Major depressive disorder (MDD) is a common chronic mental disease with diverse clinical presentation. Although the genome-wide association study (GWAS) has remarkably facilitated the understanding of genetic mechanisms of MDD at a deep molecular level, the combined effect of these disease-underlying genes still needs further investigation. A total of 1,062 unrelated patients with MDD and 992 unrelated healthy subjects were recruited from a Chinese Han population to test 16 MDD-associated genes identified by GWAS. A tag SNP-based linkage-disequilibrium map was then constructed over the loci that showed MDD association in the study sample. Of the 16 genes tested, EHD3 and FREM3 were associated with MDD in the Chinese population. The conditional test showed disease association for the rs619002(EHD3)-rs1112714(FREM3) combination (P = 0.0059) and for the rs644926(EHD3)-rs13130123(FREM3) combination (P = 0.007), of which a reduced risk was found for the rs619002(G)-rs1112714(T) combination (OR = 0, P = 4.02 × 10(-6) ) and for the rs644926(A)-rs11938298(G) combination (OR = 0.12, 95% CI = 0.035-0.39, P = 3.85 × 10(-6) ). Quantitative trait analysis revealed that rs13130123 in the FREM3 locus was strongly associated with the insomnia early symptom in patients carrying the rs619002(G) allele (P = 0.001) and those carrying the rs644926(A) allele (P = 0.00077). The combined effect of the EHD3 and FREM3 genes may play an important role in developing MDD. © 2012 Wiley Periodicals, Inc.
Copyright © 2012 Wiley Periodicals, Inc.