{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,28]],"date-time":"2026-06-28T05:16:05Z","timestamp":1782623765190,"version":"3.54.5"},"reference-count":45,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2025,5,12]],"date-time":"2025-05-12T00:00:00Z","timestamp":1747008000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>Family studies have shown that polycystic ovary syndrome (PCOS) has probable genetic transmission because of a high incidence of relatives who present clinical or biochemical characters of the syndrome. However, initial candidate gene studies were unsuccessful. Genome wide association studies (GWASs) have shown that at least 29 gene alterations are common in PCOS, but it has been calculated that the altered genes found by GWASs may represent only 10% of affected patients. Rare altered uncoding genes may explain the syndrome in an additional group of patients. In many other patients, the altered genes found by GWASs may represent a risk condition for the development of the syndrome, and new candidate gene studies have shown that some gene alterations that mainly concern androgen production may be common in PCOS. Finally, in most patients, epigenetic and environmental factors may be necessary to transform a risk condition into this common and important syndrome.<\/jats:p>","DOI":"10.3390\/jcm14103347","type":"journal-article","created":{"date-parts":[[2025,5,12]],"date-time":"2025-05-12T09:13:38Z","timestamp":1747041218000},"page":"3347","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["The Role of Gene Alterations in the Pathogenesis of Polycystic Ovary Syndrome"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7336-7610","authenticated-orcid":false,"given":"Enrico","family":"Carmina","sequence":"first","affiliation":[{"name":"Endocrinology Unit, School of Medicine, University of Palermo, 90139 Palermo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,5,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Rotterdam ESHRE\/ASRM-Sponsored PCOS Consensus Workshop Group (2004). Revised 2003 consensus on diagnostic criteria and long term health risks related to polycystic ovary syndrome. Fertil. Steril., 81, 19\u201325.","DOI":"10.1016\/j.fertnstert.2003.10.004"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1016\/j.fertnstert.2006.03.012","article-title":"Diagnosis, Phenotype and Prevalence of Polycystic Ovary Syndrome","volume":"86","author":"Carmina","year":"2006","journal-title":"Fertil Steril."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"16057","DOI":"10.1038\/nrdp.2016.57","article-title":"Polycystic ovary syndrome","volume":"2","author":"Azziz","year":"2016","journal-title":"Nat. Rev. Dis. Primers"},{"key":"ref_4","first-page":"1303","article-title":"Family history as a risk factor for the polycystic ovary syndrome","volume":"13","author":"Azziz","year":"2000","journal-title":"J. Pediatr. Endocrinol. Metab."},{"key":"ref_5","first-page":"1311","article-title":"Searching for the polycystic ovary syndrome genes","volume":"13","author":"Urbanek","year":"2000","journal-title":"J. Pediatr. Endocrinol. Metab."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"2100","DOI":"10.1210\/jc.2005-1494","article-title":"Heritability of polycystic Ovary syndrome in a dutch twin-family study","volume":"91","author":"Vink","year":"2006","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1055\/s-2007-992919","article-title":"Looking for polycystic ovary syndrome genes: Rational and best strategy","volume":"26","author":"Goodarzi","year":"2008","journal-title":"Semin. Reprod. Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1046\/j.1365-2265.1997.2321049.x","article-title":"Evidence for a primary abnormality of thecal cell steroidogenesis in the polycystic ovary syndrome","volume":"47","author":"Story","year":"1997","journal-title":"Clin. Endocrinol."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Azziz, R., Nestler, J.E., and Dewailly, D. (2006). The genetic basis of Polycystic Ovary Syndrome. Androgen Excess Disorders in Women, Humana Press Inc.","DOI":"10.1007\/978-1-59745-179-6"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"801","DOI":"10.1172\/JCI118126","article-title":"Excessive insulin receptor serine phosphorylation in cultured fibroblasts and in skeletal muscle. A potential mechanism for insulin resistance in the polycystic ovary syndrome","volume":"96","author":"Dunaif","year":"1995","journal-title":"J. Clin. Investig."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"8573","DOI":"10.1073\/pnas.96.15.8573","article-title":"Thirty-seven candidate genes for polycystic ovary syndrome: Strongest evidence for linkage is with follistatin","volume":"96","author":"Urbanek","year":"1999","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1038\/ng.732","article-title":"Genome-wide association study identifies susceptibility loci for polycystic ovary syndrome on chromosome 2p16.3, 2p21 and 9q33.3","volume":"43","author":"Chen","year":"2011","journal-title":"Nat. Genet."