Looking for Polycystic Ovary Syndrome Genes: Rational and Best Strategy

ABSTRACT

Polycystic ovary syndrome (PCOS) is a common, complex genetic disorder. Its inherited basis was established by studies demonstrating an increased prevalence of PCOS and hyperandrogenemia, insulin resistance, and disordered insulin secretion in relatives of women with PCOS. To date, efforts in elucidating the genetic basis of PCOS have focused on candidate genes chosen from logical pathways, such as steroid synthesis or insulin signaling. Whereas several positive results have been reported, no genes are universally accepted as important in PCOS pathogenesis, largely due to lack of replication of positive results. This has resulted, in part, from various factors, most importantly lack of a universally accepted diagnostic scheme for PCOS, ability to assign PCOS diagnosis only in women of reproductive age, inadequate coverage of genes by the analysis of only one or two variants, and of small case-control cohorts in most studies. Candidate gene selection has been limited by our incomplete knowledge of the pathophysiology of PCOS. In the future, strict and uniform diagnostic criteria, improved application of the candidate gene approach using haplotype-based analyses, intermediate phenotypes, replication of positive results in large cohorts, more family-based studies, gene selection from expression studies, and whole-genome approaches will enhance gene discovery in PCOS.

KEYWORDS

Candidate gene - association - replication - single nucleotide polymorphism - haplotype

