GNB3 and CREB1 gene polymorphisms combined with negative life events increase susceptibility to major depression in a Chinese Han population

Background: Major depression (MD) is caused by a combination of genetic and environmental factors. In this study we investigated the interaction of variations in the G-protein beta 3 subunit (GNB3) and cAMP response element binding protein 1 (CREB1) genes with negative life events in the pathogenesis of MD. One GNB3 polymorphism (rs5443) and four CREB1 polymorphisms (rs2253206, rs2551941, rs6740584, rs11904814) were investigated based on known associations with MD. Methods: 512 patients with MD and 513 control subjects were genotyped. The frequency and severity of negative life events were measured by the Life Events Scale (LES). Gene-environment interactions (G×E) were assessed using the generalized multifactor dimensionality reduction (GMDR) method. Results: Differences in GNB3 rs5443 allele frequencies and genotype distributions were observed between MD patients and controls. Significant G×E interactions were detected between negative life events and genotypic variation of all five single nucleotide polymorphisms (SNPs). Individuals carrying the T^- allele of rs5443 (CC), A^- allele of rs2253206 (GG), T^- allele of rs2551941 (AA), C^- allele of rs6740584 (TT) or G^- allele of rs11904814 (TT) conferred susceptibility to MD in subjects only exposed to high-negative life events. However, individuals with the T⁺ allele of rs5443 (CT, TT) were susceptible to MD when exposed to low negative life events. Conclusions: Interactions between GNB3, CREB1 and negative life events were revealed. Further evidence is provided about the role of the environment in genetic vulnerability to MD.