Abstract
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.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Ehrmann, D.A., Barnes, R.B., Rosenfield, R.L., Cavaghan, M.K. & Imperial, J. Prevalence of impaired glucose tolerance and diabetes in women with polycystic ovary syndrome. Diabetes Care 22, 141–146 (1999).
Goodarzi, M.O. & Azziz, R. Diagnosis, epidemiology, and genetics of the polycystic ovary syndrome. Best Pract. Res. Clin. Endocrinol. Metab. 20, 193–205 (2006).
Carmina, E. Cardiovascular risk and events in polycystic ovary syndrome. Climacteric 12, 22–25 (2009).
Kandaraki, E., Christakou, C. & Diamanti-Kandarakis, E. Metabolic syndrome and polycystic ovary syndrome and vice versa. Arq. Bras. Endocrinol. Metabol. 53, 227–237 (2009).
Wild, S., Pierpoint, T., Jacobs, H. & McKeigue, P. Long-term consequences of polycystic ovary syndrome: results of a 31 year follow-up study. Hum. Fertil. (Camb) 3, 101–105 (2000).
Chen, Z.J. et al. Genome-wide association study identifies susceptibility loci for polycystic ovary syndrome on chromosome 2p16.3, 2p21 and 9q33.3. Nat. Genet. 43, 55–59 (2011).
Kerns, S.L. et al. Genome-wide association study to identify single nucleotide polymorphisms (SNPs) associated with the development of erectile dysfunction in African-American men after radiotherapy for prostate cancer. Int. J. Radiat. Oncol. Biol. Phys. 78, 1292–1300 (2010).
Li, T. et al. Identification of YAP1 as a novel susceptibility gene for polycystic ovary syndrome. J. Med. Genet. 49, 254–257 (2012).
Hao, Y., Chun, A., Cheung, K., Rashidi, B. & Yang, X. Tumor suppressor LATS1 is a negative regulator of oncogene YAP. J. Biol. Chem. 283, 5496–5509 (2008).
Barrett, J.C. et al. Genome-wide association study and meta-analysis find that over 40 loci affect risk of type 1 diabetes. Nat. Genet. 41, 703–707 (2009).
Wellcome Trust Case Control Consortium. Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 447, 661–678 (2007).
Cooper, J.D. et al. Meta-analysis of genome-wide association study data identifies additional type 1 diabetes risk loci. Nat. Genet. 40, 1399–1401 (2008).
Plagnol, V. et al. Genome-wide association analysis of autoantibody positivity in type 1 diabetes cases. PLoS Genet. 7, e1002216 (2011).
Todd, J.A. et al. Robust associations of four new chromosome regions from genome-wide analyses of type 1 diabetes. Nat. Genet. 39, 857–864 (2007).
Hakonarson, H. et al. A novel susceptibility locus for type 1 diabetes on Chr12q13 identified by a genome-wide association study. Diabetes 57, 1143–1146 (2008).
Wang, H. et al. Genetically dependent ERBB3 expression modulates antigen presenting cell function and type 1 diabetes risk. PLoS ONE 5, e11789 (2010).
Weedon, M.N. et al. A common variant of HMGA2 is associated with adult and childhood height in the general population. Nat. Genet. 39, 1245–1250 (2007).
Kazmierczak, B. et al. Cloning and molecular characterization of part of a new gene fused to HMGIC in mesenchymal tumors. Am. J. Pathol. 152, 431–435 (1998).
Voight, B.F. et al. Twelve type 2 diabetes susceptibility loci identified through large-scale association analysis. Nat. Genet. 42, 579–589 (2010).
Ashar, H.R. et al. Disruption of the architectural factor HMGI-C: DNA-binding AT hook motifs fused in lipomas to distinct transcriptional regulatory domains. Cell 82, 57–65 (1995).
Moller, D.E. & Flier, J.S. Detection of an alteration in the insulin-receptor gene in a patient with insulin resistance, acanthosis nigricans, and the polycystic ovary syndrome (type A insulin resistance). N. Engl. J. Med. 319, 1526–1529 (1988).