REFERENCES

• 1 King R A, Rotter J I, Motulsky A G. The Genetic Basis of Common Diseases. 2nd ed. New York, NY; Oxford University Press 2002
• 2 Goodarzi M O, Azziz R. Diagnosis, epidemiology, and genetics of the polycystic ovary syndrome.  Best Pract Res Clin Endocrinol Metab. 2006;  20 193-205
• 3 Parikh H, Groop L. Candidate genes for type 2 diabetes.  Rev Endocr Metab Disord. 2004;  5 151-176
• 4 Pall M, Stephens K, Azziz R. Family size in women with polycystic ovary syndrome.  Fertil Steril. 2006;  85 1837-1839
• 5 Nam Menke M, Strauss J F. Genetics of polycystic ovarian syndrome.  Clin Obstet Gynecol. 2007;  50 188-204
• 6 Franks S, McCarthy M. Genetics of ovarian disorders: polycystic ovary syndrome.  Rev Endocr Metab Disord. 2004;  5 69-76
• 7 Escobar-Morreale H F, Luque-Ramirez M, San Millan J L. The molecular-genetic basis of functional hyperandrogenism and the polycystic ovary syndrome.  Endocr Rev. 2005;  26 251-282
• 8 Diamanti-Kandarakis E, Piperi C. Genetics of polycystic ovary syndrome: searching for the way out of the labyrinth.  Hum Reprod Update. 2005;  11 631-643
• 9 Urbanek M. The genetics of the polycystic ovary syndrome.  Nat Clin Pract Endocrinol Metab. 2007;  3 103-111
• 10 Unluturk U, Harmanci A, Kocaefe C, Yildiz B O. The genetic basis of the polycystic ovary syndrome: a literature review including discussion of PPAR-gamma.  PPAR Res. 2007;  49109
• 11 Thomas D C, Witte J S. Point: population stratification: a problem for case-control studies of candidate-gene associations?.  Cancer Epidemiol Biomarkers Prev. 2002;  11 505-512
• 12 Wacholder S, Rothman N, Caporaso N. Counterpoint: bias from population stratification is not a major threat to the validity of conclusions from epidemiological studies of common polymorphisms and cancer.  Cancer Epidemiol Biomarkers Prev. 2002;  11 513-520
• 13 Goodarzi M O, Shah N A, Antoine H J et al.. Variants in the 5alpha-reductase type 1 and type 2 genes are associated with polycystic ovary syndrome and the severity of hirsutism in affected women.  J Clin Endocrinol Metab. 2006;  91 4085-4091
• 14 Carmina E, Legro R S, Stamets K, Lowell J, Lobo R A. Difference in body weight between American and Italian women with polycystic ovary syndrome: influence of the diet.  Hum Reprod. 2003;  18 2289-2293
• 15 Beavis W D. QTL analyses: power, precision, and accuracy. In: Paterson AH Molecular Dissection of Complex Traits. New York, NY; CRC Press 1998: 145-162
• 16 Wild R A, Vesely S, Beebe L, Whitsett T, Owen W. Ferriman Gallwey self-scoring I: performance assessment in women with polycystic ovary syndrome.  J Clin Endocrinol Metab. 2005;  90 4112-4114
• 17 Zawadzki J K, Dunaif A. Diagnostic criteria for polycystic ovary syndrome: towards a rational approach. In: Dunaif A, Givens JR, Haseltine F, Merriam GR Polycystic Ovary Syndrome. Cambridge, MA; Blackwell Scientific 1992: 377-384
• 18 The 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 19-25
• 19 Urbanek M, Legro R S, Driscoll D A et al.. Thirty-seven candidate genes for polycystic ovary syndrome: strongest evidence for linkage is with follistatin.  Proc Natl Acad Sci USA. 1999;  96 8573-8578
• 20 Urbanek M, Woodroffe A, Ewens K G et al.. Candidate gene region for polycystic ovary syndrome on chromosome 19p13.2  J Clin Endocrinol Metab. 2005;  90 6623-6629
• 21 Stewart D R, Dombroski B, Urbanek M et al.. Fine mapping of genetic susceptibility to polycystic ovary syndrome on chromosome 19p13.2 and tests for regulatory activity.  J Clin Endocrinol Metab. 2006;  91 4112-4117
• 22 Gabriel S B, Schaffner S F, Nguyen H et al.. The structure of haplotype blocks in the human genome.  Science. 2002;  296 2225-2229
• 23 The International HapMap Consortium . The International HapMap Project.  Nature. 2003;  426 789-796
• 24 Horikawa Y, Oda N, Cox N J et al.. Genetic variation in the gene encoding calpain-10 is associated with type 2 diabetes mellitus.  Nat Genet. 2000;  26 163-175
• 25 Vollmert C, Hahn S, Lamina C et al.. Calpain-10 variants and haplotypes are associated with polycystic ovary syndrome in Caucasians.  Am J Physiol Endocrinol Metab. 2007;  292 E836-E844
• 26 Gonzalez A, Saez M E, Aragon M J et al.. Specific haplotypes of the CALPAIN-5 gene are associated with polycystic ovary syndrome.  Hum Reprod. 2006;  21 943-951
• 27 Petry C J, Ong K K, Michelmore K F et al.. Association of aromatase (CYP 19) gene variation with features of hyperandrogenism in two populations of young women.  Hum Reprod. 2005;  20 1837-1843
• 28 Goodarzi M O, Antoine H J, Pall M et al.. Preliminary evidence of glycogen synthase kinase 3 beta as a genetic determinant of polycystic ovary syndrome.  Fertil Steril. 2007;  92 2659-2664
• 29 Goodarzi M O, Antoine H J, Azziz R. Genes for enzymes regulating DHEA sulfonation are associated with levels of DHEA-sulfate in polycystic ovary syndrome.  J Clin Endocrinol Metab. 2007;  92 2659-2664
• 30 Jones M R, Wilson S G, Mullin B H et al.. Polymorphism of the follistatin gene in polycystic ovary syndrome.  Mol Hum Reprod. 2007;  13 237-241
• 31 Petry C J, Ong K K, Wingate D L et al.. Lack of association between common polymorphisms in the 17beta-hydroxysteroid dehydrogenase type V gene (HSD17B5) and precocious pubarche.  J Steroid Biochem Mol Biol. 2007;  105 176-180
• 32 Jones M R, Italiano L, Wilson S G et al.. Polymorphism in HSD17B6 is associated with key features of polycystic ovary syndrome.  Fertil Steril. 2006;  86 1438-1446
• 33 Purcell S, Cherny S S, Sham P C. Genetic Power Calculator: design of linkage and association genetic mapping studies of complex traits.  Bioinformatics. 2003;  19 149-150
• 34 Spielman R S, McGinnis R E, Ewens W J. Transmission test for linkage disequilibrium: the insulin gene region and insulin-dependent diabetes mellitus (IDDM).  Am J Hum Genet. 1993;  52 506-516
• 35 Hughes C, Elgasim M, Layfield R, Atiomo W. Genomic and post-genomic approaches to polycystic ovary syndrome-progress so far: mini review.  Hum Reprod. 2006;  21 2766-2775
• 36 Ho C K, Wood J R, Stewart D R et al.. Increased transcription and increased messenger ribonucleic acid (mRNA) stability contribute to increased GATA6 mRNA abundance in polycystic ovary syndrome theca cells.  J Clin Endocrinol Metab. 2005;  90 6596-6602
• 37 Saxena R, Voight B F, Lyssenko V et al.. Genome-wide association analysis identifies loci for type 2 diabetes and triglyceride levels.  Science. 2007;  316 1331-1336
• 38 Scott L J, Mohlke K L, Bonnycastle L L et al.. A genome-wide association study of type 2 diabetes in Finns detects multiple susceptibility variants.  Science. 2007;  316 1341-1345
• 39 Sladek R, Rocheleau G, Rung J et al.. A genome-wide association study identifies novel risk loci for type 2 diabetes.  Nature. 2007;  445 881-885
• 40 Zeggini E, Weedon M N, Lindgren C M et al.. Replication of genome-wide association signals in UK samples reveals risk loci for type 2 diabetes.  Science. 2007;  316 1336-1341