title: Rare copy number variation discovery and cross-disorder comparisons identify risk genes for ADHD.
abstract: Attention deficit hyperactivity disorder (ADHD) is a common and persistent condition characterized by developmentally atypical and impairing inattention, hyperactivity, and impulsiveness. We identified de novo and rare copy number variations (CNVs) in 248 unrelated ADHD patients using million-feature genotyping arrays. We found de novo CNVs in 3 of 173 (1.7%) ADHD patients for whom we had DNA from both parents. These CNVs affected brain-expressed genes: DCLK2, SORCS1, SORCS3, and MACROD2. We also detected rare inherited CNVs in 19 of 248 (7.7%) ADHD probands, which were absent in 2357 controls and which either overlapped previously implicated ADHD loci (for example, DRD5 and 15q13 microduplication) or identified new candidate susceptibility genes (ASTN2, CPLX2, ZBBX, and PTPRN2). Among these de novo and rare inherited CNVs, there were also examples of genes (ASTN2, GABRG1, and CNTN5) previously implicated by rare CNVs in other neurodevelopmental conditions including autism spectrum disorder (ASD). To further explore the overlap of risks in ADHD and ASD, we used the same microarrays to test for rare CNVs in an independent, newly collected cohort of 349 unrelated individuals with a primary diagnosis of ASD. Deletions of the neuronal ASTN2 and the ASTN2-intronic TRIM32 genes yielded the strongest association with ADHD and ASD, but numerous other shared candidate genes (such as CHCHD3, MACROD2, and the 16p11.2 region) were also revealed. Our results provide support for a role for rare CNVs in ADHD risk and reinforce evidence for the existence of common underlying susceptibility genes for ADHD, ASD, and other neuropsychiatric disorders.
authors.affiliation: The Centre for Applied Genomics and Program in Genetics and Genome Biology, Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada.
authors.forename: Anath C
authors.initials: AC
authors.lastname: Lionel
authors.forename: Jennifer
authors.initials: J
authors.lastname: Crosbie
authors.forename: Nicole
authors.initials: N
authors.lastname: Barbosa
authors.forename: Tara
authors.initials: T
authors.lastname: Goodale
authors.forename: Bhooma
authors.initials: B
authors.lastname: Thiruvahindrapuram
authors.forename: Jessica
authors.initials: J
authors.lastname: Rickaby
authors.forename: Matthew
authors.initials: M
authors.lastname: Gazzellone
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Carson
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Howe
authors.forename: Zhuozhi
authors.initials: Z
authors.lastname: Wang
authors.forename: John
authors.initials: J
authors.lastname: Wei
authors.forename: Alexandre F R
authors.initials: AF
authors.lastname: Stewart
authors.forename: Robert
authors.initials: R
authors.lastname: Roberts
authors.forename: Ruth
authors.initials: R
authors.lastname: McPherson
authors.forename: Andreas
authors.initials: A
authors.lastname: Fiebig
authors.forename: Andre
authors.initials: A
authors.lastname: Franke
authors.forename: Stefan
authors.initials: S
authors.lastname: Schreiber
authors.forename: Lonnie
authors.initials: L
authors.lastname: Zwaigenbaum
authors.forename: Bridget A
authors.initials: BA
authors.lastname: Fernandez
authors.forename: Wendy
authors.initials: W
authors.lastname: Roberts
authors.forename: Paul D
authors.initials: PD
authors.lastname: Arnold
authors.forename: Peter
authors.initials: P
authors.lastname: Szatmari
authors.forename: Christian R
authors.initials: CR
authors.lastname: Marshall
authors.forename: Russell
authors.initials: R
authors.lastname: Schachar
authors.forename: Stephen W
authors.initials: SW
authors.lastname: Scherer
mesh_terms: D000293:Adolescent; D001289:Attention Deficit Disorder with Hyperactivity / Q000235:genetics*; D001321:Autistic Disorder / Q000235:genetics; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D056915:DNA Copy Number Variations / Q000235:genetics*; D005260:Female; D056426:Genetic Loci / Q000235:genetics; D020022:Genetic Predisposition to Disease; D006023:Glycoproteins / Q000235:genetics; D006801:Humans; D008297:Male; D009422:Nervous System Diseases / Q000235:genetics; D010375:Pedigree; D012307:Risk Factors; D017422:Sequence Analysis, DNA; D014157:Transcription Factors / Q000235:genetics; D000070584:Tripartite Motif Proteins; D044767:Ubiquitin-Protein Ligases
chemical_list: D006023:Glycoproteins; D014157:Transcription Factors; D000070584:Tripartite Motif Proteins; C094027:TRIM32 protein, human; D044767:Ubiquitin-Protein Ligases