Introduction: Major depressive disorder (MDD) is one of the most prevalent and disabling mental disorders, although its underlying genetic mechanism remains unknown. Insulin receptor substrate-1 (IRS-1) is one of the critical downstream molecules in the insulin resistance signaling pathway, linking depression and diabetes. Therefore, we hypothesized that IRS-1 would be a susceptible gene for MDD, and we aimed to examine the genetic association between IRS-1  and MDD.
Methods: This case-control study included 583 patients with MDD and 564 controls, and the genotypic and allelic distributions of the IRS-1  gene’s four single nucleotide polymorphisms (SNPs) were detected by TaqMan SNP genotyping technology. Of the 583 patients, 191 underwent a further detailed interview about symptom severity and family history of mental illness. The chi-square or t  test was used to analyze the data, and analyses were performed using SPSS19.0 software.
Results: A haplotype in the 5ʹ-upstream region of IRS-1  consisting of rs13411764 and rs3820926 was a risk factor of MDD. Patients with a family history of mental illness were more likely to have a GG genotype in rs13411764 and a G-T haplotype containing rs13411714-rs3820926.
Discussion: The findings imply that the haplotype consisting of rs13411764 and rs3820926 in the upstream of IRS-1  is a risk factor for MDD. This haplotype could affect IRS-1  expression levels, and it is mostly inherited from parents. Thus, the presence of variants in the upstream region of IRS-1  is a risk factor of MDD, and this study could serve as a convincing reference for further studies.
Keywords: major depressive disorder, IRS-1, single nucleotide polymorphisms, haplotype, family history