Semin Reprod Med 2016; 34(04): 224-229
DOI: 10.1055/s-0036-1585403
Review Article
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Genome-Wide Association Studies for Polycystic Ovary Syndrome

Hongbin Liu
1   Center for Reproductive Medicine, Shandong University, National Research Center for Assisted Reproductive Technology and Reproductive Genetics, The Key Laboratory for Reproductive Endocrinology of Ministry of Education, Jinan, China
2   The Chinese University of Hong Kong-Shandong University Joint Laboratory on Reproductive Genetics, School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China
,
Han Zhao
1   Center for Reproductive Medicine, Shandong University, National Research Center for Assisted Reproductive Technology and Reproductive Genetics, The Key Laboratory for Reproductive Endocrinology of Ministry of Education, Jinan, China
,
Zi-Jiang Chen
1   Center for Reproductive Medicine, Shandong University, National Research Center for Assisted Reproductive Technology and Reproductive Genetics, The Key Laboratory for Reproductive Endocrinology of Ministry of Education, Jinan, China
3   Center for Reproductive Medicine, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Key Laboratory for Assisted Reproduction and Reproductive Genetics, Shanghai, China
› Author Affiliations
Further Information

Publication History

Publication Date:
11 August 2016 (online)

Abstract

Over the past several years, the field of reproductive medicine has witnessed great advances in genome-wide association studies (GWASs) of polycystic ovary syndrome (PCOS), leading to identification of several promising genes involved in hormone action, type 2 diabetes, and cell proliferation. This review summarizes the key findings and discusses their potential implications with regard to genetic mechanisms of PCOS. Limitations of GWAS are evaluated, emphasizing the understanding of the reasons for variability in results between individual studies. Root causes of misinterpretations of GWASs are also addressed. Finally, the impact of GWAS on future directions of multi- and interdisciplinary studies is discussed.

