Female Genomics: Infertility and Overall Health

Abstract

Female infertility is a complex disease linked to multiple etiologies including genetic factors. Owing to the multifactorial nature of infertility, it is often difficult to identify single causative genes. Despite this challenge, investigations into the genetic causes of infertility have been performed to shed light on the etiology and for the possibility of developing personalized medical approaches to therapy. Multiple techniques have been utilized to better characterize the genetic origins of this disease, including genome-wide association studies. We present here a review of the genetic causes of female infertility, detailing some of the more recent findings in the genetics of polycystic ovary syndrome, endometriosis, primary ovarian insufficiency, hypothalamic amenorrhea, leiomyomas, and Mullerian anomalies.

Keywords

infertility - female infertility - genetics - GWAS

• References

• 1 Zorrilla M, Yatsenko AN. The genetics of infertility: current status of the field. Curr Genet Med Rep 2013; 1 (04) 1
• 2 Carmina E, Lobo RA. Polycystic ovary syndrome (PCOS): arguably the most common endocrinopathy is associated with significant morbidity in women. J Clin Endocrinol Metab 1999; 84 (06) 1897-1899
• 3 Ehrmann DA. Polycystic ovary syndrome. N Engl J Med 2005; 352 (12) 1223-1236
• 4 Dokras A, Bochner M, Hollinrake E, Markham S, Vanvoorhis B, Jagasia DH. Screening women with polycystic ovary syndrome for metabolic syndrome. Obstet Gynecol 2005; 106 (01) 131-137
• 5 Moran LJ, Misso ML, Wild RA, Norman RJ. Impaired glucose tolerance, type 2 diabetes and metabolic syndrome in polycystic ovary syndrome: a systematic review and meta-analysis. Hum Reprod Update 2010; 16 (04) 347-363
• 6 Wild RA, Carmina E, Diamanti-Kandarakis E. , et al. Assessment of cardiovascular risk and prevention of cardiovascular disease in women with the polycystic ovary syndrome: a consensus statement by the Androgen Excess and Polycystic Ovary Syndrome (AE-PCOS) Society. J Clin Endocrinol Metab 2010; 95 (05) 2038-2049
• 7 Dokras A. Cardiovascular disease risk in women with PCOS. Steroids 2013; 78 (08) 773-776
• 8 Legro RS, Driscoll D, Strauss III JF, Fox J, Dunaif A. Evidence for a genetic basis for hyperandrogenemia in polycystic ovary syndrome. Proc Natl Acad Sci U S A 1998; 95 (25) 14956-14960
• 9 Franks S, Webber LJ, Goh M. , et al. Ovarian morphology is a marker of heritable biochemical traits in sisters with polycystic ovaries. J Clin Endocrinol Metab 2008; 93 (09) 3396-3402
• 10 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 (06) 2100-2104
• 11 Venkatesh T, Suresh PS, Tsutsumi R. New insights into the genetic basis of infertility. Appl Clin Genet 2014; 7: 235-243
• 12 Simoni M, Tempfer CB, Destenaves B, Fauser BC. Functional genetic polymorphisms and female reproductive disorders: Part I: Polycystic ovary syndrome and ovarian response. Hum Reprod Update 2008; 14 (05) 459-484
• 13 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 (01) 55-59
• 14 Mitri F, Bentov Y, Behan LA, Esfandiari N, Casper RF. A novel compound heterozygous mutation of the luteinizing hormone receptor -implications for fertility. J Assist Reprod Genet 2014; 31 (07) 787-794
• 15 Toledo SP, Brunner HG, Kraaij R. , et al. An inactivating mutation of the luteinizing hormone receptor causes amenorrhea in a 46,XX female. J Clin Endocrinol Metab 1996; 81 (11) 3850-3854
