Genome-wide association scan of quantitative traits for attention deficit hyperactivity disorder identifies novel associations and confirms candidate gene associations.
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.
Lasky-Su
Jessica
J
Channing Laboratory, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Neale
Benjamin M
BM
Franke
Barbara
B
Anney
Richard J L
RJ
Zhou
Kaixin
K
Maller
Julian B
JB
Vasquez
Alejandro Arias
AA
Chen
Wai
W
Asherson
Philip
P
Buitelaar
Jan
J
Banaschewski
Tobias
T
Ebstein
Richard
R
Gill
Michael
M
Miranda
Ana
A
Mulas
Fernando
F
Oades
Robert D
RD
Roeyers
Herbert
H
Rothenberger
Aribert
A
Sergeant
Joseph
J
Sonuga-Barke
Edmund
E
Steinhausen
Hans Christoph
HC
Taylor
Eric
E
Daly
Mark
M
Laird
Nan
N
Lange
Christoph
C
Faraone
Stephen V
SV
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
D015820:Cadherins; D005819:Genetic Markers; C099972:H-cadherin