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

Abstract

Novel linkage and association of the mineralocorticoid receptor gene (NR3C2) with familial type 2 diabetes and depression and their comorbidity Mutaz Amin a,b, Shumail Syed c, Rongling Wud,e, f,g, Teodor T. Postolache h, i, j, Claudia Gragnoli c,d,k,* a INSERM, US14-Orphanet, Paris, 75014, France b Department of Biochemistry and Molecular Biology, Faculty of Medicine, Al-Neelain University, Khartoum, 11121, Sudan c Division of Endocrinology, Department of Medicine, Creighton University School of Medicine, Omaha, NE, 68124, USA d Department of Public Health Sciences, Penn State College of Medicine, Hershey, PA, 17033, USA e Department of Statistics, Penn State College of Medicine, Hershey, PA, 17033, USA f Beijing Yanqi Lake Institute of Mathematical Sciences and Applications, Beijing, 101408, China g Yau Mathematical Sciences Center, Tsinghua University, Beijing, 100084, China h Mood and Anxiety Program, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD, 21201, USA i Rocky Mountain Mental Illness Research Education and Clinical Center (MIRECC), Veterans Integrated Service Network (VISN) 19, Military and Veteran Microbiome: Consortium for Research and Education (MVM-CoRE), Denver, CO, 80246, USA j Mental Illness Research Education and Clinical Center (MIRECC), Veterans Integrated Service Network (VISN) 5, VA Capitol Health Care Network, Baltimore, MD, 210909, USA k Molecular Biology Laboratory, Bios Biotech Multi-Diagnostic Health Center, Rome, 0019, Italy A R T I C L E I N F O Handling Editor: Prof A Angelo Azzi Keywords: Nuclear receptor subfamily 3 group C member 2 NR3C2 Major depressive disorder MDD Type 2 diabetes Mineralcorticoid receptor antagonist A B S T R A C T 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.