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....
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| Format: | Article |
| Language: | English |
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Elsevier
2023-01-01
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| Series: | Aspects of Molecular Medicine |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2949688823000035 |
| _version_ | 1797237867266703360 |
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| author | Mutaz Amin Shumail Syed Rongling Wu Teodor T. Postolache Claudia Gragnoli |
| author_facet | Mutaz Amin Shumail Syed Rongling Wu Teodor T. Postolache Claudia Gragnoli |
| author_sort | Mutaz Amin |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-24T17:26:34Z |
| format | Article |
| id | doaj.art-0e2ac63cf94e4f7e939236eac2f78d39 |
| institution | Directory Open Access Journal |
| issn | 2949-6888 |
| language | English |
| last_indexed | 2024-04-24T17:26:34Z |
| publishDate | 2023-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Aspects of Molecular Medicine |
| spelling | doaj.art-0e2ac63cf94e4f7e939236eac2f78d392024-03-28T06:39:48ZengElsevierAspects of Molecular Medicine2949-68882023-01-011100003Novel linkage and association of the mineralocorticoid receptor gene (NR3C2) with familial type 2 diabetes and depression and their comorbidityMutaz Amin0Shumail Syed1Rongling Wu2Teodor T. Postolache3Claudia Gragnoli4INSERM, US14-Orphanet, Paris, 75014, France; Department of Biochemistry and Molecular Biology, Faculty of Medicine, Al-Neelain University, Khartoum, 11121, SudanDivision of Endocrinology, Department of Medicine, Creighton University School of Medicine, Omaha, NE, 68124, USADepartment of Public Health Sciences, Penn State College of Medicine, Hershey, PA, 17033, USA; Department of Statistics, Penn State College of Medicine, Hershey, PA, 17033, USA; Beijing Yanqi Lake Institute of Mathematical Sciences and Applications, Beijing, 101408, China; Yau Mathematical Sciences Center, Tsinghua University, Beijing, 100084, ChinaMood and Anxiety Program, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD, 21201, USA; 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; Mental Illness Research Education and Clinical Center (MIRECC), Veterans Integrated Service Network (VISN) 5, VA Capitol Health Care Network, Baltimore, MD, 210909, USADivision of Endocrinology, Department of Medicine, Creighton University School of Medicine, Omaha, NE, 68124, USA; Department of Public Health Sciences, Penn State College of Medicine, Hershey, PA, 17033, USA; Molecular Biology Laboratory, Bios Biotech Multi-Diagnostic Health Center, Rome, 0019, Italy; Corresponding author. Division of Endocrinology, Department of Medicine, Creighton University School of Medicine, Omaha, NE, 68124, USA.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.http://www.sciencedirect.com/science/article/pii/S2949688823000035Nuclear receptor subfamily 3 group C member 2NR3C2Major depressive disorderMDDType 2 diabetesMineralcorticoid receptor antagonist |
| spellingShingle | Mutaz Amin Shumail Syed Rongling Wu Teodor T. Postolache Claudia Gragnoli Novel linkage and association of the mineralocorticoid receptor gene (NR3C2) with familial type 2 diabetes and depression and their comorbidity Aspects of Molecular Medicine Nuclear receptor subfamily 3 group C member 2 NR3C2 Major depressive disorder MDD Type 2 diabetes Mineralcorticoid receptor antagonist |
| title | Novel linkage and association of the mineralocorticoid receptor gene (NR3C2) with familial type 2 diabetes and depression and their comorbidity |
| title_full | Novel linkage and association of the mineralocorticoid receptor gene (NR3C2) with familial type 2 diabetes and depression and their comorbidity |
| title_fullStr | Novel linkage and association of the mineralocorticoid receptor gene (NR3C2) with familial type 2 diabetes and depression and their comorbidity |
| title_full_unstemmed | Novel linkage and association of the mineralocorticoid receptor gene (NR3C2) with familial type 2 diabetes and depression and their comorbidity |
| title_short | Novel linkage and association of the mineralocorticoid receptor gene (NR3C2) with familial type 2 diabetes and depression and their comorbidity |
| title_sort | novel linkage and association of the mineralocorticoid receptor gene nr3c2 with familial type 2 diabetes and depression and their comorbidity |
| topic | Nuclear receptor subfamily 3 group C member 2 NR3C2 Major depressive disorder MDD Type 2 diabetes Mineralcorticoid receptor antagonist |
| url | http://www.sciencedirect.com/science/article/pii/S2949688823000035 |
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