, Child and Adolescent Psychiatric Unit, Karolinska Institutet, Stockholm, Sweden.
    Genetic contributions to the development of ADHD subtypes from childhood to adolescence2006In: Journal of the American Academy of Child and Adolescent Psychiatry, ISSN 0890-8567, E-ISSN 1527-5418, Vol. 45, no 8, p. 973-981Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES: Little is known about how genes influence the development of symptoms included in the DSM-IV subtypes of attention-deficit/hyperactivity disorder (ADHD) from childhood to adolescence. The aim of this study was to examine genetic influences contributing to the development of hyperactive-impulsive symptoms and inattentive symptoms of ADHD from childhood to adolescence.

    METHOD: The sample included all 1,480 twin pairs born in Sweden between May 1985 and December 1986. Parents responded to mailed questionnaires on three occasions, when the twins were 8 to 9, 13 to 14, and 16 to 17 years old. The authors used dimensional scales of hyperactivity-impulsivity and inattention derived from a checklist of items based on the DSM symptoms of ADHD.

    RESULTS: Symptoms of hyperactivity-impulsivity declined with increasing age, whereas there was no decline in symptoms of inattention. Persistent genetic influences explain between 45% and 90% of the total genetic variance in hyperactivity-impulsivity and inattention across age. Persistent genetic variance was primarily operating across subtypes, even though persistent subtype-specific influences were also significant.

    CONCLUSIONS: The finding of persistent cross-subtype (i.e., combined) and persistent subtype-specific genetic influences (i.e., primarily hyperactive-impulsive and primarily inattentive) are in line with a genetic basis for the DSM-IV classification of ADHD subtypes.

  • 9.
    Larsson, Jan-Olov
    et al.
    Department of Child and Adolescent Psychiatry, The Karolinska Hospital, 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.
    Genetic and environmental contributions to stability and change of ADHD symptoms between 8 and 13 years of age: a longitudinal twin study2004In: Journal of the American Academy of Child and Adolescent Psychiatry, ISSN 0890-8567, E-ISSN 1527-5418, Vol. 43, no 10, p. 1267-1275Article in journal (Refereed)
    Abstract [en]

    Objective: To study the genetic and environmental contributions to stability and change of attention-deficit/hyperactivity disorder (ADHD) symptoms between 8 and 9 and 13 and 14 years of age.

    Method: The sample included 1,480 twin pairs born in Sweden between May 1985 and December 1986. At wave 1 in 1994, when twins were 8-9 years old, 1,106 (75%) of the parents responded to a mailed questionnaire, and at wave 2 when the twins were 13-14 years old, 1,063 (73%) responded. A checklist with 14 items based on the 14 DSM-III-R symptoms for ADHD was completed. Structural equation modeling was used to analyze the data.

    Results: A relatively high stability of ADHD symptoms over this 5-year period was found. This continuity was mainly due to the same genetic effects operating at both points in time. Change in symptoms between childhood and early adolescence was to a large extent due to new genetic effects in early adolescence but also due to new nonshared environmental effects that became important during adolescence.

    Conclusions: The genetic stability highlights the importance of the continuing search for genes and endophenotypes of ADHD.

