Effects of corticotropin-releasing hormone receptor 1 SNPs on major depressive disorder are influenced by sex and smoking status

•CRHR1 SNPs have sex-specific effects on MDD susceptibility.•The influence of CRHR1 SNPs on MDD is limited to never-smokers.•Clinical heterogeneity may blunt the effects of genetic factors affecting MDD.

BackgroundThe corticotropin-releasing hormone receptor 1 (CRHR1) gene has been repeatedly implicated in Major Depressive Disorder (MDD) in humans and animal models; however, the findings are not absolutely convergent. Since recent evidence from genome-wide association studies suggests that narrowing the phenotypic heterogeneity may be crucial in genetic studies of MDD, the aim of this study was to evaluate the effects of CRHR1 polymorphisms on MDD while addressing the influence of sex and smoking status.MethodsThe association of the CRHR1 SNPs rs12944712, rs110402, and rs878886 with MDD was evaluated in 629 Brazilian adults of European descent recruited from the general population [180 (28.6%) with lifetime MDD]. The sample was subdivided according to sex and smoking statusResultsAmong nonsmokers, there were nominal associations between MDD and all tested SNPs (rs12944712, P=0.042; rs110402, P=0.031, and rs878886, P=0.040), regardless of sex. In addition, there were significant effects of rs110402 in women (Pcorr=0.034) and rs878886 in men (Pcorr=0.013). Among lifetime smokers, there were no significant associations between CRHR1 SNPs and MDDLimitationsThe lack of a depression rating scale; scarcity of information on the functionality of the CRHR1 SNPs; and relatively small sample sizes in some subgroups.ConclusionsOur results strengthen the evidence for the role of CRHR1 SNPs in MDD susceptibility and suggest that their effects may be modulated by sex and smoking status. These findings suggest the perspective that reducing phenotypic heterogeneity is warranted in genetic studies of MDD.