{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T17:49:17Z","timestamp":1788544157049,"version":"build-2803163510"},"reference-count":65,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2022,8,29]],"date-time":"2022-08-29T00:00:00Z","timestamp":1661731200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000071","name":"NICHD","doi-asserted-by":"publisher","award":["5R01HD086911"],"award-info":[{"award-number":["5R01HD086911"]}],"id":[{"id":"10.13039\/100000071","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The corticotropin-releasing hormone receptor 2 (CRHR2) gene encodes CRHR2, contributing to the hypothalamic\u2013pituitary\u2013adrenal stress response and to hyperglycemia and insulin resistance. CRHR2\u2212\/\u2212 mice are hypersensitive to stress, and the CRHR2 locus has been linked to type 2 diabetes and depression. While CRHR2 variants confer risk for mood disorders, MDD, and type 2 diabetes, they have not been investigated in familial T2D and MDD. In 212 Italian families with type 2 diabetes and depression, we tested 17 CRHR2 single nucleotide polymorphisms (SNPs), using two-point parametric-linkage and linkage-disequilibrium (i.e., association) analysis (models: dominant-complete-penetrance-D1, dominant-incomplete-penetrance-D2, recessive-complete-penetrance-R1, recessive-incomplete-penetrance-R2). We detected novel linkage\/linkage-disequilibrium\/association to\/with depression (3 SNPs\/D1, 2 SNPs\/D2, 3 SNPs\/R1, 3 SNPs\/R2) and type 2 diabetes (3 SNPs\/D1, 2 SNPs\/D2, 2 SNPs\/R1, 1 SNP\/R2). All detected risk variants are novel. Two depression-risk variants within one linkage-disequilibrium block replicate each other. Two independent novel SNPs were comorbid while the most significant conferred either depression- or type 2 diabetes-risk. Although the families were primarily ascertained for type 2 diabetes, depression-risk variants showed higher significance than type 2 diabetes-risk variants, implying CRHR2 has a stronger role in depression-risk than type 2 diabetes-risk. In silico analysis predicted variants\u2019 dysfunction. CRHR2 is for the first time linked to\/in linkage-disequilibrium\/association with depression-type 2 diabetes comorbidity and may underlie the shared genetic pathogenesis via pleiotropy.<\/jats:p>","DOI":"10.3390\/ijms23179819","type":"journal-article","created":{"date-parts":[[2022,8,29]],"date-time":"2022-08-29T21:01:31Z","timestamp":1661806891000},"page":"9819","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Comorbidity of Novel CRHR2 Gene Variants in Type 2 Diabetes and Depression"],"prefix":"10.3390","volume":"23","author":[{"given":"Mutaz","family":"Amin","sequence":"first","affiliation":[{"name":"Institut National de la Sant\u00e9 et de la Recherche M\u00e9dicale (INSERM), US14-Orphanet, 75014 Paris, France"},{"name":"Department of Biochemistry and Molecular Biology, Faculty of Medicine, Al-Neelain University, Khartoum 11121, Sudan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6188-1388","authenticated-orcid":false,"given":"Jurg","family":"Ott","sequence":"additional","affiliation":[{"name":"Laboratory of Statistical Genetics, Rockefeller University, New York, NY 10065, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2945-1748","authenticated-orcid":false,"given":"Derek","family":"Gordon","sequence":"additional","affiliation":[{"name":"Department of Genetics, Rutgers University, Piscataway, NJ 08854, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2334-6421","authenticated-orcid":false,"given":"Rongling","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Public Health Sciences, Penn State College of Medicine, Hershey, PA 17033, USA"},{"name":"Departments of Statistics, Penn State College of Medicine, Hershey, PA 17033, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6056-4244","authenticated-orcid":false,"given":"Teodor T.","family":"Postolache","sequence":"additional","affiliation":[{"name":"Mood and Anxiety Program, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD 21201, USA"},{"name":"Rocky Mountain Mental Illness Research Education and Clinical Center (MIRECC), Veterans Integrated Service Network (VISN) 19, Denver, CO 80246, USA"},{"name":"Military and Veteran Microbiome: Consortium for Research and Education (MVM-CoRE), Aurora, CO 80246, USA"},{"name":"Mental Illness Research Education and Clinical Center (MIRECC), Veterans Integrated Service Network (VISN) 5, VA Capitol Health Care Network, Baltimore, MD 21090, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Vergare","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Human Behavior, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA 19107, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudia","family":"Gragnoli","sequence":"additional","affiliation":[{"name":"Department of Public Health Sciences, Penn State College of Medicine, Hershey, PA 17033, USA"},{"name":"Division of Endocrinology, Department of Medicine, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA 19107, USA"},{"name":"Division of Endocrinology, Department of Medicine, Creighton University School of Medicine, Omaha, NE 68124, USA"},{"name":"Molecular Biology Laboratory, Bios Biotech Multi-Diagnostic Health Center, 00197 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,8,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"383","DOI":"10.31887\/DCNS.2006.8.4\/ssmith","article-title":"The role of the hypothalamic-pituitary-adrenal axis in neuroendocrine responses to stress","volume":"8","author":"Smith","year":"2006","journal-title":"Dialogues Clin. 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