  • 10.
    Merwood, Andrew
    et al.
    Medical Research Council (MRC) Social Genetic and Developmental Psychiatry Centre, King's College London, London, UK; University of Bath, Bath, UK.
    Chen, Wai
    Medical Research Council (MRC) Social Genetic and Developmental Psychiatry Centre, King's College London, London, UK; Division of Clinical Neuroscience, School of Medicine, University of Southampton, Southampton, UK.
    Rijsdijk, Fruhling
    Medical Research Council (MRC) Social Genetic and Developmental Psychiatry Centre, King's College London, London, UK.
    Skirrow, Caroline
    Developmental Cognitive Neuroscience Unit at the Institute of Child Health, University College London, London, UK.
    Larsson, Henrik
    Karolinska Institutet, Stockholm, Sweden.
    Thapar, Anita
    Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, UK; MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, UK.
    Kuntsi, Jonna
    Medical Research Council (MRC) Social Genetic and Developmental Psychiatry Centre, King's College London, London, UK.
    Asherson, Philip
    Medical Research Council (MRC) Social Genetic and Developmental Psychiatry Centre, King's College London, London, UK.
    Genetic associations between the symptoms of attention-deficit/hyperactivity disorder and emotional lability in child and adolescent twins2014In: Journal of the American Academy of Child and Adolescent Psychiatry, ISSN 0890-8567, E-ISSN 1527-5418, Vol. 53, no 2, p. 209-224.e4Article in journal (Refereed)
    Abstract [en]

    Objective: Emotional lability is recognized as an associated feature of attention-deficit/hyperactivity disorder (ADHD). However, the degree of phenotypic and etiologic overlap between emotional lability and the ADHD dimensions of hyperactivity-impulsivity and inattention remains unclear. The present study examines these associations in a large, community twin sample.

    Method: Structural equation models were fit to data from 1,920 child and adolescent twin pairs (age range, 5-18 years). Symptoms of hyperactivity-impulsivity (HI) and inattention (IA) were assessed using a modified version of the DuPaul rating scale, completed by parents. Symptoms of emotional lability (EL) were assessed using the parent-rated Conners 10-item scale.

    Results: There were moderate to strong phenotypic correlations between HI, IA, and EL. Multivariate twin modeling revealed that a common pathway model best accounted for the covariance among these dimensions, represented by a highly heritable latent factor. Ad hoc analyses confirmed that all additive genetic influences on HI, IA, and EL were shared, and identified a significantly stronger association of EL with the latent ADHD factor in older than in younger individuals.

    Conclusions: Emotional lability was phenotypically and genetically associated with hyperactivity-impulsivity and inattention in children and adolescents. The finding that a single, heritable, latent factor accounted for covariation among these phenotypes indicates that their co-occurrence is primarily the result of overlapping genetic effects. These data support the hypothesis that emotional lability is etiologically relevant to the core ADHD phenotype, and that it should be targeted in assessment and treatment in clinical practice.

  • 11.
    Ottosen, Cæcilie
    et al.
    National Centre for Register-based Research, School of Business and Social Sciences, Aarhus University, Aarhus, Denmark; The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Aarhus, Denmark; Centre for Integrated Register-based Research at Aarhus University (CIRRAU), Aarhus, Denmark.
    Larsen, Janne Tidselbak
    National Centre for Register-based Research, School of Business and Social Sciences, Aarhus University, Aarhus, Denmark; The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Aarhus, Denmark; Centre for Integrated Register-based Research at Aarhus University (CIRRAU), Aarhus, Denmark.
    Faraone, Stephen V
    SUNY Upstate Medical University, Syracuse, NY, and the K.G. Jebsen Centre for Research on Neuropsychiatric Disorders, University of Bergen, Norway.
    Chen, Qi
    Karolinska Institutet, Stockholm, Sweden.
    Hartman, Catharina
    University of Groningen, The Netherlands.
    Larsson, Henrik
    Örebro University, School of Medical Sciences. Karolinska Institutet, Stockholm, Sweden.
    Petersen, Liselotte
    National Centre for Register-based Research, School of Business and Social Sciences, Aarhus University, Aarhus, Denmark; The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Aarhus, Denmark; Centre for Integrated Register-based Research at Aarhus University (CIRRAU), Aarhus, Denmark.
    Dalsgaard, Søren
    National Centre for Register-based Research, School of Business and Social Sciences, Aarhus University, Aarhus, Denmark; The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Aarhus, Denmark; Hospital of Telemark, Kragerø, Norway.
    Sex Differences in Comorbidity Patterns of Attention-Deficit/Hyperactivity Disorder2019In: Journal of the American Academy of Child and Adolescent Psychiatry, ISSN 0890-8567, E-ISSN 1527-5418, Vol. 58, no 4, p. 412-422.e3Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: To investigate sex differences in associations between attention-deficit/hyperactivity disorder (ADHD) and a spectrum of comorbid disorders.

