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Comment |
Polycystic ovary syndrome susceptibility single nucleotide polymorphisms in women with a single PCOS clinical feature. Cui L et al. (2015) 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? 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. 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. 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. 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. 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). The sample size of some case groups was relatively small, which therefore limited the statistical power of the analysis to a certain extent. 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. 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.//////////////////
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Mutations |
3 mutations
Species: human
Mutation name: None
type: naturally occurring
fertility: subfertile
Comment: Genome-wide association study identifies eight new risk loci for polycystic ovary syndrome. Shi Y et al. Following a previous genome-wide association study (GWAS 1) including 744 cases and 895 controls, we analyzed genome-wide association data from a new cohort of Han Chinese (GWAS 2) with 1,510 polycystic ovary syndrome (PCOS) cases and 2,016 controls. We followed up significantly associated signals identified in the combined results of GWAS 1 and 2 in a total of 8,226 cases and 7,578 controls. In addition to confirming the three loci we previously reported, we identify eight new PCOS association signals at P < 5 ?10(-8): 9q22.32, 11q22.1, 12q13.2, 12q14.3, 16q12.1, 19p13.3, 20q13.2 and a second independent signal at 2p16.3 (the FSHR gene). These PCOS association signals show evidence of enrichment for candidate genes related to insulin signaling, sexual hormone function and type 2 diabetes (T2D). Other candidate genes were related to calcium signaling and endocytosis. Our findings provide new insight and direction for discovering the biological mechanisms of PCOS.
Species: human
Mutation name: None
type: naturally occurring
fertility: subfertile
Comment: Cross-Ethnic Meta-analysis of Genetic Variants for Polycystic Ovary Syndrome. Louwers YV 2013 et al.
ContextGenome Wide Association Studies (GWAS) have revealed new susceptibility loci for Chinese patients with Polycystic Ovary Syndrome (PCOS). Since ethnic background adds to phenotypic diversities in PCOS, it seems plausible that genetic variants associated with PCOS act differently in various ethnic populations.ObjectiveWe studied cross-ethnic effects of Chinese PCOS loci, i.e., LHCGR, THADA, DENND1A, FSHR, c9orf3, YAP1, RAB5B/SUOX, HMGA2, TOX3, INSR, SUMO1P1, in patients of Northern European descent.DesignGenetic association study conducted at an University Medical Center.PatientsAssociation was studied in 703 Dutch PCOS patients and 2164 Dutch controls. To assess the cross-effect, we performed a meta-analysis of the Dutch data combined with results of previously published studies in PCOS patients from China (n=2254) and the United States (n=2618) (US). Adjusted for multiple testing, a p-value < 3.110(-3) was considered statistically significant.ResultsMeta-analysis of the Chinese, US and Dutch data resulted 12 significant variants mapping to the YAP1 (p-value=1.010(-9)), RAB5B/SUOX (p-value=3.810(-11)), LHCGR (p-value=4.110(-4)), THADA (p-value=2.210(-4) and p-value=1.310(-3)), DENND1A (p-value=2.310(-3) and p-value=2.510(-3)), FSHR (p-value=3.810(-5) and p-value=3.610(-4)), c9orf3 (p-value=2.010(-6) and p-value=9.210(-6)), SUMO1P1 (p-value=2.310(-3)) loci with ORs ranging from 1.19-1.45 and 0.79-0.87.ConclusionsOverall, we observed for 12 out of 17 genetic variants mapping to the Chinese PCOS loci similar effect size and identical direction in PCOS patients from Northern European ancestry, indicating a common genetic risk profile for PCOS across populations. Therefore, it is expected, that large GWAS in PCOS patients from Northern European ancestry will partly identify similar loci as the GWAS in Chinese PCOS patients.
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Species: human
Mutation name:
type: naturally occurring
fertility: subfertile
Comment: Family-based analysis of eight susceptibility loci in polycystic ovary syndrome. Zhao S et al. (2015) Polycystic ovary syndrome (PCOS) is a complex endocrine disorder that is proposed to have a genetic basis. A recent genome-wide association study (GWAS) identified eight new risk loci that are independently associated with PCOS. To further validate the findings, a total of 321 case-parent trios (963 participants) who had a proband affected with PCOS were recruited for the family-based study. The transmission disequilibrium test (TDT) was used to analyze associations between PCOS and ten single nucleotide polymorphisms (SNPs) mapped to eight new susceptibility loci. Significant differences in transmission were observed for the SNPs rs2349415 (located in the FSHR gene, P = 0.0001) and rs3802457 (located in the C9orf3 gene, P = 0.0001), even after correction for multiple testing bias. The present data provides further evidence for an association between two susceptibility loci, 2p16.3 and 9q22.32, and PCOS. Follow-up functional studies on the FSHR and C9orf3 genes are required to understand their roles in PCOS development.//////////////////
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