• Users Online: 205
  • Print this page
  • Email this page

 Table of Contents  
REVIEW ARTICLE
Year : 2019  |  Volume : 3  |  Issue : 3  |  Page : 185-190

Advances in genetic studies related to polycystic ovary syndrome in the post-genome-wide association studies era


1 Department of Gynecology, Traditional Chinese Medicine College, Shandong University of Traditional Chinese Medicine, Jinan 250011, China
2 Reproductive Medicine Center of Integration of Traditional and Western Medicine, The Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, 250011, China

Date of Submission09-May-2019
Date of Web Publication27-Sep-2019

Correspondence Address:
Zhen-Gao Sun
No. 42, Wenhuaxi Road, Lixia District, Jinan 250011
China
Login to access the Email id

Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2096-2924.268159

Rights and Permissions
  Abstract 


Polycystic ovary syndrome (PCOS) is a common endocrine disorder characterized by reproductive and metabolic dysfunction with a genetic predisposition evidenced by familial clustering and twin studies. Patients with PCOS often produce oocytes of poor quality, leading to lower rates of fertilization, cleavage, and implantation, but higher rates of miscarriages and long-term complications. However, the etiology of PCOS still remains uncertain due to unavailability of unified diagnostic criteria and prevalence of clinical heterogeneity. Owing to advances in technology and methods employed for research, large-scale genetic/other studies have provided many new insights into the genetic pathogenesis of PCOS. However, although genome-wide association studies have been conducted, we still need to evaluate the association between specific loci and their relevance in the manifestation of this disease. In this article, we have presented a review of the recent studies.

Keywords: Genome-Wide Association; MicroRNAs; Mitochondrial DNA; Polycystic Ovary Syndrome; Subtype


How to cite this article:
Cao XL, Sun ZG. Advances in genetic studies related to polycystic ovary syndrome in the post-genome-wide association studies era. Reprod Dev Med 2019;3:185-90

How to cite this URL:
Cao XL, Sun ZG. Advances in genetic studies related to polycystic ovary syndrome in the post-genome-wide association studies era. Reprod Dev Med [serial online] 2019 [cited 2019 Nov 18];3:185-90. Available from: http://www.repdevmed.org/text.asp?2019/3/3/185/268159




  Introduction Top


Polycystic ovary syndrome (PCOS) is a common reproductive and endocrine metabolic disorder that is caused by the interaction of predisposed genetic factors with those of the environment, dependent largely on the ethnicity, and affects approximately 5%–10% of women of childbearing age worldwide.[1],[2] Women with PCOS demonstrate four main symptoms, namely hyperandrogenism, ovulatory dysfunction, polycystic ovarian morphology, and gandonadotropich abnormalities. Clinically, hyperandrogenism is manifested in the form of hirsutism and the development of acne, whereas gandonadotropich abnormalities contribute to oligo-ovulation.[3] PCOS also has significant long-term health effects as it is associated with an increased risk of type 2 diabetes (T2DM), hyperinsulinemia, insulin resistance (IR), cardiovascular disease, and dyslipidemia.[4] As the precise etiology of PCOS remains elusive, there is ongoing controversy regarding the most appropriate criteria that can be employed in its diagnosis, and preventive measures to mitigate its long-term health impacts are not available. An in-depth study regarding the pathogenesis of PCOS is necessary to determine its potential diagnostic indicators and therapeutic targets. Increasing evidence proves that genetic factors play an important role in the pathogenesis of PCOS.[5] With the use of modern genetic approaches such as genome-wide association studies (GWAS), Mendelian randomization, and next-generation sequencing, an increasing number of candidate genes are being identified.[6] Nevertheless, further experimental verification is required to establish how the role of these candidate genes contribute to the development of PCOS. In this review, we have discussed the current state of candidate–gene association studies, with particular emphasis on the genes involved in ovulation and endocrine functions. Here, the literature published since 2016 has mainly been reviewed, as earlier studies have already been discussed in detail.