Moller, D.E., Yokota, A., White, M.F., Pazianos, A.G. & Flier, J.S. A naturally occurring mutation of insulin receptor alanine 1134 impairs tyrosine kinase function and is associated with dominantly inherited insulin resistance. J. Biol. Chem. 265, 14979–14985 (1990).
Taylor, S.I. et al. Mutations in insulin-receptor gene in insulin-resistant patients. Diabetes Care 13, 257–279 (1990).
Chen, Z.J. et al. Correlation between single nucleotide polymorphism of insulin receptor gene with polycystic ovary syndrome. Zhonghua Fu Chan Ke Za Zhi 39, 582–585 (2004).
Siegel, S. et al. AC/T single nucleotide polymorphism at the tyrosine kinase domain of the insulin receptor gene is associated with polycystic ovary syndrome. Fertil. Steril. 78, 1240–1243 (2002).
Accili, D. et al. Early neonatal death in mice homozygous for a null allele of the insulin receptor gene. Nat. Genet. 12, 106–109 (1996).
Simoni, M., Tempfer, C.B., Destenaves, B. & Fauser, B. Functional genetic polymorphisms and female reproductive disorders: Part I: polycystic ovary syndrome and ovarian response. Hum. Reprod. Update 14, 459–484 (2008).
Sun, L. et al. FSH directly regulates bone mass. Cell 125, 247–260 (2006).
O'Flaherty, E. & Kaye, J. TOX defines a conserved subfamily of HMG-box proteins. BMC Genomics 4, 13 (2003).
Huang, G. et al. ZNF217 suppresses cell death associated with chemotherapy and telomere dysfunction. Hum. Mol. Genet. 14, 3219–3225 (2005).
Sudo, S. et al. Genetic and functional analyses of polymorphisms in the human FSH receptor gene. Mol. Hum. Reprod. 8, 893–899 (2002).
Zeggini, E. et al. Meta-analysis of genome-wide association data and large-scale replication identifies additional susceptibility loci for type 2 diabetes. Nat. Genet. 40, 638–645 (2008).
Cooper, J.D. et al. Analysis of 55 autoimmune disease and type II diabetes loci: further confirmation of chromosomes 4q27, 12q13.2 and 12q24.13 as type I diabetes loci, and support for a new locus, 12q13.3-q14.1. Genes Immun. 10, S95–S120 (2009).
Mi, H. et al. PANTHER version 7: improved phylogenetic trees, orthologs and collaboration with the Gene Ontology Consortium. Nucleic Acids Res. 38, D204–D210 (2010).
Thomas, P.D. et al. PANTHER: a browsable database of gene products organized by biological function, using curated protein family and subfamily classification. Nucleic Acids Res. 31, 334–341 (2003).
Joshi-Tope, G. et al. Reactome: a knowledgebase of biological pathways. Nucleic Acids Res. 33, D428–D432 (2005).
Matthews, L. et al. Reactome knowledgebase of human biological pathways and processes. Nucleic Acids Res. 37, D619–D622 (2009).
Ogata, H. et al. KEGG: Kyoto encyclopedia of genes and genomes. Nucleic Acids Res. 27, 29–34 (1999).
Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group. Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome. Fertil. Steril. 81, 19–25 (2004).
Li, Y., Willer, C.J., Ding, J., Scheet, P. & Abecasis, G.R. MaCH: using sequence and genotype data to estimate haplotypes and unobserved genotypes. Genet. Epidemiol. 34, 816–834 (2010).
Li, Y., Willer, C., Sanna, S. & Abecasis, G. Genotype imputation. Annu. Rev. Genomics Hum. Genet. 10, 387–406 (2009).
Marchini, J., Howie, B., Myers, S., McVean, G. & Donnelly, P. A new multipoint method for genome-wide association studies by imputation of genotypes. Nat. Genet. 39, 906–913 (2007).
Howie, B.N., Donnelly, P. & Marchini, J. A flexible and accurate genotype imputation method for the next generation of genome-wide association studies. PLoS Genet. 5, e1000529 (2009).
Price, A.L. et al. Principal components analysis corrects for stratification in genome-wide association studies. Nat. Genet. 38, 904–909 (2006).