    METHOD: The study population included all children born in Denmark from 1981 through 2013 (N = 1,665,729). Data were merged from Danish registers and information was obtained on birth characteristics, socioeconomic status, familial psychiatric history, and diagnoses of ADHD (n = 32,308) and comorbid disorders. To estimate absolute and relative risks of comorbid disorders, incidence rates and adjusted hazard ratios (HRs) with 95% CIs were calculated for female and male individuals. In addition, interactions between ADHD and sex in association with comorbid disorders were estimated as HR ratios (HRRs) in female and male individuals (95% CIs).

    RESULTS: Individuals diagnosed with ADHD had significantly increased absolute and relative risks of all 12 comorbid psychiatric disorders investigated. ADHD-sex interactions were found for some comorbid disorders. Compared with male individuals, ADHD in female individuals showed a stronger association with autism spectrum disorder (HRR 1.86, 95% CI 1.62-2.14), oppositional defiant/conduct disorder (HRR 1.97, 95% CI 1.68-2.30), intellectual disability (HRR 1.79, 95% CI 1.54-2.09), personality disorders (HRR 1.23, 95% CI 1.06-1.43), schizophrenia (HRR 1.21, 95% CI 1.02-1.43), substance use disorders (HRR 1.21, 95% CI 1.07-1.38), and suicidal behavior (1.28, 95% CI 1.12-1.47). The remaining disorders showed no significant sex differences in association with ADHD.

    CONCLUSION: This study indicates that the association between ADHD and several comorbid disorders is stronger in female than in male individuals. These important findings add to the literature on sex differences in ADHD and suggest that female individuals diagnosed with ADHD are a more vulnerable group of patients.

  • 12.
    Pettersson, Erik
    et al.
    Karolinska Institutet, Stockholm, Sweden.
    Lahey, Benjamin B.
    University of Chicago, Chicago IL, USA.
    Larsson, Henrik
    Örebro University, School of Medical Sciences. Karolinska Institutet, Stockholm, Sweden.
    Lichtenstein, Paul
    Karolinska Institutet, Stockholm, Sweden.
    Criterion Validity and Utility of the General Factor of Psychopathology in Childhood: Predictive Associations With Independently Measured Severe Adverse Mental Health Outcomes in Adolescence2018In: Journal of the American Academy of Child and Adolescent Psychiatry, ISSN 0890-8567, E-ISSN 1527-5418, Vol. 57, no 6, p. 372-383Article in journal (Refereed)
    Abstract [en]

    Objective: We examined whether a parent-rated general factor of psychopathology in childhood would predict independently measured, severe adverse mental health outcomes in adolescence.

    Method: We used the Child and Adolescent Twin Study in Sweden, which targets all twin children in Sweden. Parents rated their children (N = 16,806) on 43 symptoms of inattention, hyperactivity/impulsivity, conduct problems, and anxiety/emotionality when the twins turned 9 or 12 years of age. Adverse mental health outcomes in adolescence were retrieved from national registers, and included psychiatric diagnoses, prescription of anxiolytic or antidepressant medication, court convictions of crimes, and failure to achieve eligibility for high school.

    Results: Parent-rated inattention, hyperactivity/impulsivity, conduct problems, and anxiety/emotionality in childhood predicted all adverse mental health outcomes in adolescence (mean odds ratio = 1.76; range = 1.41-2.18; all p <.05). However, several of these associations were nonsignificant in a multiple regression framework, suggesting the influence of common variance. A general factor of psychopathology uniquely predicted all outcomes (mean odds ratio = 1.58; range = 1.34-1.84; all p <.05), whereas the specific factors predicted only a subset of the outcomes.