  Previous Knowledge Top


In 1968, Cooper et al. provided the first evidence of PCOS being a genetically predisposed disorder.[7] Several small-family studies confirmed this hypothesis, and it was found that the prevalence of PCOS ranged from 51% to 66% among the first-degree relatives of the probands.[8],[9] Studies on the incidence of PCOS in twins have confirmed that some of its symptoms are hereditary;[10] however, PCOS does not demonstrate clear Mendelian inheritance and is considered to be a complex trait.[11] Due to differences in the results, it was difficult to confirm whether PCOS is a disease characterized by dominant autosomal inheritance, but both studies confirmed that it is an X-linked disorder.[10],[11],[12] These findings confirm that differences in the clinical manifestations of the disorder among patients may have a genetic basis, and the phenomenon of familial aggregation in PCOS has aroused the interest of scholars in studying its genetic attributes at a molecular level. As PCOS is a polygenic disease, the current research on candidate genes involves genes related to sex hormones and gonadotropins, insulin, hyperandrogenism, and chronic inflammatory factors.[13]


  What Was Discovered in Genome-Wide Association Studies? Top


Genes associated with steroidogenesis, sex hormones, and their receptors are considered to be the essential candidates of PCOS due to their roles in folliculogenesis. These genes mainly include CYP11A1, CYP17A, CYP19, CYP21, HSD17B5, HSD17B6, those of the androgen receptor (AR), SHBG, FSH, FSHR, and LHCGR.[14] In the past, many studies depended on the assumption that candidate genes provide limited scope for statistical analysis due to inadequate sample sizes.[14] Surprisingly, the impact of sample sizes was reduced by the wide use of GWAS in the research of PCOS. From the time that the application of GWAS was first reported till now, in Han, five GWAS were conducted on female populations with PCOS belonging to the Chinese,[15],[16] Korean,[17] and European ancestries.[18],[19] In total, 16 robust loci were identified (P < 5 × 10−8). The genes, thus identified, are as follows: LHCGR, FSHR, THADA, ERBB4, RAD50, GATA4, DENND1A, C9orf3, FSHB, YAP1, HMGA2, RAB5B/SUOX, KRR1, TOX3, INSR, and SUMO1P1, which were located near the 2p16.3, 2p21, 2q34, 5q31.1, 8p32.1, 9q33.3, 9q22.32, 11p14.1, 11q22.1, 12q14.3, 12q13.2, 12q21.2, 16q12.1, 19p13.3, and 20q13.2 regions, respectively. Among these, corrections were made in the data of the 8p32.1 locus, which was changed later to 8p23.1 by the author.[19] However, only few loci have been discovered in both GWAS that may suggest the involvement of ethnic differences. We also found that the diagnostic criteria used by the authors were not very consistent. Surprisingly, recent findings suggest little influence of genetic heterogeneity between the diagnostic criteria at the identified risk loci.[20] Although significant progress had been made in the past, considerable amount of work remains to be conducted to fully understand the pathogenesis of PCOS. Importantly, although GWAS were commonly employed to analyze the correlation between DNA polymorphisms and specific traits of the disease, they do not pinpoint the causal variants, regulatory elements, or genes responsible for these association signals.[20] Finally, studies have been conducted in the “post-GWAS” era, in which interpretation of the functional effects of individual genetic variations that confer susceptibility to PCOS is a major challenge for the researchers.

Genotype–phenotype correlations based on genome-wide association studies

The influence of single-nucleotide polymorphisms (SNPs) identified in the previous GWAS on specific subtypes and their role in the pathogenesis of PCOS remain unknown. To determine this, a cross-sectional study involving 1,731 patients with PCOS and 4,964 controls was conducted. Finally, the researchers found that the SNPs in THADA and DENND1A were associated with the subtypes of PCOS, whereas the probability of the involvement of LHCGR (rs13405728) in oligo- or anovulation was higher. Besides, the rs13429458 AA genotype in the THADA gene and GG and GA groups of rs2479106 in the DENNDIA gene were considered to be significantly risky genotypes which were involved in the manifestation of hyperandrogenemia (HA) and IR in PCOS, respectively.[21] These results have inspired researchers to conduct functional studies further which may help in the identification of individuals most likely to respond to specific targeted therapies. Similarly, researchers had adopted methods used in the GWAS to gather information on SNPs that may be associated with PCOS. Three SNP sites containing significantly different allele frequencies between the patient and control groups (P < 0.05) were found. They are as follows: rs346795081 on THADA, rs346803513 on DENND1A, and rs346999236 on TOX3.[22] However, the sample size of several subgenotype groups was low (n < 4), which decreased the credibility of the results. Therefore, further studies should focus on involving women from different genetic backgrounds and elaborate on genetic functions associated with the etiological mechanisms of PCOS phenotypes. Finally, the attributes of PCOS vary depending on the phenotypes. The metabolic features available in literature suggest that the specific subtypes should be focused upon.[23] Interestingly, different subphenotypes are associated with genotypes demonstrating different risk attributes,[24] and studies conducted on them may present new insights for the personalized diagnosis and treatment of PCOS in future.

