title: Genome-wide association scan of quantitative traits for attention deficit hyperactivity disorder identifies novel associations and confirms candidate gene associations.
abstract: Attention deficit hyperactivity disorder (ADHD) is a complex condition with environmental and genetic etiologies. Up to this point, research has identified genetic associations with candidate genes from known biological pathways. In order to identify novel ADHD susceptibility genes, 600,000 SNPs were genotyped in 958 ADHD proband-parent trios. After applying data cleaning procedures we examined 429,981 autosomal SNPs in 909 family trios. We generated six quantitative phenotypes from 18 ADHD symptoms to be used in genome-wide association analyses. With the PBAT screening algorithm, we identified 2 SNPs, rs6565113 and rs552655 that met the criteria for significance within a specified phenotype. These SNPs are located in intronic regions of genes CDH13 and GFOD1, respectively. CDH13 has been implicated previously in substance use disorders. We also evaluated the association of SNPs from a list of 37 ADHD candidate genes that was specified a priori. These findings, along with association P-values with a magnitude less than 10(-5), are discussed in this manuscript. Seventeen of these candidate genes had association P-values lower then 0.01: SLC6A1, SLC9A9, HES1, ADRB2, HTR1E, DDC, ADRA1A, DBH, DRD2, BDNF, TPH2, HTR2A, SLC6A2, PER1, CHRNA4, SNAP25, and COMT. Among the candidate genes, SLC9A9 had the strongest overall associations with 58 association test P-values lower than 0.01 and multiple association P-values at a magnitude of 10(-5) in this gene. In sum, these findings identify novel genetic associations at viable ADHD candidate genes and provide confirmatory evidence for associations at previous candidate genes. Replication of these results is necessary in order to confirm the proposed genetic variants for ADHD.
authors.affiliation: Channing Laboratory, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Jessica
authors.initials: J
authors.lastname: Lasky-Su
authors.forename: Benjamin M
authors.initials: BM
authors.lastname: Neale
authors.forename: Barbara
authors.initials: B
authors.lastname: Franke
authors.forename: Richard J L
authors.initials: RJ
authors.lastname: Anney
authors.forename: Kaixin
authors.initials: K
authors.lastname: Zhou
authors.forename: Julian B
authors.initials: JB
authors.lastname: Maller
authors.forename: Alejandro Arias
authors.initials: AA
authors.lastname: Vasquez
authors.forename: Wai
authors.initials: W
authors.lastname: Chen
authors.forename: Philip
authors.initials: P
authors.lastname: Asherson
authors.forename: Jan
authors.initials: J
authors.lastname: Buitelaar
authors.forename: Tobias
authors.initials: T
authors.lastname: Banaschewski
authors.forename: Richard
authors.initials: R
authors.lastname: Ebstein
authors.forename: Michael
authors.initials: M
authors.lastname: Gill
authors.forename: Ana
authors.initials: A
authors.lastname: Miranda
authors.forename: Fernando
authors.initials: F
authors.lastname: Mulas
authors.forename: Robert D
authors.initials: RD
authors.lastname: Oades
authors.forename: Herbert
authors.initials: H
authors.lastname: Roeyers
authors.forename: Aribert
authors.initials: A
authors.lastname: Rothenberger
authors.forename: Joseph
authors.initials: J
authors.lastname: Sergeant
authors.forename: Edmund
authors.initials: E
authors.lastname: Sonuga-Barke
authors.forename: Hans Christoph
authors.initials: HC
authors.lastname: Steinhausen
authors.forename: Eric
authors.initials: E
authors.lastname: Taylor
authors.forename: Mark
authors.initials: M
authors.lastname: Daly
authors.forename: Nan
authors.initials: N
authors.lastname: Laird
authors.forename: Christoph
authors.initials: C
authors.lastname: Lange
authors.forename: Stephen V
authors.initials: SV
authors.lastname: Faraone
mesh_terms: D000465:Algorithms; D001289:Attention Deficit Disorder with Hyperactivity / Q000175:diagnosis / Q000235:genetics*; D015820:Cadherins / Q000235:genetics; D016000:Cluster Analysis; D005260:Female; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease; D015894:Genome, Human; D055106:Genome-Wide Association Study; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D007438:Introns; D008297:Male; D008957:Models, Genetic; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D011336:Probability; D040641:Quantitative Trait Loci
chemical_list: D015820:Cadherins; D005819:Genetic Markers; C099972:H-cadherin