Evidence for chromosome 2p16.3 polycystic ovary syndrome susceptibility locus in affected women of European ancestry.

CONTEXT A previous genome-wide association study in Chinese women with polycystic ovary syndrome (PCOS) identified a region on chromosome 2p16.3 encoding the LH/choriogonadotropin receptor (LHCGR) and FSH receptor (FSHR) genes as a reproducible PCOS susceptibility locus. OBJECTIVE The objective of the study was to determine the role of the LHCGR and/or FSHR gene in the etiology of PCOS in women of European ancestry. DESIGN This was a genetic association study in a European ancestry cohort of women with PCOS. SETTING The study was conducted at an academic medical center. PARTICIPANTS Participants in the study included 905 women with PCOS diagnosed by National Institutes of Health criteria and 956 control women. INTERVENTION We genotyped 94 haplotype-tagging single-nucleotide polymorphisms and two coding single-nucleotide polymorphisms mapping to the coding region of LHCGR and FSHR plus 20 kb upstream and downstream of the genes and test for association in the case control cohort and for association with nine quantitative traits in the women with PCOS. RESULTS We found strong evidence for an association of PCOS with rs7562215 (P = 0.0037) and rs10495960 (P = 0.0046). Although the marker with the strongest association in the Chinese PCOS genome-wide association study (rs13405728) was not informative in the European populations, we identified and genotyped three markers (rs35960650, rs2956355, and rs7562879) within 5 kb of rs13405728. Of these, rs7562879 was nominally associated with PCOS (P = 0.020). The strongest evidence for association mapping to FSHR was observed with rs1922476 (P = 0.0053). Furthermore, markers with the FSHR gene region were associated with FSH levels in women with PCOS. CONCLUSIONS Fine mapping of the chromosome 2p16.3 Chinese PCOS susceptibility locus in a European ancestry cohort provides evidence for association with two independent loci and PCOS. The gene products LHCGR and FSHR therefore are likely to be important in the etiology of PCOS, regardless of ethnicity.

[1]  K. Brusgaard,et al.  Association of polycystic ovary syndrome susceptibility single nucleotide polymorphism rs2479106 and PCOS in Caucasian patients with PCOS or hirsutism as referral diagnosis. , 2012, European journal of obstetrics, gynecology, and reproductive biology.

[2]  U. Thorsteinsdóttir,et al.  Variants in DENND1A are associated with polycystic ovary syndrome in women of European ancestry. , 2012, The Journal of clinical endocrinology and metabolism.

[3]  R. Krauss,et al.  Replication of association of DENND1A and THADA variants with polycystic ovary syndrome in European cohorts , 2011, Journal of Medical Genetics.

[4]  T. Pieber,et al.  Susceptibility Loci for Polycystic Ovary Syndrome on Chromosome 2p16.3, 2p21, and 9q33.3 in a Cohort of Caucasian Women , 2011, Hormone and Metabolic Research.

[5]  B. Zhang,et al.  Genome-wide association study identifies susceptibility loci for polycystic ovary syndrome on chromosome 2p16.3, 2p21 and 9q33.3 , 2011, Nature Genetics.

[6]  Wendy A. Wolf,et al.  Public and Biobank Participant Attitudes toward Genetic Research Participation and Data Sharing , 2010, Public Health Genomics.

[7]  David Reich,et al.  Discerning the Ancestry of European Americans in Genetic Association Studies , 2007, PLoS genetics.

[8]  R. Legro,et al.  Evidence for Pancreatic β-Cell Dysfunction in Brothers of Women with Polycystic Ovary Syndrome , 2008 .

[9]  Manuel A. R. Ferreira,et al.  PLINK: a tool set for whole-genome association and population-based linkage analyses. , 2007, American journal of human genetics.

[10]  R. Norman,et al.  Positions statement: criteria for defining polycystic ovary syndrome as a predominantly hyperandrogenic syndrome: an Androgen Excess Society guideline. , 2006, The Journal of clinical endocrinology and metabolism.

[11]  Mark Daly,et al.  Haploview: analysis and visualization of LD and haplotype maps , 2005, Bioinform..

[12]  P. Claman.  Men at risk: occupation and male infertility. , 2004, Fertility and sterility.

[13]  B. Fauser,et al.  Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome (PCOS). , 2004, Human reproduction.

[14]  A. Dunaif,et al.  Polycystic ovary syndrome: Syndrome XX? , 2003, Trends in Endocrinology & Metabolism.

[15]  D. Driscoll,et al.  Insulin resistance in the sisters of women with polycystic ovary syndrome: association with hyperandrogenemia rather than menstrual irregularity. , 2002, The Journal of clinical endocrinology and metabolism.

[16]  R. Azziz,et al.  Prevalence of polycystic ovary syndrome (PCOS) in first-degree relatives of patients with PCOS. , 2001, Fertility and sterility.

[17]  J. Dejong,et al.  Identification of a General Transcription Factor TFIIAα/β Homolog Selectively Expressed in Testis* , 1999, The Journal of Biological Chemistry.

[18]  D. Driscoll,et al.  Evidence for a genetic basis for hyperandrogenemia in polycystic ovary syndrome. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[19]  M. Dufau.  The luteinizing hormone receptor. , 1998, Annual review of physiology.

[20]  S. Franks,et al.  Polycystic ovary syndrome. , 1995, Archives of disease in childhood.