Familial Linkage and Association of the NR3C1 Gene with Type 2 Diabetes and Depression Comorbidity

Impairment in the hypothalamic-pituitary-adrenal (HPA) axis and cortisol pathway may be major contributing factors to the common pathogenesis of major depressive disorders (MDD) and type 2 diabetes (T2D). A significant player in the neuroendocrine HPA axis and cortisol response is the glucocorticoid receptor (GR), which is encoded by the nuclear receptor subfamily 3 group C member (NR3C1) gene. Variants in the NR3C1 gene have been reported in patients with MDD and obesity and found to confer reduced risk for quantitative metabolic traits and T2D in Cushing syndrome; variants have not been reported in T2D and MDD-T2D comorbid patients. We studied 212 original Italian families with a rich family history for T2D and tested 24 single nucleotide polymorphisms (SNPs) in the NR3C1 gene for linkage to and linkage disequilibrium (LD) with T2D and MDD across different inheritance models. We identified a total of 6 novel SNPs significantly linked/in LD to/with T2D (rs6196, rs10482633, rs13186836, rs13184611, rs10482681 and rs258751) and 1 SNP (rs10482668) significantly linked to/in LD with both T2D and MDD. These findings expand understanding of the role that NR3C1 variants play in modulating the risk of T2D-MDD comorbidity. Replication and functional studies are needed to confirm these findings.