The SNP-set based association study identifies ITGA1 as a susceptibility gene of attention-deficit/hyperactivity...

Genome-wide association studies, which detect the association between single-nucleotide polymorphisms (SNPs) and disease susceptibility, have been extensively applied to study attention-deficit/hyperactivity disorder (ADHD), but genome-wide significant associations have not been found yet. Genetic heterogeneity and insufficient genomic coverage may account for the missing heritability. We performed a two-stage association study for ADHD in the Han Chinese population. In the discovery stage, 1033 ADHD patients and 950 healthy controls were genotyped using both the Affymetrix Genome-Wide Human SNP Array 6.0 and the Illumina Infinium HumanExome BeadChip. The genotyped SNPs were combined to generate a powerful SNP set with better genomic coverage especially for the nonsynonymous variants. In addition to the association of single SNPs, we collected adjacent SNPs as SNP sets, which were determined by either genes or successive sliding windows, to evaluate their synergetic effect. The candidate susceptibility SNPs were further replicated in an independent cohort of 1441 ADHD patients and 1447 healthy controls. No genome-wide significant SNPs or gene-based SNP sets were found to be associated with ADHD. However, two continuous sliding windows located in ITGA1 (P-value=8.33E-7 and P-value=8.43E-7) were genome-wide significant. The quantitative trait analyses also demonstrated their association with ADHD core symptoms and executive functions. The association was further validated by follow-up replications for four selected SNPs: rs1979398 (P-value=2.64E-6), rs16880453 (P-value=3.58E-4), rs1531545 (P-value=7.62E-4) and rs4074793 (P-value=2.03E-4). Our results suggest that genetic variants in ITGA1 may be involved in the etiology of ADHD and the SNP-set based analysis is a promising strategy for the detection of underlying genetic risk factors.