Analysis of the genome-wide association studies-based pathways involved in polycystic ovary syndrome

The pathway-based approach integrates the results of GWAS with those of the studies involving genes associated with biological pathways or gene sets from predefined human databases, which could improve on the limitations of the GWAS in determining biological functions. Moreover, analysis of the GWAS-based pathways helps in the identification of additional risk factors with moderate statistical significance.[24] Several studies had applied post-GWAS analysis to the GWAS dataset of patients with PCOS and identified significant pathways involved in ovulation and insulin secretion. INS, GNAQ, STXBP1, PLCB3, PLCB2, SMC3, and PLCZ1 were the important genes involved in the induction and regulation of these biological pathways (P values of all the genes were <0.05).[25] In conclusion, it can be stated that, by applying pathway analysis to a GWAS dataset, it is possible to understand the mechanisms underlying PCOS better.


  Other Genes Associated With Polycystic Ovary Syndrome Top


Sex hormones and gonadotropin-related genes

Hyperandrogenism is an important endocrine disorder found in patients with PCOS, which also helps in its diagnosis. Elevated levels of androgens in the ovary and blood circulation can inhibit the development and maturation of ovarian follicles, resulting in anovulation, hypertrichosis, acne, and a number of other clinical manifestations. Studies have found that heredity and variation are mainly linked to hyperandrogenism in patients with PCOS, whereas other factors account only for 5%–10% of the symptoms.[26] MicroRNA (miRNA) is a single small noncoding RNA with a length of about 22 nucleotides. It was found that miRNA changes the structure of the target genes or chromosomes and affects separation and transcription, resulting in conditions such as restructuring, mutation, and changes in the cell cycle.[27],[28] Furthermore, because the development of 60% of diseases associated with the human body is dependent on the efficiency of protein coding, it was recently determined that the miRNA can be used as a biomarker for the diagnosis and prognosis of a wide range of diseases including cancer and cardiovascular diseases. Studies have tried to link miRNA to the occurrence of HAin patients with PCOS. When the follicular fluid of patients with PCOS demonstrating HA as well as that of normal females was analyzed, 236 miRNAs were found to be significantly different in the experimental group and 7 in the control group, which are as follows: 200a-3p, 10b-3P, 200b-3p, 29c-3p, 99a-3p, 125a-5p, and 105-3p. It has been confirmed previously that miRNAs are involved in the manifestation of HA in patients with PCOS. Although a significant rise in their levels was observed, their exact mechanism of inducing HA was unclear. Using gene ontology analysis, it was speculated that these 263 miRNAs were related to 31,770 genes, which were mainly involved in the apoptosis and insulin receptor signaling,[29] indicating the possible relationship between HA-related genes and PCOS. For example, there are researchers which have found that overexpressed DENND1A could increase CYP17A1 and CYP11A1 gene transcription, mRNA abundance, and androgen biosynthesis, and thus resulted in a PCOS phenotype.[30] What is more, CAPN 10 gene UCSNP-43 polymorphism may play a role in PCOS's HA due to the association with increased D4 androstenedione.[31] In future, we should focus on the specific mechanism of more genetic action in order to better understand this disease.

Genes associated with luteinizing hormone

In PCOS, changes occurring in the gonadotropins were mainly manifested as an increase in the levels of luteinizing hormone (LH), normal or decreased levels of follicle-stimulating hormone (FSH), and an increased LH/FSH ratio. In a recent study conducted to confirm the susceptibility of two other loci in the Han population, it was found that the FSHB gene was associated with an increased susceptibility to PCOS and an increase in the levels of LH in the Han population. In addition, it was determined that the high-risk allele A for PCOS in the FSHB variant rs11031010 was closely related to the presence of high amounts of LH. Studies have found that increased levels of LH induce an increased production of androgen T by cells in the ovarian membranes which can regulate the process of gonadotropin production by the hypothalamus through a feedback mechanism,[18] which may explain the high levels of LH associated with the functioning of the FSHB gene.