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1020","DOI":"10.1038\/ng.2384","article-title":"Genome-wide association study identifies eight new risk loci for polycystic ovary syndrome","volume":"44","author":"Shi","year":"2012","journal-title":"Nat Genet."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"7502","DOI":"10.1038\/ncomms8502","article-title":"Genome-wide association of polycystic ovary syndrome implicates alterations in gonadotropin secretion in European ancestry populations","volume":"6","author":"Hayes","year":"2015","journal-title":"Nat. Commun."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"8464","DOI":"10.1038\/ncomms9464","article-title":"Causal mechanisms and balancing selection inferred from genetic associations with polycystic ovary syndrome","volume":"6","author":"Day","year":"2015","journal-title":"Nat. Commun."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"559-e1","DOI":"10.1016\/j.ajog.2020.04.004","article-title":"A genome-wide association study of polycystic ovary syndrome identified from electronic health records","volume":"223","author":"Zhang","year":"2020","journal-title":"Am. J. Obstet. Gynecol."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Moolhuijsen, L.M., Zhu, J., Mullin, B.H., Pujol-Gualdo, N., Actkins, K.V., Mack, J.A., Rao, H., Trivedi, B., Kentistou, K.A., and Zhao, J. (2024). Genomic and proteomic evidence for hormonal and metabolic foundations of polycystic ovary syndrome. MedRxiv.","DOI":"10.1101\/2024.04.18.24306020"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"4191","DOI":"10.1210\/jc.2007-0761","article-title":"Identification of a Polycystic Ovary Syndrome Susceptibility Variant in Fibrillin-3 and Association with a Metabolic Phenotype","volume":"92","author":"Urbanek","year":"2007","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"E1519","DOI":"10.1073\/pnas.1400574111","article-title":"Overexpression of a DENND1A isoform produces a polycystic ovary syndrome theca phenotype","volume":"111","author":"McAllister","year":"2014","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1964","DOI":"10.1210\/en.2019-00013","article-title":"miRNA Profiling Reveals miRNA-130b-3p Mediates DENND1A Variant 2 Expression and Androgen Biosynthesis","volume":"160","author":"McAllister","year":"2019","journal-title":"Endocrinology"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"bvac078","DOI":"10.1210\/jendso\/bvac078","article-title":"The PCOS GWAS Candidate Gene ZNF217 Influences Theca Cell Expression of DENND1A.V2, CYP17A1, and Androgen Production","volume":"6","author":"Waterbury","year":"2022","journal-title":"J. Endocr. Soc."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Harris, R.A., McAllister, J.M., and Strauss, J.F. (2023). Single-Cell RNA-Seq Identifies Pathways and Genes Contributing to the Hyperandrogenemia Associated with Polycystic Ovary Syndrome. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms241310611"},{"key":"ref_23","unstructured":"Dunaif, A., Givens, J.R., Haseltine, F., and Merriam, G.R. (1992). Diagnostic criteria for polycystic ovary syndrome: Toward a rationale approach. Polycystic Ovary Syndrome, Blackwell Scientific Publications."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1415","DOI":"10.4158\/EP15748.DSCPT2","article-title":"Guide to the best practices in the evaluation and treatment of Polycystic Ovary Syndrome-part 2","volume":"21","author":"Goodman","year":"2015","journal-title":"Endocr. Pract."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Shang, Y., Zhou, H., He, R., and Lu, W. (2021). Dietary Modification for Reproductive Health in Women With Polycystic Ovary Syndrome: A Systematic Review and Meta-Analysis. Front. Endocrinol., 12.","DOI":"10.3389\/fendo.2021.735954"},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Carmina, E., and Longo, R.A. (2023). Semaglutide Treatment of Excessive Body Weight in Obese PCOS Patients Unresponsive to Lifestyle Programs. J. Clin. Med., 12.","DOI":"10.3390\/jcm12185921"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Zhou, L., Qu, H., Yang, L., and Shou, L. (2023). Effects of GLP1RAs on pregnancy rate and menstrual cyclicity in women with polycystic ovary syndrome: A meta-analysis and systematic review. BMC Endocr. Disord., 23.","DOI":"10.1186\/s12902-023-01500-5"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Carmina, E., and Lobo, R.A. (2022). Comparing Lean and Obese PCOS in Different PCOS Phenotypes: Evidence That the Body Weight Is More Important than the Rotterdam Phenotype in Influencing the Metabolic Status. Diagnostics, 12.","DOI":"10.3390\/diagnostics12102313"},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Carmina, E. (2022). Need to Introduce the Finding of Obesity or Normal Body Weight in the Current Diagnostic Criteria and in the Classification of PCOS. Diagnostics, 12.","DOI":"10.3390\/diagnostics12102555"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"2289","DOI":"10.1093\/humrep\/deg440","article-title":"Difference in body weight between American and Italian women with Polycystic Ovary Syndrome: Influence of the diet","volume":"11","author":"Carmina","year":"2003","journal-title":"Hum. Reprod."