title: 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.
authors.affiliation: MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University School of Medicine, Cardiff, UK.
authors.forename: Marian L
authors.initials: ML
authors.lastname: Hamshere
authors.forename: Kate
authors.initials: K
authors.lastname: Langley
authors.forename: Joanna
authors.initials: J
authors.lastname: Martin
authors.forename: Sharifah Shameem
authors.initials: SS
authors.lastname: Agha
authors.forename: Evangelia
authors.initials: E
authors.lastname: Stergiakouli
authors.forename: Richard J L
authors.initials: RJ
authors.lastname: Anney
authors.forename: Jan
authors.initials: J
authors.lastname: Buitelaar
authors.forename: Stephen V
authors.initials: SV
authors.lastname: Faraone
authors.forename: Klaus-Peter
authors.initials: KP
authors.lastname: Lesch
authors.forename: Benjamin M
authors.initials: BM
authors.lastname: Neale
authors.forename: Barbara
authors.initials: B
authors.lastname: Franke
authors.forename: Edmund
authors.initials: E
authors.lastname: Sonuga-Barke
authors.forename: Philip
authors.initials: P
authors.lastname: Asherson
authors.forename: Andrew
authors.initials: A
authors.lastname: Merwood
authors.forename: Jonna
authors.initials: J
authors.lastname: Kuntsi
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Medland
authors.forename: Stephan
authors.initials: S
authors.lastname: Ripke
authors.forename: Hans-Christoph
authors.initials: HC
authors.lastname: Steinhausen
authors.forename: Christine
authors.initials: C
authors.lastname: Freitag
authors.forename: Andreas
authors.initials: A
authors.lastname: Reif
authors.forename: Tobias J
authors.initials: TJ
authors.lastname: Renner
authors.forename: Marcel
authors.initials: M
authors.lastname: Romanos
authors.forename: Jasmin
authors.initials: J
authors.lastname: Romanos
authors.forename: Andreas
authors.initials: A
authors.lastname: Warnke
authors.forename: Jobst
authors.initials: J
authors.lastname: Meyer
authors.forename: Haukur
authors.initials: H
authors.lastname: Palmason
authors.forename: Alejandro Arias
authors.initials: AA
authors.lastname: Vasquez
authors.forename: Nanda
authors.initials: N
authors.lastname: Lambregts-Rommelse
authors.forename: Herbert
authors.initials: H
authors.lastname: Roeyers
authors.forename: Joseph
authors.initials: J
authors.lastname: Biederman
authors.forename: Alysa E
authors.initials: AE
authors.lastname: Doyle
authors.forename: Hakon
authors.initials: H
authors.lastname: Hakonarson
authors.forename: Aribert
authors.initials: A
authors.lastname: Rothenberger
authors.forename: Tobias
authors.initials: T
authors.lastname: Banaschewski
authors.forename: Robert D
authors.initials: RD
authors.lastname: Oades
authors.forename: James J
authors.initials: JJ
authors.lastname: McGough
authors.forename: Lindsey
authors.initials: L
authors.lastname: Kent
authors.forename: Nigel
authors.initials: N
authors.lastname: Williams
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Owen
authors.forename: Peter
authors.initials: P
authors.lastname: Holmans
authors.forename: Michael C
authors.initials: MC
authors.lastname: O'Donovan
authors.forename: Anita
authors.initials: A
authors.lastname: Thapar
mesh_terms: D000374:Aggression / Q000523:psychology*; D001008:Anxiety Disorders / Q000175:diagnosis / Q000235:genetics / Q000523:psychology; D001289:Attention Deficit Disorder with Hyperactivity / Q000175:diagnosis / Q000235:genetics* / Q000523:psychology; D002648:Child; D002675:Child, Preschool; D015897:Comorbidity; D019955:Conduct Disorder / Q000175:diagnosis / Q000235:genetics* / Q000523:psychology; D003866:Depressive Disorder / Q000175:diagnosis / Q000235:genetics / Q000523:psychology; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D014644:Genetic Variation / Q000235:genetics; D006801:Humans; D008297:Male; D020412:Multifactorial Inheritance / Q000235:genetics*; D006113:United Kingdom