High Loading of Polygenic Risk for ADHD in Children With Comorbid Aggression

• DOI: 10.1176/appi.ajp.2013.12081129
• Publication Date: 2013-07-04T01:33:34Z
• Authors: Marian L. Hamshere; Kate Langley; Joanna Martin; Sharifah Shameem ...; Evangelia Stergia...; Richard J.L. Anney; Jan Buitelaar; Stephen V. Faraone; Klaus-Peter Lesch; Benjamin M. Neale; Barbara Franke; Edmund Sonuga-Barke; Philip Asherson; Andrew Merwood; Jonna Kuntsi; Sarah E. Medland; Stephan Ripke; Hans-Christoph St...; Christine Freitag; Andreas Reif; Tobias J. Renner; Marcel Romanos; Jasmin Romanos; Andreas Warnke; Jobst Meyer; Haukur Palmason; Alejandro Arias V...; Nanda Lambregts-R...; Herbert Roeyers; Joseph Biederman; Alysa E. Doyle; Hakon Hakonarson; Aribert Rothenberger; Tobias Banaschewski; Robert D. Oades; James J. McGough; Lindsey Kent; Nigel Williams; Michael J. Owen; Peter Holmans; Michael C. O’Donovan; Anita Thapar
• Keywords: Male; Multifactorial Inheritance; SYMPTOMS; 150; Medizin; Social Sciences; Comorbidity; Medical and Health Sciences; ddc:61; Psychosomatik und Psychotherapie des Kindes- und Jugendalters; 2738 Psychiatry and Mental Health; 0302 clinical medicine; 10058 Child and Adolescent Psychiatry; 2.1 Biological and endogenous factors; Aetiology; Child; 10. No inequality; Pediatric; Psychiatry; ddc:610; ATTENTION-DEFICIT/HYPERACTIVITY DISORDER; Great Britain; Articles; ANTISOCIAL-BEHAVIOR; New Research; Anxiety Disorders; Aggression; Mental Health; Child, Preschool; Mental health; Female; DCN PAC - Perception action and control IGMD 3: Genomic disorders and inherited multi-system disorders; Conduct Disorder; 61; GENETIC-BASIS; 610; 610 Medicine & health; 03 medical and health sciences; Clinical Research; 2738 Psychiatry and Mental health; Behavioral and Social Science; Genetics; ddc:61; Humans; Genetic Predisposition to Disease; ddc:610; Medizinische Fakultät » Universitätsklinikum Essen » LVR-Klinikum Essen » Klinik für Psychiatrie, Psychosomatik und Psychotherapie des Kindes- und Jugendalters; DCN PAC - Perception action and control NCEBP 9 - Mental health; GENOME-WIDE ASSOCIATION; AUTISM; IGMD 3: Genomic disorders and inherited multi-system disorders DCN MP - Plasticity and memory; Preschool; DEFICIT-HYPERACTIVITY-DISORDER; Depressive Disorder; Medizinische Fakultät » Universitätsklinikum Essen » LVR-Klinikum Essen » Klinik für Psychiatrie; Prevention; Human Genome; Psychology and Cognitive Sciences; Genetic Variation; OPPOSITIONAL DEFIANT; Attention Deficit Hyperactivity Disorder (ADHD); United Kingdom; Brain Disorders; DE-NOVO MUTATIONS; Attention Deficit Disorder with Hyperactivity; CONDUCT DISORDER

OBJECTIVE Although attention deficit hyperactivity disorder (ADHD) is highly heritable, genome-wide association studies (GWAS) have not yet identified any common genetic variants that contribute to risk. There is evidence that aggression or conduct disorder in children with ADHD indexes higher genetic loading and clinical severity. The authors examine whether common genetic variants considered en masse as polygenic scores for ADHD are especially enriched in children with comorbid conduct disorder. METHOD Polygenic scores derived from an ADHD GWAS meta-analysis were calculated in an independent ADHD sample (452 case subjects, 5,081 comparison subjects). Multivariate logistic regression analyses were employed to compare polygenic scores in the ADHD and comparison groups and test for higher scores in ADHD case subjects with comorbid conduct disorder relative to comparison subjects and relative to those without comorbid conduct disorder. Association with symptom scores was tested using linear regression. RESULTS Polygenic risk for ADHD, derived from the meta-analysis, was higher in the independent ADHD group than in the comparison group. Polygenic score was significantly higher in ADHD case subjects with conduct disorder relative to ADHD case subjects without conduct disorder. ADHD polygenic score showed significant association with comorbid conduct disorder symptoms. This relationship was explained by the aggression items. CONCLUSIONS Common genetic variation is relevant to ADHD, especially in individuals with comorbid aggression. The findings suggest that the previously published ADHD GWAS meta-analysis contains weak but true associations with common variants, support for which falls below genome-wide significance levels. The findings also highlight the fact that aggression in ADHD indexes genetic as well as clinical severity.