    Conclusion: Mental health problems in childhood are associated with a host of adverse outcomes in adolescence, and, to a considerable extent, these associations are driven by a general factor of psychopathology. The general factor may therefore be important to clinical prognosis, which informs clinical decision making for children.

  • 13.
    Rommel, Anna-Sophie
    et al.
    Medical Research Council Social, Genetic and Developmental Psychiatry Centre, at the Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, UK.
    Lichtenstein, Paul
    Karolinska Institutet, Stockholm, Sweden.
    Rydell, Mina
    Karolinska Institutet, Stockholm, Sweden.
    Kuja-Halkola, Ralf
    Karolinska Institutet, Stockholm, Sweden.
    Asherson, Philip
    Medical Research Council Social, Genetic and Developmental Psychiatry Centre, at the Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, UK.
    Kuntsi, Jonna
    Medical Research Council Social, Genetic and Developmental Psychiatry Centre, at the Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, UK.
    Larsson, Henrik
    Karolinska Institutet, Stockholm, Sweden.
    Is Physical Activity Causally Associated With Symptoms of Attention-Deficit/Hyperactivity Disorder?2015In: Journal of the American Academy of Child and Adolescent Psychiatry, ISSN 0890-8567, E-ISSN 1527-5418, Vol. 54, no 7, p. 565-570Article in journal (Refereed)
    Abstract [en]

    Objective: Emerging evidence suggests that physical activity (PA) enhances cognition and may be a protective factor for attention-deficit/hyperactivity disorder (ADHD). Yet the impact of PA on ADHD symptoms has been investigated only in a few undersized, nonrandomized, and retrospective studies. We examined the effect of PA during late adolescence on ADHD symptoms in early adulthood while controlling for unmeasured genetic and shared environmental confounding.

    Method: The effect of PA at age 16 to 17 years (baseline) on ADHD symptoms at age 19 to 20 years (follow-up) was examined using a within-monozygotic (MZ) twins fixed-effects model in 232 MZ twin pairs born in Sweden between May 1985 and December 1986. Parents rated their children's DSM ADHD symptoms at baseline and follow-up. Participants' weekly energy expenditure (in metabolic equivalent task minutes per week) was based on self-reports at baseline of PA frequency, intensity, and duration.

    Results: Greater weekly energy expenditure in adolescence was significantly associated with reduced ADHD symptom levels in early adulthood, even when controlling for unmeasured confounding (all genetic and environmental factors shared within MZ twin pairs) as well as ADHD symptoms and body mass index (BMI) at baseline, β = -0.21, p = .013 (95% CI = -0.38 to -0.05). Similar results were observed for the 2 ADHD subcomponents: hyperactivity/impulsivity, β = -0.21, p = .022 (95% CI = -0.39 to -0.03), and inattention, β = -0.19, p = .049 (95% CI = -0.36 to -0.0005).

    Conclusion: In line with a causal hypothesis, PA was inversely associated with ADHD symptoms, even after adjusting for unmeasured confounding. These findings suggest that PA in adolescence might decrease ADHD symptoms in early adulthood. However, given the size of the effect, the clinical value of this intervention needs to be explored further.

  • 14.
    Taylor, Mark J.
    et al.
    Karolinska Institutet, Stockholm, Sweden.
    Gustafsson, Peik
    Child and Adolescent Psychiatry, Lund University, Lund, Sweden.
    Larsson, Henrik
    Örebro University, School of Medical Sciences. Karolinska Institutet, Stockholm, Sweden.
    Gillberg, Christopher
    Gillberg Neuropsychiatry Centre, University of Gothenburg, Gothenburg, Sweden.
    Lundström, Sebastian
    Gillberg Neuropsychiatry Centre, University of Gothenburg, Gothenburg, Sweden; Sweden Centre for Ethics, Law and Mental Health, University of Gothenburg, Gothenburg, Sweden.
    Lichstenstein, Paul
    Karolinska Institutet, Stockholm, Sweden.
    Examining the Association Between Autistic Traits and Atypical Sensory Reactivity: A Twin Study2018In: Journal of the American Academy of Child and Adolescent Psychiatry, ISSN 0890-8567, E-ISSN 1527-5418, Vol. 57, no 2, p. 96-102Article in journal (Refereed)
    Abstract [en]

