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High loading of polygenic risk for ADHD in children with comorbid aggression.

ABSTRACT: 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.

SUBMITTER: Hamshere ML

PROVIDER: S-EPMC3935265 | biostudies-literature | 2013 Aug

REPOSITORIES: biostudies-literature

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High loading of polygenic risk for ADHD in children with comorbid aggression.

Hamshere Marian L ML Langley Kate K Martin Joanna J Agha Sharifah Shameem SS Stergiakouli Evangelia E Anney Richard J L RJ Buitelaar Jan J Faraone Stephen V SV Lesch Klaus-Peter KP Neale Benjamin M BM Franke Barbara B Sonuga-Barke Edmund E Asherson Philip P Merwood Andrew A Kuntsi Jonna J Medland Sarah E SE Ripke Stephan S Steinhausen Hans-Christoph HC Freitag Christine C Reif Andreas A Renner Tobias J TJ Romanos Marcel M Romanos Jasmin J Warnke Andreas A Meyer Jobst J Palmason Haukur H Vasquez Alejandro Arias AA Lambregts-Rommelse Nanda N Roeyers Herbert H Biederman Joseph J Doyle Alysa E AE Hakonarson Hakon H Rothenberger Aribert A Banaschewski Tobias T Oades Robert D RD McGough James J JJ Kent Lindsey L Williams Nigel N Owen Michael J MJ Holmans Peter P O'Donovan Michael C MC Thapar Anita A

The American journal of psychiatry 20130801 8

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 disorde ...[more]

PMID: 23599091

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Project description:Many psychiatric disorders are associated with impaired executive functioning (EF). The associated EF component varies by psychiatric disorders, and this variation might be due to genetic liability. We explored the genetic association between five psychiatric disorders and EF in clinically-recruited attention deficit hyperactivity disorder (ADHD) children using polygenic risk score (PRS) methodology. Genome-wide association study (GWAS) summary data for ADHD, major depressive disorder (MDD), schizophrenia (SZ), bipolar disorder (BIP) and autism were used to calculate the PRSs. EF was evaluated by the Stroop test for inhibitory control, the trail-making test for cognitive flexibility, and the digital span test for working memory in a Chinese ADHD cohort (n?=?1147). Exploratory factor analysis of the three measures identified one principal component for EF (EF-PC). Linear regression models were used to analyze the association between each PRS and the EF measures. The role of EF measures in mediating the effects of the PRSs on ADHD symptoms was also analyzed. The result showed the PRSs for MDD, ADHD and BIP were all significantly associated with the EF-PC. For each EF component, the association results were different for the PRSs of the five psychiatric disorders: the PRSs for ADHD and MDD were associated with inhibitory control (adjusted P?=?0.0183 and 0.0313, respectively), the PRS for BIP was associated with working memory (adjusted P?=?0.0416), and the PRS for SZ was associated with cognitive flexibility (adjusted P?=?0.0335). All three EF measures were significantly correlated with ADHD symptoms. In mediation analyses, the ADHD and MDD PRSs, which were associated with inhibitory control, had significant indirect effects on ADHD symptoms through the mediation of inhibitory control. These findings indicate that the polygenic risks for several psychiatric disorders influence specific executive dysfunction in children with ADHD. The results helped to clarify the relationship between risk genes of each mental disorder and the intermediate cognitive domain, which may further help elucidate the risk genes and motivate efforts to develop EF measures as a diagnostic marker and future treatment target.

Dataset Information

High loading of polygenic risk for ADHD in children with comorbid aggression.

Publications

High loading of polygenic risk for ADHD in children with comorbid aggression.

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