title: Polycystic ovary syndrome susceptibility single nucleotide polymorphisms in women with a single PCOS clinical feature.
abstract: OBJECTIVE
  What is the direct genetic contribution of the polycystic ovary syndrome (PCOS) susceptibility single nucleotide polymorphisms (SNPs), identified by previous genome-wide association studies (GWAS) to the definitive clinical features of the syndrome?
  
  
  CONCLUSIONS
  Each single PCOS clinical feature had a specific genetic association, and rs4385527 in the chromosome 9 open reading frame 3 (C9orf3) conferred a particular risk to the three defined PCOS clinical features in this study, which suggested its fundamental role in the etiology of PCOS.
  
  
  BACKGROUND
  PCOS is a heterogeneous disorder characterized by anovulation (OA), hyperandrogenism (HA) and polycystic ovary morphology (PCOM). Two previous GWAS in China have identified 15 independent susceptibility SNPs related to PCOS (PCOS-SNPs). However, little is known about the candidate gene of each clinical feature.
  
  
  METHODS
  Case-control study. Three independent groups of women were recruited from 2010 to 2012: 746 subjects with OA only, 278 subjects with HA only and 536 subjects with PCOM only. A total of 1790 healthy women with none of the above pathological characteristics were also enrolled as control subjects during the same time period.
  
  
  METHODS
  All participants were women of reproductive age. Genotype and allelic frequencies of 15 PCOS-SNPs were determined in all subjects using direct sequencing and Sequenom Arrays. The allelic frequencies of each case group were compared with the controls.
  
  
  RESULTS
  After adjustment for age and BMI, variants in luteinizing hormone/choriogonadotropin receptor (LHCGR) (rs13405728), C9orf3 (rs4385527) and insulin receptor gene (INSR) (rs2059807) were strongly associated with OA (Padjust < 0.01, <0.001 and <0.05, respectively); rs4385527 in C9orf3 was strongly associated with HA (Padjust< 0.001); variants in the thyroid adenoma associated gene (THADA) (rs13429458 and rs12478601), DENN/MADD domain containing 1A (DENND1A)(rs10818854), and C9orf3 (rs4385527) were significantly associated with PCOM (Padjust < 0.01, <0.001, <0.05 and <0.001, respectively).
  
  
  CONCLUSIONS
  The sample size of some case groups was relatively small, which therefore limited the statistical power of the analysis to a certain extent.
  
  
  CONCLUSIONS
  The present study indicates a potential common genetic basis of three PCOS clinical features. Other specific associated genes may play a synergistic role, leading to heterogeneous pathophysiological changes. Additionally, the increased frequency of PCOS-risk alleles in women with single PCOS clinical features suggests that these subjects have an elevated risk of developing the syndrome, although they cannot be currently diagnosed.
  
  
  BACKGROUND
  This research was supported by the National Basic Research Program of China (973 Program) (2012CB944700, 2011CB944502), the National Key Technology Research and Development Program(2011BAI17B00), the National Natural Science Foundation of China (81430029, 81201441, 81490743, 31371453), the Scientific Research Foundation of Shandong Province of Outstanding Young Scientist (2012BSE27089) and the Fundamental Research Funds of Shandong University(2014GN025). There were no competing interests.
authors.affiliation: Center for Reproductive Medicine, Provincial Hospital Affiliated to Shandong University, Jingliu Road 157, Jinan 250001, China The Key Laboratory for Reproductive Endocrinology of Ministry of Education, Jinan, China Shandong Provincial Key Laboratory of Reproductive Medicine, Jinan 250001 China National Research Center for Assisted Reproductive Technology and Reproductive Genetics, Jinan 250001 China.
authors.forename: Linlin
authors.initials: L
authors.lastname: Cui
authors.affiliation: Reproductive Medical Hospital Affiliated to Shandong University, Jinan 250001, China.
authors.forename: Guangyu
authors.initials: G
authors.lastname: Li
authors.affiliation: Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200000, China Shanghai Key Laboratory for Assisted Reproduction and Reproductive Genetics, Shanghai 200000, China.
authors.forename: Wanxia
authors.initials: W
authors.lastname: Zhong
authors.affiliation: Reproductive Medical Hospital Affiliated to Shandong University, Jinan 250001, China.
authors.forename: Yuehong
authors.initials: Y
authors.lastname: Bian
authors.affiliation: Reproductive Medical Hospital Affiliated to Shandong University, Jinan 250001, China.
authors.forename: Shizhen
authors.initials: S
authors.lastname: Su
authors.affiliation: Center for Reproductive Medicine, Provincial Hospital Affiliated to Shandong University, Jingliu Road 157, Jinan 250001, China The Key Laboratory for Reproductive Endocrinology of Ministry of Education, Jinan, China Shandong Provincial Key Laboratory of Reproductive Medicine, Jinan 250001 China National Research Center for Assisted Reproductive Technology and Reproductive Genetics, Jinan 250001 China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Sheng
authors.affiliation: Center for Reproductive Medicine, Provincial Hospital Affiliated to Shandong University, Jingliu Road 157, Jinan 250001, China The Key Laboratory for Reproductive Endocrinology of Ministry of Education, Jinan, China Shandong Provincial Key Laboratory of Reproductive Medicine, Jinan 250001 China National Research Center for Assisted Reproductive Technology and Reproductive Genetics, Jinan 250001 China.
authors.forename: Yuhua
authors.initials: Y
authors.lastname: Shi
authors.affiliation: Reproductive Medical Hospital Affiliated to Shandong University, Jinan 250001, China.
authors.forename: Daimin
authors.initials: D
authors.lastname: Wei
authors.affiliation: Department of Joint and Bone Oncology, Provincial Hospital Affiliated to Shandong University, Jinan 250001, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Center for Reproductive Medicine, Provincial Hospital Affiliated to Shandong University, Jingliu Road 157, Jinan 250001, China The Key Laboratory for Reproductive Endocrinology of Ministry of Education, Jinan, China Shandong Provincial Key Laboratory of Reproductive Medicine, Jinan 250001 China National Research Center for Assisted Reproductive Technology and Reproductive Genetics, Jinan 250001 China chenzijiang@hotmail.com hanzh80@yahoo.com.
authors.forename: Han
authors.initials: H
authors.lastname: Zhao
authors.affiliation: Center for Reproductive Medicine, Provincial Hospital Affiliated to Shandong University, Jingliu Road 157, Jinan 250001, China The Key Laboratory for Reproductive Endocrinology of Ministry of Education, Jinan, China Shandong Provincial Key Laboratory of Reproductive Medicine, Jinan 250001 China National Research Center for Assisted Reproductive Technology and Reproductive Genetics, Jinan 250001 China Reproductive Medical Hospital Affiliated to Shandong University, Jinan 250001, China Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200000, China Shanghai Key Laboratory for Assisted Reproduction and Reproductive Genetics, Shanghai 200000, China chenzijiang@hotmail.com hanzh80@yahoo.com.
authors.forename: Zi-Jiang
authors.initials: ZJ
authors.lastname: Chen
mesh_terms: D000328:Adult; D016022:Case-Control Studies; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D011085:Polycystic Ovary Syndrome / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide
keywords: PCOS; SNP; anovulation; hyperandrogenism; polycystic ovary