    Objective: Atypical responses to sensory stimuli are common features of autism spectrum disorders (ASD). Consequently, atypical sensory reactivity (SR) is now a diagnostic feature of ASD. Quantitative genetic research on ASD has overlooked these symptoms, however. We therefore investigated the association between autistic traits and SR using twin methods.

    Method: Autistic traits and SR were assessed by 2 separate scales in 12,419 Swedish twin pairs (n = 3,586 monozygotic [MZ], n = 8,833 dizygotic [DZ]) when the twins were 9 or 12 years of age. The classic twin design estimated the degree to which etiological factors associated with autistic traits were also associated with SR, and the degree to which such shared factors explained the covariance between these phenotypes. DeFries Fulker analysis estimated the genetic correlation between screening diagnoses of ASD, defined broadly and strictly, and SR.

    Results: Autistic traits and SR were both highly heritable (62%-75% and 66%-71%, respectively). There was a moderate phenotypic correlation between autistic traits and SR (r = 0.47). Genetic influences on these phenotypes correlated moderately (genetic correlation = 0.60). These overlapping genetic factors explained most of the correlation between autistic traits and SR. Genetic correlations with SR increased for broad ASD (genetic correlation = 0.72) and strict ASD (genetic correlation = 0.80).

    Conclusion: The genetic overlap observed between autistic traits and SR lends quantitative genetic support to the notion that ASD and SR are strongly linked. Stich symptoms may thus comprise part of the ASD genotype, as well as phenotype. Associations persisted across all definitions of ASD, indicating a genetic link between the broader ASD phenotype and SR.

  • 15.
    Taylor, Mark J.
    et al.
    Karolinska Institutet, Stockholm, Sweden.
    Lichtenstein, Paul
    Karolinska Institutet, Stockholm, Sweden.
    Larsson, Henrik
    Karolinska Institutet, Stockholm, Sweden.
    Anckarsäter, Henrik
    Centre for Ethics, Law and Mental Health (CELAM), University of Gothenburg, Gothenburg, Sweden.
    Greven, Corina U.
    Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands; Karakter Child and Adolescent Psychiatry Center, Nijmegen, The Netherlands; Medical Research Council Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
    Ronald, Angelica
    Centre for Brain and Cognitive Development Birkbeck, University of London, London, UK.
    Is There a Female Protective Effect Against Attention-Deficit/Hyperactivity Disorder? Evidence From Two Representative Twin Samples2016In: Journal of the American Academy of Child and Adolescent Psychiatry, ISSN 0890-8567, E-ISSN 1527-5418, Vol. 55, no 6, p. 504-512Article in journal (Refereed)
    Abstract [en]

    Objective: Attention-deficit/hyperactivity disorder (ADHD) is more frequent in males than in females. The "female protective effect" posits that females undergo greater exposure to etiological factors than males in order to develop ADHD, leading to the prediction that relatives of females with ADHD will display more ADHD behaviors. We thus tested whether cotwins of females displaying extreme ADHD traits would display more ADHD traits than cotwins of males displaying extreme ADHD traits.

    Method: Parents of approximately 7,000 pairs of nonidentical twins in Sweden, and approximately 4,000 pairs of twins in England and Wales, completed dimensional assessments of ADHD traits. Probands were selected on the basis of scoring within the highest 10% of the distribution in each sample. Dimensional scores of cotwins of probands, as well as the categorical recurrence rate, were investigated by proband sex.

