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As a heritable disease that impairs fertility, PCOS should diminish rapidly in prevalence; however, it is the most common cause of female subfertility globally. Few scientific genetic studies have attempted to provide evidence for the positive selection of gene variants underlying PCOS.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>STUDY DESIGN, SIZE, DURATION<\/jats:title>\n                  <jats:p>We performed an evolutionary analysis of 2,504 individuals from 14 populations of the 1000 Genomes Project.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>PARTICIPANTS\/MATERIALS, SETTING, METHODS<\/jats:title>\n                  <jats:p>We tested the signature of positive selection for 37 single-nucleotide polymorphisms (SNPs) associated with PCOS in previous genome-wide association studies using six parameters of positive selection.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>MAIN RESULTS AND THE ROLE OF CHANCE<\/jats:title>\n                  <jats:p>Analyzing the evolutionary indices together, there was obvious positive selection at the PCOS-related SNPs loci, especially within the original evolution window of humans, demonstrated by significant Tajima\u2019s D values. Compared to the genome background, six of the 37 SNPs in or close to five genes (DENN domain-containing protein 1A: DENND1A, chromosome 9 open reading frame 3: AOPEP, aminopeptidase O: THADA, diacylglycerol kinase iota: DGKI, and netrin receptor UNC5C: UNC5C) showed significant evidence of positive selection, among which DENND1A, AOPEP, and THADA represent the set of most established susceptibility genes for PCOS.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>LIMITATIONS, REASONS FOR CAUTION<\/jats:title>\n                  <jats:p>First, only well-documented SNPs were selected from well-designed experiments. Second, it is difficult to determine which hypothesis of PCOS evolution is at play. After considering the most significant functions of these genes, we found that they had a wide variety of functions with no obvious association between them.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>WIDER IMPLICATIONS OF THE FINDINGS<\/jats:title>\n                  <jats:p>Our findings provide additional evidence for the positive evolution of PCOS. Our analyses require confirmation in a larger study with more evolutionary indicators and larger data range. Further research to identify the roles of the DENND1A, AOPEP, THADA, DGKI, and UNC5C genes is also necessary.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>STUDY FUNDING\/COMPETING INTEREST(S)<\/jats:title>\n                  <jats:p>This study was supported by the National Key Research and Development Program of China (2021YFC2700400 and 2021YFC2700701), Basic Science Center Program of NSFC (31988101), CAMS Innovation Fund for Medical Sciences (2021-I2M-5-001), National Natural Science Foundation of China (82192874, 31871509, and 82071606), Shandong Provincial Key Research and Development Program (2020ZLYS02), Taishan Scholars Program of Shandong Province (ts20190988), and Fundamental Research Funds of Shandong University. The authors have no conflicts of interest to disclose.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>TRIAL REGISTRATION NUMBER<\/jats:title>\n                  <jats:p>N\/A.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/humrep\/dead106","type":"journal-article","created":{"date-parts":[[2023,11,20]],"date-time":"2023-11-20T10:53:23Z","timestamp":1700477603000},"page":"ii57-ii68","source":"Crossref","is-referenced-by-count":11,"title":["Evidence of positive selection of genetic variants associated with PCOS"],"prefix":"10.1093","volume":"38","author":[{"given":"Zhiheng","family":"Yu","sequence":"first","affiliation":[{"name":"Hospital for Reproductive Medicine, Shandong University , Jinan, China"},{"name":"Key Laboratory of Reproductive Endocrinology of Ministry of Education, Shandong University , Jinan, China"},{"name":"Shandong Key Laboratory of Reproductive Medicine , Jinan, China"},{"name":"National Research Center for 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and Reproductive Genetics, Shandong University, Jinan, China"},{"name":"State Key Laboratory of Reproductive Medicine and Offspring Health , Jinan, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fan","family":"Liu","sequence":"additional","affiliation":[{"name":"CAS Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences , Beijing, China"},{"name":"Department of Forensic Science, College of Justice, Naif Arab University for Security Sciences , Riyadh, Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9515-7534","authenticated-orcid":false,"given":"Han","family":"Zhao","sequence":"additional","affiliation":[{"name":"Hospital for Reproductive Medicine, Shandong University , Jinan, China"},{"name":"Key Laboratory of Reproductive Endocrinology of Ministry of Education, Shandong University , Jinan, China"},{"name":"Shandong Key Laboratory of Reproductive 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