• 16 McAllister JM, Modi B, Miller BA. , et al. Overexpression of a DENND1A isoform produces a polycystic ovary syndrome theca phenotype. Proc Natl Acad Sci U S A 2014; 111 (15) E1519-E1527
• 17 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 (09) 1020-1025
• 18 Krook A, Kumar S, Laing I, Boulton AJ, Wass JA, O'Rahilly S. Molecular scanning of the insulin receptor gene in syndromes of insulin resistance. Diabetes 1994; 43 (03) 357-368
• 19 Voight BF, Scott LJ, Steinthorsdottir V. , et al; MAGIC investigators; GIANT Consortium. Twelve type 2 diabetes susceptibility loci identified through large-scale association analysis. Nat Genet 2010; 42 (07) 579-589
• 20 Brower MA, Jones MR, Rotter JI. , et al. Further investigation in Europeans of susceptibility variants for polycystic ovary syndrome discovered in genome-wide association studies of Chinese individuals. J Clin Endocrinol Metab 2015; 100 (01) E182-E186
• 21 Lee H, Oh JY, Sung YA. , et al. Genome-wide association study identified new susceptibility loci for polycystic ovary syndrome. Hum Reprod 2015; 30 (03) 723-731
• 22 Li Q, Du J, Feng R. , et al. A possible new mechanism in the pathophysiology of polycystic ovary syndrome (PCOS): the discovery that leukocyte telomere length is strongly associated with PCOS. J Clin Endocrinol Metab 2014; 99 (02) E234-E240
• 23 Sahin E, Colla S, Liesa M. , et al. Telomere dysfunction induces metabolic and mitochondrial compromise. Nature 2011; 470 (7334): 359-365
• 24 Guo N, Parry EM, Li LS. , et al. Short telomeres compromise β-cell signaling and survival. PLoS One 2011; 6 (03) e17858
• 25 Apridonidze T, Essah PA, Iuorno MJ, Nestler JE. Prevalence and characteristics of the metabolic syndrome in women with polycystic ovary syndrome. J Clin Endocrinol Metab 2005; 90 (04) 1929-1935
• 26 Daan NM, Louwers YV, Koster MP. , et al. Cardiovascular and metabolic profiles amongst different polycystic ovary syndrome phenotypes: who is really at risk?. Fertil Steril 2014; 102 (05) 1444-1451.e3
• 27 Diamanti-Kandarakis E, Dunaif A. Insulin resistance and the polycystic ovary syndrome revisited: an update on mechanisms and implications. Endocr Rev 2012; 33 (06) 981-1030
• 28 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
• 29 Watkins PC, Eddy R, Beck AK. , et al. DNA sequence and regional assignment of the human follicle-stimulating hormone beta-subunit gene to the short arm of human chromosome 11. DNA 1987; 6 (03) 205-212
• 30 LaVoie HA. The role of GATA in mammalian reproduction. Exp Biol Med (Maywood) 2003; 228 (11) 1282-1290
• 31 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 (08) e1005455
• 32 Stratton P, Berkley KJ. Chronic pelvic pain and endometriosis: translational evidence of the relationship and implications. Hum Reprod Update 2011; 17 (03) 327-346
• 33 de Ziegler D, Borghese B, Chapron C. Endometriosis and infertility: pathophysiology and management. Lancet 2010; 376 (9742): 730-738
• 34 Giudice LC, Kao LC. Endometriosis. Lancet 2004; 364 (9447): 1789-1799
• 35 Treloar SA, O'Connor DT, O'Connor VM, Martin NG. Genetic influences on endometriosis in an Australian twin sample. [e-mail]. Fertil Steril 1999; 71 (04) 701-710
• 36 Treloar SA, Zhao ZZ, Le L. , et al. Variants in EMX2 and PTEN do not contribute to risk of endometriosis. Mol Hum Reprod 2007; 13 (08) 587-594
• 37 Zhao ZZ, Nyholt DR, Le L, Treloar SA, Montgomery GW. Common variation in the CYP17A1 and IFIT1 genes on chromosome 10 does not contribute to the risk of endometriosis. Open Reprod Sci J 2008; 1: 35-40