 
  • References

  • 1 Ehrmann DA, Barnes RB, Rosenfield RL, Cavaghan MK, Imperial J. Prevalence of impaired glucose tolerance and diabetes in women with polycystic ovary syndrome. Diabetes Care 1999; 22 (1) 141-146
  • 2 Goodarzi MO, Azziz R. Diagnosis, epidemiology, and genetics of the polycystic ovary syndrome. Best Pract Res Clin Endocrinol Metab 2006; 20 (2) 193-205
  • 3 Knochenhauer ES, Key TJ, Kahsar-Miller M, Waggoner W, Boots LR, Azziz R. Prevalence of the polycystic ovary syndrome in unselected black and white women of the southeastern United States: a prospective study. J Clin Endocrinol Metab 1998; 83 (9) 3078-3082
  • 4 Diamanti-Kandarakis E, Kouli CR, Bergiele AT , et al. A survey of the polycystic ovary syndrome in the Greek island of Lesbos: hormonal and metabolic profile. J Clin Endocrinol Metab 1999; 84 (11) 4006-4011
  • 5 Carmina E. Cardiovascular risk and events in polycystic ovary syndrome. Climacteric 2009; 12 (Suppl. 01) 22-25
  • 6 Kandaraki E, Christakou C, Diamanti-Kandarakis E. Metabolic syndrome and polycystic ovary syndrome... and vice versa. Arq Bras Endocrinol Metabol 2009; 53 (2) 227-237
  • 7 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) 2000; 3 (2) 101-105
  • 8 McAllister JM, Legro RS, Modi BP, Strauss III JF. Functional genomics of PCOS: from GWAS to molecular mechanisms. Trends Endocrinol Metab 2015; 26 (3) 118-124
  • 9 Welt CK, Duran JM. Genetics of polycystic ovary syndrome. Semin Reprod Med 2014; 32 (3) 177-182
  • 10 Chen ZJ, Zhao H, He L , et al. Genome-wide association study identifies susceptibility loci for polycystic ovary syndrome on chromosome 2p16.3, 2p21 and 9q33.3. Nat Genet 2011; 43 (1) 55-59
  • 11 Shi Y, Zhao H, Shi Y , et al. Genome-wide association study identifies eight new risk loci for polycystic ovary syndrome. Nat Genet 2012; 44 (9) 1020-1025
  • 12 Goodarzi MO, Jones MR, Li X , et al. Replication of association of DENND1A and THADA variants with polycystic ovary syndrome in European cohorts. J Med Genet 2012; 49 (2) 90-95
  • 13 Welt CK, Styrkarsdottir U, Ehrmann DA , et al. Variants in DENND1A are associated with polycystic ovary syndrome in women of European ancestry. J Clin Endocrinol Metab 2012; 97 (7) E1342-E1347
  • 14 Eriksen MB, Nielsen MFB, Brusgaard K , et al. Genetic alterations within the DENND1A gene in patients with polycystic ovary syndrome (PCOS). PLoS ONE 2013; 8 (9) e77186
  • 15 Gammoh E, Arekat MR, Saldhana FL, Madan S, Ebrahim BH, Almawi WY. DENND1A gene variants in Bahraini Arab women with polycystic ovary syndrome. Gene 2015; 560 (1) 30-33
  • 16 Zhao H, Xu X, Xing X , et al. Family-based analysis of susceptibility loci for polycystic ovary syndrome on chromosome 2p16.3, 2p21 and 9q33.3. Hum Reprod 2012; 27 (1) 294-298
  • 17 Cui L, Zhao H, Zhang B , et al. Genotype-phenotype correlations of PCOS susceptibility SNPs identified by GWAS in a large cohort of Han Chinese women. Hum Reprod 2013; 28 (2) 538-544
  • 18 Hayes MG, Urbanek M, Ehrmann DA , et al; Reproductive Medicine Network. Genome-wide association of polycystic ovary syndrome implicates alterations in gonadotropin secretion in European ancestry populations. Nat Commun 2015; 6: 7502
  • 19 Hwang JY, Lee EJ, Jin Go M , et al. Genome-wide association study identifies GYS2 as a novel genetic factor for polycystic ovary syndrome through obesity-related condition. J Hum Genet 2012; 57 (10) 660-664
  • 20 Lee H, Oh JY, Sung YA , et al. Genome-wide association study identified new susceptibility loci for polycystic ovary syndrome. Hum Reprod 2015; 30 (3) 723-731
  • 21 Liu YJ, Zhang L, Pei Y, Papasian CJ, Deng HW. On genome-wide association studies and their meta-analyses: lessons learned from osteoporosis studies. J Clin Endocrinol Metab 2013; 98 (7) E1278-E1282
  • 22 Vink JM, Sadrzadeh S, Lambalk CB, Boomsma DI. Heritability of polycystic ovary syndrome in a Dutch twin-family study. J Clin Endocrinol Metab 2006; 91 (6) 2100-2104
  • 23 Chang J, Azziz R, Legro R , et al; 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 2004; 81 (1) 19-25
  • 24 Yilmaz M, Isaoglu U, Delibas IB, Kadanali S. Anthropometric, clinical and laboratory comparison of four phenotypes of polycystic ovary syndrome based on Rotterdam criteria. J Obstet Gynaecol Res 2011; 37 (8) 1020-1026
  • 25 Panidis D, Tziomalos K, Misichronis G , et al. Insulin resistance and endocrine characteristics of the different phenotypes of polycystic ovary syndrome: a prospective study. Hum Reprod 2012; 27 (2) 541-549
  • 26 McCarroll SA, Altshuler DM. Copy-number variation and association studies of human disease. Nat Genet 2007; 39 (7, Suppl): S37-S42
  • 27 D'Angelo CS, Koiffmann CP. Copy number variants in obesity-related syndromes: review and perspectives on novel molecular approaches. J Obes 2012; 2012: 845480
  • 28 Yang TL, Chen XD, Guo Y , et al. Genome-wide copy-number-variation study identified a susceptibility gene, UGT2B17, for osteoporosis. Am J Hum Genet 2008; 83 (6) 663-674
  • 29 Oei L, Hsu YH, Styrkarsdottir U , et al. A genome-wide copy number association study of osteoporotic fractures points to the 6p25.1 locus. J Med Genet 2014; 51 (2) 122-131
  • 30 Cantor RM, Lange K, Sinsheimer JS. Prioritizing GWAS results: a review of statistical methods and recommendations for their application. Am J Hum Genet 2010; 86 (1) 6-22
  • 31 Ramanan VK, Shen L, Moore JH, Saykin AJ. Pathway analysis of genomic data: concepts, methods, and prospects for future development. Trends Genet 2012; 28 (7) 323-332
  • 32 Wang K, Li M, Bucan M. Pathway-based approaches for analysis of genomewide association studies. Am J Hum Genet 2007; 81 (6) 1278-1283
  • 33 Shim U, Kim HN, Lee H, Oh JY, Sung YA, Kim HL. Pathway analysis based on a genome-wide association study of polycystic ovary syndrome. PLoS ONE 2015; 10 (8) e0136609
  • 34 Day FR, Hinds DA, Tung JY , et al. Causal mechanisms and balancing selection inferred from genetic associations with polycystic ovary syndrome. Nat Commun 2015; 6: 8464
  • 35 Liu YZ, Pei YF, Liu JF , et al. Powerful bivariate genome-wide association analyses suggest the SOX6 gene influencing both obesity and osteoporosis phenotypes in males. PLoS ONE 2009; 4 (8) e6827
  • 36 Li H, Durbin R. Inference of human population history from individual whole-genome sequences. Nature 2011; 475 (7357) 493-496
  • 37 Gronau I, Hubisz MJ, Gulko B, Danko CG, Siepel A. Bayesian inference of ancient human demography from individual genome sequences. Nat Genet 2011; 43 (10) 1031-1034
  • 38 Azziz R, Dumesic DA, Goodarzi MO. Polycystic ovary syndrome: an ancient disorder?. Fertil Steril 2011; 95 (5) 1544-1548
  • 39 Gorlov IP, Gorlova OY, Sunyaev SR, Spitz MR, Amos CI. Shifting paradigm of association studies: value of rare single-nucleotide polymorphisms. Am J Hum Genet 2008; 82 (1) 100-112
  • 40 Bodmer W, Bonilla C. Common and rare variants in multifactorial susceptibility to common diseases. Nat Genet 2008; 40 (6) 695-701
  • 41 Wang P, Zhao H, Li T , et al. Hypomethylation of the LH/choriogonadotropin receptor promoter region is a potential mechanism underlying susceptibility to polycystic ovary syndrome. Endocrinology 2014; 155 (4) 1445-1452
  • 42 Jones MR, Brower MA, Xu N , et al. Systems genetics reveals the functional context of PCOS loci and identifies genetic and molecular mechanisms of disease heterogeneity. PLoS Genet 2015; 11 (8) e1005455