title: Psychiatric gene discoveries shape evidence on ADHD's biology.
abstract: A strong motivation for undertaking psychiatric gene discovery studies is to provide novel insights into unknown biology. Although attention-deficit hyperactivity disorder (ADHD) is highly heritable, and large, rare copy number variants (CNVs) contribute to risk, little is known about its pathogenesis and it remains commonly misunderstood. We assembled and pooled five ADHD and control CNV data sets from the United Kingdom, Ireland, United States of America, Northern Europe and Canada. Our aim was to test for enrichment of neurodevelopmental gene sets, implicated by recent exome-sequencing studies of (a) schizophrenia and (b) autism as a means of testing the hypothesis that common pathogenic mechanisms underlie ADHD and these other neurodevelopmental disorders. We also undertook hypothesis-free testing of all biological pathways. We observed significant enrichment of individual genes previously found to harbour schizophrenia de novo non-synonymous single-nucleotide variants (SNVs; P=5.4 × 10(-4)) and targets of the Fragile X mental retardation protein (P=0.0018). No enrichment was observed for activity-regulated cytoskeleton-associated protein (P=0.23) or N-methyl-D-aspartate receptor (P=0.74) post-synaptic signalling gene sets previously implicated in schizophrenia. Enrichment of ADHD CNV hits for genes impacted by autism de novo SNVs (P=0.019 for non-synonymous SNV genes) did not survive Bonferroni correction. Hypothesis-free testing yielded several highly significantly enriched biological pathways, including ion channel pathways. Enrichment findings were robust to multiple testing corrections and to sensitivity analyses that excluded the most significant sample. The findings reveal that CNVs in ADHD converge on biologically meaningful gene clusters, including ones now established as conferring risk of other neurodevelopmental disorders.
authors.affiliation: Institute of Psychological Medicine and Clinical Neurosciences and MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University School of Medicine, Cardiff, UK.
authors.forename: A
authors.initials: A
authors.lastname: Thapar
authors.affiliation: Institute of Psychological Medicine and Clinical Neurosciences and MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University School of Medicine, Cardiff, UK.
authors.forename: J
authors.initials: J
authors.lastname: Martin
authors.affiliation: Department of Quantitative Health Sciences, Department of Psychiatry, University of Massachusetts Medical School, Worcester, MA, USA.|Department of Psychiatry, University of Massachusetts Medical School, Worcester, MA, USA.
authors.forename: E
authors.initials: E
authors.lastname: Mick
authors.affiliation: Radboud University Medical Center, Donders Institute for Brain, Cognition and Behaviour, Departments of Psychiatry and Human Genetics, Nijmegen, The Netherlands.|Radboud University Medical Center, Donders Institute for Brain, Cognition and Behaviour, Department of Cognitive Neuroscience, Nijmegen, The Netherlands.
authors.forename: A
authors.initials: A
authors.lastname: Arias Vásquez
authors.affiliation: Institute of Psychological Medicine and Clinical Neurosciences and MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University School of Medicine, Cardiff, UK.|School of Psychology, Cardiff University, Cardiff, UK.
authors.forename: K
authors.initials: K
authors.lastname: Langley
authors.affiliation: Centre for Applied Genomics, Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: S W
authors.initials: SW
authors.lastname: Scherer
authors.affiliation: Department of Psychiatry, Neurosciences and Mental Health, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.
authors.forename: R
authors.initials: R
authors.lastname: Schachar
authors.affiliation: Department of Psychiatry, Neurosciences and Mental Health, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.
authors.forename: J
authors.initials: J
authors.lastname: Crosbie
authors.affiliation: Institute of Psychological Medicine and Clinical Neurosciences and MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University School of Medicine, Cardiff, UK.
authors.forename: N
authors.initials: N
authors.lastname: Williams
authors.affiliation: Radboud University Medical Center, Donders Institute for Brain, Cognition and Behaviour, Departments of Psychiatry and Human Genetics, Nijmegen, The Netherlands.
authors.forename: B
authors.initials: B
authors.lastname: Franke
authors.affiliation: Department of Pediatrics and Psychiatry, Sidney Kimmel College of Medicine, Thomas Jefferson University, Philadelphia, PA, USA.|Nemours Neuroscience Center, Wilmington, DE, USA.|Department of Psychiatry, University of Pennsylvania, Pennsylvania, PA, USA.
authors.forename: J
authors.initials: J
authors.lastname: Elia
authors.affiliation: Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA, USA.
authors.forename: J
authors.initials: J
authors.lastname: Glessner
authors.affiliation: Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
authors.forename: H
authors.initials: H
authors.lastname: Hakonarson
authors.affiliation: Institute of Psychological Medicine and Clinical Neurosciences and MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University School of Medicine, Cardiff, UK.
authors.forename: M J
authors.initials: MJ
authors.lastname: Owen
authors.affiliation: Departments of Psychiatry and of Neuroscience and Physiology, SUNY Upstate Medical University, Syracuse, NY, USA.|K.G. Jebsen Centre for Research on Neuropsychiatric Disorders, University of Bergen, Bergen, Norway.
authors.forename: S V
authors.initials: SV
authors.lastname: Faraone
authors.affiliation: Institute of Psychological Medicine and Clinical Neurosciences and MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University School of Medicine, Cardiff, UK.
authors.forename: M C
authors.initials: MC
authors.lastname: O'Donovan
authors.affiliation: Institute of Psychological Medicine and Clinical Neurosciences and MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University School of Medicine, Cardiff, UK.
authors.forename: P
authors.initials: P
authors.lastname: Holmans
mesh_terms: D000293:Adolescent; D001289:Attention Deficit Disorder with Hyperactivity / Q000235:genetics*; D001321:Autistic Disorder / Q000235:genetics; D001689:Biological Psychiatry / Q000379:methods*; D002170:Canada; D002648:Child; D002675:Child, Preschool; D056915:DNA Copy Number Variations / Q000235:genetics; D030561:Databases, Nucleic Acid; D005060:Europe; D005260:Female; D056726:Genetic Association Studies / Q000379:methods; D020022:Genetic Predisposition to Disease / Q000235:genetics; D055106:Genome-Wide Association Study; D006801:Humans; D007494:Ireland; D008297:Male; D065886:Neurodevelopmental Disorders / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012559:Schizophrenia / Q000235:genetics; D006113:United Kingdom