• 38 Lin J, Zong L, Kennedy SH, Zondervan KT. Coding regions of INHBA, SFRP4 and HOXA10 are not implicated in familial endometriosis linked to chromosome 7p13-15. Mol Hum Reprod 2011; 17 (10) 605-611
• 39 Uno S, Zembutsu H, Hirasawa A. , et al. A genome-wide association study identifies genetic variants in the CDKN2BAS locus associated with endometriosis in Japanese. Nat Genet 2010; 42 (08) 707-710
• 40 Goumenou AG, Arvanitis DA, Matalliotakis IM, Koumantakis EE, Spandidos DA. Loss of heterozygosity in adenomyosis on hMSH2, hMLH1, p16Ink4 and GALT loci. Int J Mol Med 2000; 6 (06) 667-671
• 41 Guida M, Sanguedolce F, Bufo P. , et al. Aberrant DNA hypermethylation of hMLH-1 and CDKN2A/p16 genes in benign, premalignant and malignant endometrial lesions. Eur J Gynaecol Oncol 2009; 30 (03) 267-270
• 42 Vainio S, Heikkilä M, Kispert A, Chin N, McMahon AP. Female development in mammals is regulated by Wnt-4 signalling. Nature 1999; 397 (6718): 405-409
• 43 Boyer A, Lapointe E, Zheng X. , et al. WNT4 is required for normal ovarian follicle development and female fertility. FASEB J 2010; 24 (08) 3010-3025
• 44 Painter JN, Anderson CA, Nyholt DR. , et al. Genome-wide association study identifies a locus at 7p15.2 associated with endometriosis. Nat Genet 2011; 43 (01) 51-54
• 45 Rahmioglu N, Nyholt DR, Morris AP, Missmer SA, Montgomery GW, Zondervan KT. Genetic variants underlying risk of endometriosis: insights from meta-analysis of eight genome-wide association and replication datasets. Hum Reprod Update 2014; 20 (05) 702-716
• 46 Rae JM, Johnson MD, Scheys JO, Cordero KE, Larios JM, Lippman ME. GREB 1 is a critical regulator of hormone dependent breast cancer growth. Breast Cancer Res Treat 2005; 92 (02) 141-149
• 47 Pellegrini C, Gori I, Achtari C. , et al. The expression of estrogen receptors as well as GREB1, c-MYC, and cyclin D1, estrogen-regulated genes implicated in proliferation, is increased in peritoneal endometriosis. Fertil Steril 2012; 98 (05) 1200-1208
• 48 Verschuur-Maes AH, de Bruin PC, van Diest PJ. Epigenetic progression of columnar cell lesions of the breast to invasive breast cancer. Breast Cancer Res Treat 2012; 136 (03) 705-715
• 49 Kobayashi A, Behringer RR. Developmental genetics of the female reproductive tract in mammals. Nat Rev Genet 2003; 4 (12) 969-980
• 50 Du H, Taylor HS. The role of Hox genes in female reproductive tract development, adult function, and fertility. Cold Spring Harb Perspect Med 2015; 6 (01) a023002
• 51 Hyenne V, Harf JC, Latz M, Maro B, Wolfrum U, Simmler MC. Vezatin, a ubiquitous protein of adherens cell-cell junctions, is exclusively expressed in germ cells in mouse testis. Reproduction 2007; 133 (03) 563-574
• 52 Pagliardini L, Gentilini D, Sanchez AM, Candiani M, Viganò P, Di Blasio AM. Replication and meta-analysis of previous genome-wide association studies confirm vezatin as the locus with the strongest evidence for association with endometriosis. Hum Reprod 2015; 30 (04) 987-993
• 53 Qin Y, Jiao X, Simpson JL, Chen ZJ. Genetics of primary ovarian insufficiency: new developments and opportunities. Hum Reprod Update 2015; 21 (06) 787-808
• 54 Allingham-Hawkins DJ, Babul-Hirji R, Chitayat D. , et al. Fragile X premutation is a significant risk factor for premature ovarian failure: the International Collaborative POF in Fragile X study--preliminary data. Am J Med Genet 1999; 83 (04) 322-325
