The Reanalysis Of Genes Identified By GWAS And The Potential Combined Effect Mechanisms In Major Depressive Disorder

Major depressive disorder (MDD), also called major depression, is an extremely common, chronic, and recurrent mental disease that affects millions of individuals worldwide with a high lifelong morbidity, a high risk of recurrence, a high suicide rate and heavy economic burden. Although family, twin and adoption studies have supported the involvement of a genetic component in the development of MDD, the molecular mechanism of this disease, by which the pathophysiology of the disease can be fully explained, has yet to be completely clarified. In recent years, the genome-wide association study (GWAS), which carries out a hypothesis-free search for potential new susceptibility genes throughout the whole genome, has shed new light on research into common polygenic diseases or quantitative traits. A number of GWA studies have identified some genetic variants associated with human complex diseases or traits, including MDD. And the GWAS has remarkably facilitated the understanding of the genetic mechanisms of MDD at a deep molecular level.However, because the present GWA studies of MDD mainly focus on the European population and there may be many differences in allele frequencies and linkage disequilibrium blocks between human populations, it is very necessary to conduct repeated verification in Chinese Han population. In addition, due to the low contribution of each single risk variant (odds radios<2) for the development of common psychiatric diseases and their complexity of genetic mechanisms involving the combined effects of multiple genetic variations (the gene-gene interactions and gene internal interactions, for example), the gene-environment interactions and so on, we should pay more attention to these complex combined effects of multiple genetic variants conferring susceptibility to these multi-factorial diseases.Based on the initial findings shown by the previous study which tested16MDD-associated genes in a Han Chinese population, we constructed a tag single nucleotide polymorphism (SNP)-based LD map using the information of the HapMap for the Han Chinese in Beijing (CHB) population in the loci that showed association with MDD in the study sample. We recruited a total of519unrelated patients with MDD (237males and282female, aged30.80±8.85(SD) years through the Department of Psychiatry, First Hospital of Shanxi Medical University, Taiyuan, China, between January2006and December2009. Meanwhile,468unrelated healthy subjects (214males and254females), aged27.50±7.89(SD) years, were also recruited as controls. Patients were also interviewed with the same psychiatrists using the17-item Hamilton Rating Scale for Depression (HAMD-17) and Hamilton Anxiety Scale (HAMA) during sampling. Further more, in order to verify the relationship between this three genes and cognitive impairments in MDD patients, we used the association study in47MDD patients with fully clinical data.In case-control study, none of the SNPs in EHD3gene and FREM3gene showed allelic and genotypic association with MDD, but the rs1513105of PTPRR gene was the only one showing allelic association (χ2=9.019,p=0.0027) and genotypic association (χ22=8.813, df=2, p=0.012), of which the rs1513105(C) allele was associated with an increased risk of MDD (OR=1.331,95%CI1.104-1.604), but the rs1513105association resulted mainly from female subjects (χ2=12.35, p=0.00044for allelic association; χ2=11.26, df=2,p=0.0036for genotypic association). Gender-specific analysis also revealed that the two SNPs of EHD3gene association was more likely to occur in female subjects (χ2=8.07,p=0.0045, for rs619002;χ2=7.17,p=0.0074for rs644926).The gene-gene interaction analysis showed disease association for the rs619002(EHD3)-rs1112714(FREM3) combination (χ2=7.56,p=0.0059) and the rs644926(EHD3)-rs13130123(FREM3) combination (χ2=7.25, p=0.007), of which a reduced risk was found for the rs619002(G)-rs1112714(T) combination (OR=0, χ2=21.25, p=4.02×10-6) and the rs644926(A)-rs11938298(G) combination (OR=0.117,95%CI=0.035-0.393,χ2=21.34,p=3.85×10-6). Further analysis revealed that among the individuals carrying the rs619002-G and rs644926-A allele in the EHD3gene, the five. SNPs in the FREM3gene was associated with susceptibility to MDD, respectively, of which the rs11938298showed the strongest association with MDD in the rs619002-G and rs644926-A alleles carriers, respectively (χ2=12.12, p=0.00049for rs619002-G carner;χ2=14.73,p=0.0001for rs644926-A carrier).. However, none of the five SNPs in the FREM3gene showed association when the individuals carrying the rs619002A/A genotype and the rs644926G/G genotype. There also showed the same effects evidence in conferring contribution to the insomnia early symptom.Endophenotype analysis analysis revealed that rs3769621in the EHD3locus showed strongly allelic association and genotypic association with the impairment of operational capacity and memory in patients with MDD; Allele and genotype of rs1553067in the FREM3locus showed strongly association with the impairment of verbal ability in MDD patients; rs2203231in the PTPRR locus showed strongly association with the impairment of long-term memory and short-term memory in patients.We concluded that the combined effect of the EHD3and FREM3genes plays an important role in developing MDD and the insomnia early symptom. The PTPRR gene may play a role in conferring risk of MDD in the female subjects. EHD3, FREM3and PTPRR gene may play a role in conferring risk of the impairment of operational capacity, verbal ability and memory in patients with MDD.