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To investigate the role of the <jats:italic>CRHR1<\/jats:italic> gene in familial T2D, MDD, and MDD-T2D comorbidity, we tested 152 CRHR1 single-nucleotide-polymorphisms (SNPs), via 2-point parametric linkage and linkage disequilibrium (LD; i.e., association) analyses using 4 models, in 212 peninsular families with T2D and MDD. We detected linkage\/LD\/association to\/with MDD and T2D with 122 (116 novel) SNPs. MDD and T2D had 4 and 3 disorder-specific novel risk LD blocks, respectively, whose risk variants reciprocally confirm one another. Comorbidity was conferred by 3 novel independent SNPs. In silico analyses reported novel functional changes, including the binding site of glucocorticoid receptor-alpha [GR-\u03b1] on <jats:italic>CRHR1<\/jats:italic> for transcription regulation. This is the first report of <jats:italic>CRHR1<\/jats:italic> pleiotropic linkage\/LD\/association with peninsular familial MDD and T2D. <jats:italic>CRHR1<\/jats:italic> contribution to MDD is stronger than to T2D and may antecede T2D onset. Our findings suggest a new molecular-based clinical entity of MDD-T2D and should be replicated in other ethnic groups.<\/jats:p>","DOI":"10.1007\/s00406-023-01710-x","type":"journal-article","created":{"date-parts":[[2023,12,14]],"date-time":"2023-12-14T04:27:34Z","timestamp":1702528054000},"page":"1025-1035","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["LD block disorder-specific pleiotropic roles of novel CRHR1 in type 2 diabetes and depression disorder comorbidity"],"prefix":"10.1007","volume":"275","author":[{"given":"Laura","family":"del Bosque-Plata","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mutaz","family":"Amin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ricardo","family":"Gonz\u00e1lez-Ram\u00edrez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rongling","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Teodor T.","family":"Postolache","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Vergare","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Derek","family":"Gordon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3873-6617","authenticated-orcid":false,"given":"Claudia","family":"Gragnoli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2023,12,14]]},"reference":[{"issue":"1","key":"1710_CR1","doi-asserted-by":"publisher","first-page":"24","DOI":"10.1055\/s-2003-36684","volume":"71","author":"S Prestele","year":"2003","unstructured":"Prestele S, Aldenhoff J, Reiff J (2003) Die HPA-achse als m\u00f6gliches bindeglied zwischen depression, diabetes mellitus und kognitiven st\u00f6rungen. 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