• 55 Gleicher N, Weghofer A, Barad DH. A pilot study of premature ovarian senescence: I. Correlation of triple CGG repeats on the FMR1 gene to ovarian reserve parameters FSH and anti-Müllerian hormone. Fertil Steril 2009; 91 (05) 1700-1706
• 56 Voorhuis M, Onland-Moret NC, Janse F. , et al; Dutch Primary Ovarian Insufficiency Consortium The significance of fragile X mental retardation gene 1 CGG repeat sizes in the normal and intermediate range in women with primary ovarian insufficiency. Hum Reprod 2014; 29 (07) 1585-1593
• 57 De Baere E, Dixon MJ, Small KW. , et al. Spectrum of FOXL2 gene mutations in blepharophimosis-ptosis-epicanthus inversus (BPES) families demonstrates a genotype--phenotype correlation. Hum Mol Genet 2001; 10 (15) 1591-1600
• 58 Kuo FT, Bentsi-Barnes IK, Barlow GM, Pisarska MD. Mutant Forkhead L2 (FOXL2) proteins associated with premature ovarian failure (POF) dimerize with wild-type FOXL2, leading to altered regulation of genes associated with granulosa cell differentiation. Endocrinology 2011; 152: 3917-3929
• 59 Pisarska MD, Barlow G, Kuo FT. Minireview: roles of the forkhead transcription factor FOXL2 in granulosa cell biology and pathology. Endocrinology 2011; 152: 1199-1208
• 60 Fridovich-Keil JL, Gubbels CS, Spencer JB, Sanders RD, Land JA, Rubio-Gozalbo E. Ovarian function in girls and women with GALT-deficiency galactosemia. J Inherit Metab Dis 2011; 34 (02) 357-366
• 61 Wang CY, Davoodi-Semiromi A, Huang W, Connor E, Shi JD, She JX. Characterization of mutations in patients with autoimmune polyglandular syndrome type 1 (APS1). Hum Genet 1998; 103 (06) 681-685
• 62 Fogli A, Rodriguez D, Eymard-Pierre E. , et al. Ovarian failure related to eukaryotic initiation factor 2B mutations. Am J Hum Genet 2003; 72 (06) 1544-1550
• 63 Kang H, Lee SK, Kim MH. , et al. Parathyroid hormone-responsive B1 gene is associated with premature ovarian failure. Hum Reprod 2008; 23 (06) 1457-1465
• 64 Dang Y, Zhao S, Qin Y, Han T, Li W, Chen ZJ. MicroRNA-22-3p is down-regulated in the plasma of Han Chinese patients with premature ovarian failure. Fertil Steril 2015; 103 (03) 802-7.e1
• 65 Caronia LM, Martin C, Welt CK. , et al. A genetic basis for functional hypothalamic amenorrhea. N Engl J Med 2011; 364 (03) 215-225
• 66 Cramer SF, Patel A. The frequency of uterine leiomyomas. Am J Clin Pathol 1990; 94 (04) 435-438
• 67 Lepine LA, Hillis SD, Marchbanks PA. , et al. Hysterectomy surveillance--United States, 1980-1993. MMWR CDC Surveill Summ 1997; 46 (04) 1-15
• 68 Treloar SA, Martin NG, Dennerstein L, Raphael B, Heath AC. Pathways to hysterectomy: insights from longitudinal twin research. Am J Obstet Gynecol 1992; 167 (01) 82-88
• 69 Vikhlyaeva EM, Khodzhaeva ZS, Fantschenko ND. Familial predisposition to uterine leiomyomas. Int J Gynaecol Obstet 1995; 51 (02) 127-131
• 70 Baird DD, Dunson DB, Hill MC, Cousins D, Schectman JM. High cumulative incidence of uterine leiomyoma in black and white women: ultrasound evidence. Am J Obstet Gynecol 2003; 188 (01) 100-107
• 71 Marshall LM, Spiegelman D, Barbieri RL. , et al. Variation in the incidence of uterine leiomyoma among premenopausal women by age and race. Obstet Gynecol 1997; 90 (06) 967-973
• 72 Cha PC, Takahashi A, Hosono N. , et al. A genome-wide association study identifies three loci associated with susceptibility to uterine fibroids. Nat Genet 2011; 43 (05) 447-450
• 73 Storbeck CJ, Daniel K, Zhang YH. , et al. Ste20-like kinase SLK displays myofiber type specificity and is involved in C2C12 myoblast differentiation. Muscle Nerve 2004; 29 (04) 553-564
