In this study, we aimed to test for the first time whether the CRHR1 gene, whose protein mediates the stress response, is linked to and/or in linkage disequilibrium (LD), understanding that LD is association, with MDD, T2D, and MDD-T2D comorbidity in very homogeneous well-characterized Italian families with T2D and positive familial T2D history and the presence of MDD, thus carrying the potential for the genetic comorbidity of these clinically associated disorders. This evidence concerns the gene CRHR1 and major depressive disorder.