A high-density single-nucleotide polymorphism screen of 23 candidate genes in attention deficit hyperactivity disorder: suggesting multiple susceptibility genes among Chinese Han population

Attention deficit hyperactivity disorder (ADHD) is a common childhood-onset behavioral disorder with a definite genetic component. The search for genes predisposing to ADHD has focused on genes involved in the regulation of monoamine systems. In this study, we emphasized genes that underlie various aspects of dopamine, norepinephrine and serotonin neurotransmissions and performed a comprehensive association analysis by screening with 245 single-nucleotide polymorphisms (SNPs) of 23 candidate genes in a sample of Chinese Han descent. A total of 182 DSM-IV ADHD children and 184 healthy controls were genotyped and analyzed with an average density of one SNP every 6.1 kb. Both single-SNP and multi-marker haplotype analyses were implemented to exploit association signal for ADHD and its diagnostic subtypes. Empirical P-values were derived on the basis of 5000 permutations to evaluate gene-wide statistical significance. MAOA yielded highly suggestive evidence of association (empirical P < 0.01, OR = 1.94) with ADHD. For inattentive ADHD, MAOA, DDC and SYP showed suggestive evidence of association (empirical P < 0.05). ADRA2C achieved suggestive significance (empirical P < 0.05) for ADHD combined type. Additionally, for six genes (SNAP25, NET1, DBH, CHRNA4, DRD3 and SYT1) we detected one or more SNPs with nominal P-values <= 0.05. This study has identified several genes as promising susceptibility loci for ADHD. Replication efforts and further investigations remain necessary to provide definite proof of association.