Novel linkage and association of the mineralocorticoid receptor gene (NR3C2) with familial type 2 diabetes and depression and their comorbidity

Introduction: The mineralocorticoid receptor gene (NR3C2) appears to modulate stress and cognitive performance in patients with major depressive disorder (MDD). In addition, abnormalities in NR3C2 are associated in rodents with type 2 diabetes (T2D) and in humans with features of metabolic syndrome. Of note, NR3C2 antagonists are approved treatments in heart failure and chronic kidney disease with T2D. The NR3C2 gene is therefore a candidate gene for studying T2D-MDD comorbidity. To our knowledge, no study has so far reported risk variants in the NR3C2 gene with either MDD and/or T2D. Materials and methods: In 212 multigenerational Italian families with enriched family history of T2D and with MDD, we analyzed 86 single nucleotide polymorphisms (SNPs) within the NR3C2 gene for parametric linkage to and/or linkage disequilibrium (LD) with T2D and MDD. Results: We identified a total of 7 independent SNPs significantly linked to/in LD with MDD only, 20 SNPs significantly linked to/in LD with T2D only, and 9 SNP significantly linked to/in LD with both T2D and MDD. The SNPs were statistically significant across different models. Two sets of LD blocks were MDD-specific, and one set was T2D-specific. In silico analysis of the risk variants predicted 3 variants with potential functional effects. Conclusions: This is the first study to report NR3C2 as a novel risk gene in T2D and MDD comorbidity. However, our results need to be replicated in other ethnicities.