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"927","DOI":"10.1210\/endrev\/bnac001","article-title":"Deconstructing a Syndrome: Genomic Insights Into PCOS Causal Mechanisms and Classification","volume":"43","author":"Dapas","year":"2022","journal-title":"Endocr. Rev."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"2197","DOI":"10.1016\/j.fertnstert.2010.02.014","article-title":"Clinical and endocrine characteristics of the main PCOS phenotypes","volume":"94","author":"Guastella","year":"2010","journal-title":"Fertil. Steril."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"252","DOI":"10.1038\/s41591-020-0751-5","article-title":"Using human genetics to understand the disease impacts of testosterone in men and women","volume":"26","author":"Ruth","year":"2020","journal-title":"Nat. Med."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1055\/s-0044-1787525","article-title":"Anti-M\u00fcllerian Hormone: A Molecular Key to Unlocking Polycystic Ovary Syndrome?","volume":"42","author":"Abbott","year":"2024","journal-title":"Semin. Reprod. Med."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1055\/s-0044-1786050","article-title":"Role of anti-Mullerian hormone in the central regulation of fertility","volume":"42","author":"Cotellessa","year":"2024","journal-title":"Semin. Reprod. Med."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"19","DOI":"10.5802\/crbiol.147","article-title":"Polycystic ovary syndrome (PCOS): Progress towards a better understanding and treatment of the syndrome","volume":"347","author":"Mimouni","year":"2024","journal-title":"C. R. Biol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"3835","DOI":"10.1210\/jc.2018-02496","article-title":"Family-Based Quantitative Trait Meta-Analysis Implicates Rare Noncoding Variants in DENND1A in Polycystic Ovary Syndrome","volume":"104","author":"Dapas","year":"2019","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Dhar, S., and Bhattacharjee, P. (2024). Clinical-exome sequencing unveils the genetic landscape of polycystic ovarian syndrome (PCOS) focusing on lean and obese phenotypes: Implications for cost-effective diagnosis and personalized treatment. Sci. Rep., 14.","DOI":"10.1038\/s41598-024-75719-0"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"3096","DOI":"10.1210\/clinem\/dgae298","article-title":"Clustering Identifies Subtypes With Different Phenotypic Characteristics in Women With Polycystic Ovary Syndrome","volume":"109","author":"Moolhuijsen","year":"2024","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Burns, K., Mullin, B.H., Moolhuijsen, L.M.E., Laisk, T., Tyrmi, J.S., Cui, J., Actkins, K.V., Louwers, Y.V., Davis, L.K., and Dudbridge, F. (2024). Body mass index stratified meta-analysis of genome-wide association studies of polycystic ovary syndrome in women of European ancestry. BMC Genom., 25.","DOI":"10.1186\/s12864-024-09990-w"},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Chen, Y., Wu, W.-J., Xing, L.-W., Zhang, X.-J., Wang, J., Xia, X.-Y., Zhao, R., and Zhao, R. (2023). Investigating the role of mitochondrial DNA D-loop variants, haplotypes, and copy number in polycystic ovary syndrome: Implications for clinical phenotypes in the Chinese population. Front. Endocrinol., 14.","DOI":"10.3389\/fendo.2023.1206995"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"631","DOI":"10.1007\/s00404-020-05951-2","article-title":"Association of metabolic and inflammatory markers with polycystic ovarian syndrome (PCOS): An update","volume":"303","author":"Gnanadass","year":"2021","journal-title":"Arch. Gynecol. Obstet."},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Wang, J., Yin, T., and Liu, S. (2023). Dysregulation of immune response in PCOS organ system. Front. Immunol., 14.","DOI":"10.3389\/fimmu.2023.1169232"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"e41359","DOI":"10.1097\/MD.0000000000041359","article-title":"Circulating cytokines levels and the risk of polycystic ovary syndrome: A Mendelian randomization analysis","volume":"104","author":"Jiang","year":"2025","journal-title":"Medicine"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"472","DOI":"10.1016\/j.tem.2024.12.002","article-title":"Epigenetic inheritance of PCOS by developmental programming and germline transmission","volume":"36","author":"Deng","year":"2025","journal-title":"Trends Endocrinol. Metab."}],"container-title":["Journal of Clinical Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2077-0383\/14\/10\/3347\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T17:31:05Z","timestamp":1760031065000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2077-0383\/14\/10\/3347"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,5,12]]},"references-count":45,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2025,5]]}},"alternative-id":["jcm14103347"],"URL":"https:\/\/doi.org\/10.3390\/jcm14103347","relation":{},"ISSN":["2077-0383"],"issn-type":[{"value":"2077-0383","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,5,12]]}}}