• 74 Levy D, Neuhausen SL, Hunt SC. , et al. Genome-wide association identifies OBFC1 as a locus involved in human leukocyte telomere biology. Proc Natl Acad Sci U S A 2010; 107 (20) 9293-9298
• 75 Meister G, Landthaler M, Peters L. , et al. Identification of novel argonaute-associated proteins. Curr Biol 2005; 15 (23) 2149-2155
• 76 Luo X, Chegini N. The expression and potential regulatory function of microRNAs in the pathogenesis of leiomyoma. Semin Reprod Med 2008; 26 (06) 500-514
• 77 Xu Y, Martin S, James DE, Hong W. GS15 forms a SNARE complex with syntaxin 5, GS28, and Ykt6 and is implicated in traffic in the early cisternae of the Golgi apparatus. Mol Biol Cell 2002; 13 (10) 3493-3507
• 78 Thomas CJ, Tall GG, Adhikari A, Sprang SR. Ric-8A catalyzes guanine nucleotide exchange on G alphai1 bound to the GPR/GoLoco exchange inhibitor AGS3. J Biol Chem 2008; 283 (34) 23150-23160
• 79 Kim HS, Patel K, Muldoon-Jacobs K. , et al. SIRT3 is a mitochondria-localized tumor suppressor required for maintenance of mitochondrial integrity and metabolism during stress. Cancer Cell 2010; 17 (01) 41-52
• 80 Eggert SL, Huyck KL, Somasundaram P. , et al. Genome-wide linkage and association analyses implicate FASN in predisposition to Uterine Leiomyomata. Am J Hum Genet 2012; 91 (04) 621-628
• 81 Kusakabe T, Maeda M, Hoshi N. , et al. Fatty acid synthase is expressed mainly in adult hormone-sensitive cells or cells with high lipid metabolism and in proliferating fetal cells. J Histochem Cytochem 2000; 48 (05) 613-622
• 82 Alò PL, Visca P, Trombetta G. , et al. Fatty acid synthase (FAS) predictive strength in poorly differentiated early breast carcinomas. Tumori 1999; 85 (01) 35-40
• 83 Rossi S, Graner E, Febbo P. , et al. Fatty acid synthase expression defines distinct molecular signatures in prostate cancer. Mol Cancer Res 2003; 1 (10) 707-715
• 84 Ogino S, Nosho K, Meyerhardt JA. , et al. Cohort study of fatty acid synthase expression and patient survival in colon cancer. J Clin Oncol 2008; 26 (35) 5713-5720
• 85 Wise LA, Ruiz-Narvaez EA, Palmer JR. , et al. African ancestry and genetic risk for uterine leiomyomata. Am J Epidemiol 2012; 176 (12) 1159-1168
• 86 Patterson N, Hattangadi N, Lane B. , et al. Methods for high-density admixture mapping of disease genes. Am J Hum Genet 2004; 74 (05) 979-1000
• 87 Biason-Lauber A, Konrad D, Navratil F, Schoenle EJ. A WNT4 mutation associated with Müllerian-duct regression and virilization in a 46,XX woman. N Engl J Med 2004; 351 (08) 792-798
• 88 Maher B. Personal genomes: the case of the missing heritability. Nature 2008; 456 (7218): 18-21
• 89 Hou L, Zhao H. A review of post-GWAS prioritization approaches. Front Genet 2013; 4: 280
• 90 Montgomery GW, Zondervan KT, Nyholt DR. The future for genetic studies in reproduction. Mol Hum Reprod 2014; 20 (01) 1-14
• 91 ENCODE Project Consortium. An integrated encyclopedia of DNA elements in the human genome. Nature 2012; 489 (7414): 57-74
• 92 Bamshad MJ, Ng SB, Bigham AW. , et al. Exome sequencing as a tool for Mendelian disease gene discovery. Nat Rev Genet 2011; 12 (11) 745-755
• 93 Cirulli ET, Goldstein DB. Uncovering the roles of rare variants in common disease through whole-genome sequencing. Nat Rev Genet 2010; 11 (06) 415-425
• 94 Sanseau P, Agarwal P, Barnes MR. , et al. Use of genome-wide association studies for drug repositioning. Nat Biotechnol 2012; 30 (04) 317-320