Lindgren, C.M. et al. Genome-wide association scan meta-analysis identifies three loci influencing adiposity and fat distribution. PLoS Genet. 5, e1000508 (2009).
Purcell, S. et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am. J. Hum. Genet. 81, 559–575 (2007).
Pruim, R.J. et al. LocusZoom: regional visualization of genome-wide association scan results. Bioinformatics 26, 2336–2337 (2010).
Shi, Y.Y. & He, L. SHEsis, a powerful software platform for analyses of linkage disequilibrium, haplotype construction, and genetic association at polymorphism loci. Cell Res. 15, 97–98 (2005).
Petukhova, L. et al. Genome-wide association study in alopecia areata implicates both innate and adaptive immunity. Nature 466, 113–117 (2010).
Shi, Y. et al. Common variants on 8p12 and 1q24. 2 confer risk of schizophrenia. Nat. Genet. 43, 1224–1227 (2011).
Acknowledgements
We thank all participants involved in this study. This study was supported by grants from the National Basic Research Program of China (973 Program: 2012CB944700, 2010CB529600, 2011CB944502 and 2010CB945002), the 863 Program (2012AA02A515), the National Natural Science Foundation of China (81130022, 30973170, 81121001, 31000553, 81000238, 81070461 and 81000236), the National Key Technology Research and Development Program (2011BAI17B00), the Science Research Foundation Item of No-earnings Health Vocation (201002013), the Program for Changjiang Scholars and the Innovative Research Team in University (IRT1025), the Foundation for the Author of National Excellent Doctoral Dissertation of China (201026) and the Program for New Century Excellent Talents in University (NCET-09-0550).
Author information
Authors and Affiliations
Contributions
Z.-J.C., L.H. and Yongyong Shi designed the whole study. Yongyong Shi supervised the experiments and data analysis. Z.-J.C. supervised patient diagnosis and sample recruitment. Yongyong Shi, Z.L., H.Z., T.L. and J. Shen conducted data analyses and drafted the manuscript. H.Z., Yuhua Shi, L.G., J.M., Yingying Qin and J. Yan recruited samples. Y.C., D.Y., B.Z., X. Liang, Junzhao Zhao, D. Zhu, X.Z., Y.Y., Junli Zhao, S.Z., A.Y., J.L., J. Shi, J. Yang, H.J., J.X., X.Q., Y. Sun, Yajie Zhang, C.H., X.J., D. Zhao, C.R., X. Li, W.Z. and Yiwen Zhang coordinated and provided samples from different hospitals. J.C., Wenjin Li, Q.W., G.H., A.Z., Weidong Li, C.W., B.L. and Ying Qin performed or contributed to the main experiments. L.Y., Y. Zhao, D.W. and C.Z. performed DNA extraction. X.G and J.Z. performed endocrine biochemical examination. All authors critically reviewed the manuscript and approved the final version.
Corresponding authors
Ethics declarations
Competing interests
The authors declare no competing financial interests.
Supplementary information
Rights and permissions
About this article
Cite this article
Shi, Y., Zhao, H., Shi, Y. et al. Genome-wide association study identifies eight new risk loci for polycystic ovary syndrome. Nat Genet 44, 1020–1025 (2012). https://doi.org/10.1038/ng.2384
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/ng.2384
This article is cited by
-
Molecular Mechanisms in the Etiology of Polycystic Ovary Syndrome (PCOS): A Multifaceted Hypothesis Towards the Disease with Potential Therapeutics
Indian Journal of Clinical Biochemistry (2024)
-
Obesity contributes to telomere shortening in polycystic ovary syndrome
Reproductive Sciences (2024)
-
Susceptibility loci identified in Han Chinese influence genetic predisposition of PCOS in Indian women
Molecular Biology Reports (2024)
-
Induced Pluripotent Stem Cells as a Possible Approach for Exploring the Pathophysiology of Polycystic Ovary Syndrome (PCOS)
Stem Cell Reviews and Reports (2024)
-
Body mass index stratified meta-analysis of genome-wide association studies of polycystic ovary syndrome in women of European ancestry
BMC Genomics (2024)
