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In women with PCOS, the corticotropin-releasing hormone (CRH) induces an exaggerated HPA response, possibly mediated by one of the CRH receptors (CRHR1 or CRHR2). Both CRHR1 and CRHR2 are implicated in insulin secretion, and variants in <jats:italic>CRHR1<\/jats:italic> and <jats:italic>CRHR2<\/jats:italic> genes may predispose to the mental-metabolic risk for PCOS.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>We phenotyped 212 Italian families with type 2 diabetes (T2D) for PCOS following the Rotterdam diagnostic criteria. We analyzed within <jats:italic>CRHR1<\/jats:italic> and <jats:italic>CRHR2<\/jats:italic> genes, respectively, 36 and 18 microarray-variants for parametric linkage to and\/or linkage disequilibrium (LD) with PCOS under the recessive with complete penetrance (R1) and dominant with complete penetrance (D1) models. Subsequentially, we ran a secondary analysis under the models dominant with incomplete penetrance (D2) and recessive with incomplete penetrance (R2).<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>We detected 22 variants in <jats:italic>CRHR1<\/jats:italic> and 1 variant in <jats:italic>CRHR2<\/jats:italic> significantly (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.05) linked to or in LD with PCOS across different inheritance models.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusions<\/jats:title>\n                <jats:p>This is the first study to report <jats:italic>CRHR1<\/jats:italic> and <jats:italic>CRHR2<\/jats:italic> as novel risk genes in PCOS. In silico analysis predicted that the detected <jats:italic>CRHR1<\/jats:italic> and <jats:italic>CRHR2<\/jats:italic> risk variants promote negative chromatin activation of their related genes in the ovaries, potentially affecting the female cycle and ovulation. However, <jats:italic>CRHR1<\/jats:italic>- and <jats:italic>CRHR2<\/jats:italic>-risk variants might also lead to hypercortisolism and confer mental-metabolic pleiotropic effects. Functional studies are needed to confirm the pathogenicity of genes and related variants.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1186\/s13048-023-01159-5","type":"journal-article","created":{"date-parts":[[2023,8,5]],"date-time":"2023-08-05T08:01:49Z","timestamp":1691222509000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Novel corticotropin-releasing hormone receptor genes (CRHR1 and CRHR2) linkage to and association with polycystic ovary syndrome"],"prefix":"10.1186","volume":"16","author":[{"given":"Mutaz","family":"Amin","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicholas","family":"Horst","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rongling","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudia","family":"Gragnoli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2023,8,5]]},"reference":[{"issue":"6","key":"1159_CR1","doi-asserted-by":"publisher","first-page":"2745","DOI":"10.1210\/jc.2003-032046","volume":"89","author":"R Azziz","year":"2004","unstructured":"Azziz R, et al. 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