    Results: Cotwins of female probands displayed higher mean ADHD trait scores (mean = 0.62-0.79) than cotwins of male probands (mean = 0.38-0.55) in both samples. This trend was significant in the Swedish sample (p < .01) and when the 2 samples were merged into a single, larger sample (p < .001). When the samples were merged, there was also a significant association between proband sex and cotwin's categorical status, with more cotwins of female probands also being probands than cotwins of male probands.

    Conclusion: These findings support a female protective effect against ADHD behaviors, suggesting that females require greater exposure to genetic and environmental factors associated with ADHD in order to develop the condition.

  • 16.
    Younan, Diana
    et al.
    Keck School of Medicine of the University of Southern California, Los Angeles, USA.
    Tuvblad, Catherine
    Örebro University, School of Law, Psychology and Social Work. Dornsife College of Letters, Arts, and Sciences, University of Southern California, Los Angeles, USA.
    Li, Lianfa
    Keck School of Medicine of the University of Southern California, Los Angeles, USA.
    Wu, Jun
    Program in Public Health, Irvine College of Health Sciences, University of California, Irvine, USA.
    Lurmann, Fred
    Sonoma Technology Inc., Petaluma, USA.
    Franklin, Meredith
    Keck School of Medicine, University of Southern California, Los Angeles, USA.
    Berhane, Kiros
    Keck School of Medicine, University of Southern California, Los Angeles, USA.
    McConnell, Rob
    Keck School of Medicine, University of Southern California, Los Angeles, USA.
    Wu, Anna H.
    Keck School of Medicine, University of Southern California, Los Angeles, USA.
    Baker, Laura A.
    Dornsife College of Letters, Arts, and Sciences, University of Southern California, Los Angeles, USA.
    Chen, Jiu-Chiuan
    Keck School of Medicine, University of Southern California, Los Angeles, USA.
    Environmental Determinants of Aggression in Adolescents: Role of Urban Neighborhood Greenspace2016In: Journal of the American Academy of Child and Adolescent Psychiatry, ISSN 0890-8567, E-ISSN 1527-5418, Vol. 55, no 7, p. 591-601Article in journal (Refereed)
    Abstract [en]

    Objective: Neighborhood greenspace improves mental health of urban-dwelling populations, but its putative neurobehavioral benefits in adolescents remain unclear. We conducted a prospective study on urban-dwelling adolescents to examine the association between greenspace in residential neighborhood and aggressive behaviors.

    Method: Participants (n = 1,287) of the Risk Factors for Antisocial Behavior Study, a multi-ethnic cohort of twins and triplets born in 1990 to 1995 and living in Southern California, were examined in 2000 to 2012 (aged 9-18 years) with repeated assessments of their aggressive behaviors by the parent-reported Child Behavior Checklist. Normalized Difference Vegetation Index (NDVI) derived from satellite imagery was used as a proxy for residential neighborhood greenspace aggregated over various spatiotemporal scales before each assessment. Multilevel mixed-effects models were used to estimate the effects of greenspace on aggressive behaviors, adjusting for within-family/within-individual correlations and other potential confounders.

    Results: Both short-term (1- to 6-month) and long-term (1- to 3-year) exposures to greenspace within 1,000 meters surrounding residences were associated with reduced aggressive behaviors. The benefit of increasing vegetation over the range (∼0.12 in NDVI) commonly seen in urban environments was equivalent to approximately 2 to 2.5 years of behavioral maturation. Sociodemographic factors (e.g., age, gender, race/ethnicity, and socioeconomic status) and neighborhood quality did not confound or modify these associations, and the benefits remained after accounting for temperature.

    Conclusion: Our novel findings support the benefits of neighborhood greenspace in reducing aggressive behaviors of urban-dwelling adolescents. Community-based interventions are needed to determine the efficacy of greenspace as a preemptive strategy to reduce aggressive behaviors in urban environments.

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