Genes associated with follicle-stimulating hormone receptor

The FSH plays an important role in follicular growth, maturation, and generation of steroid hormones via the involvement of the FSHR. One of the characteristics of PCOS is the failure of follicular growth. Therefore, it can be suggested that the FSHR gene is likely to play a crucial role in the pathogenesis of PCOS. The FSHR gene is located on chromosome 2p21, and includes 10 exons and 9 introns, with very few variants. Only two variants have been identified so far, which are as follows: p. Thr307Ala (c.919A > G, rs6165) and p. Asn680Ser (c.2039A > G, rs6166). In the latest study on women belonging to Korean origin, a significant correlation between p. Thr307Ala (c.919A > G, rs6165), p. Asn680Ser (c.2039A > G, rs6166), and PCOS was found.[32] However, it failed to explain their causal relationship and hence, further studies are needed for its determination. However, the results of previous studies on the susceptibility of the variant and PCOS are not consistent,[18] which may be due to the differences among the races.

Genes involved in metabolism: Insulin-related genes

One of the main manifestations of PCOS is IR and hyperinsulinemia, which can be associated with the probability of the corresponding genes playing a role in its pathogenesis. Many genetic mutations lead to IR and T2DM, of which, involvement of the transcription factor gene (TCF7L2) only has been clearly identified. TCF7L2 on chromosome 10 q25. 2 influences multiple gene transcriptions. It has been confirmed that in different ethnicities, TCF7L2 acts as the promoter for suppression and transactivation of genes by mediating the Wnt signaling pathways, which play a different role in the activation of islet cells.[33] Some scholars have analyzed the relationship between the susceptibility of the SNP rs7903146 and PCOS, which is very closely related to the occurrence of T2M by the involvement of TCF7L2. However, in a previous study, different results showing the genotypic variants CC, CT, and TT in TCF7L2 were found.[34] Besides, thyroid adenoma-associated gene (THADA) was also found to play an important role in the regulation of pancreatic beta-cell function which could lead to IR.[35] However, in the study involving the gene TCF7L2, the results were not consistent because different sample sizes yielded different results, suggesting that further studies with larger sample sizes are needed to obtain more accurate conclusions.

Other discoveries

Genes associated with pro-inflammatory response factors such as tumor necrosis factor-α

The imbalance of pro-inflammatory/anti-inflammatory cytokines has become a key factor in immunity, in which, tumor necrosis factor (TNF) activation plays an important role. TNF-α is secreted by ovarian macrophages, granular luteal cells, and immune cells. It is coded by a gene on the chromosome 6P21.3 and has a promoter of 1,100 bp length.[34] Replacement of nucleotides in this region can affect the binding affinity of the transcription factors, thus affecting the expression levels of the genes. Therefore, different concentrations of serum TNF-α are produced, resulting in the occurrence of a variety of diseases. In addition to interfering with the immune and inflammatory responses, differentiation, proliferation, and apoptosis, previous studies have also found that the production of TNF-α is associated with obesity, IR, and HA in patients with PCOS. In patients with POCS, the production of TNF-α in the granulocytes has been found to reduce the expression of the aromatase gene. This process leads to a decrease in the production of 17-β-estradiol in the ovary by inhibiting the induction of adenosine cyclase and cyclic phosphate signaling pathways, resulting in an increase in the levels of ovarian androgens indirectly.[36] In addition, TNF-α was also found to induce serine phosphorylation in the insulin receptor substrate 1, leading to an inhibition of the activity of the insulin receptor tyrosine kinase that consequently results in IR and hyperinsulinemia.[36] Thus, TNF-α may indirectly lead to the development of PCOS.

MicroRNAs

MiRNAs are small noncoding RNA molecules that regulate gene expression posttranscriptionally by interacting with the mRNAs, particularly at 3' untranslated region.[27] miRNAs have received increasing attention in recent studies because it is believed that a dysregulation in their expression may result in the occurrence of disorder during folliculogenesis and reduction in the ovulation rate, which are the main characteristics of PCOS. Moreover, as the miRNA functions by employing complementary sequences, hundreds of mRNAs could be targeted by a single miRNA molecule, which makes them potential biomarkers of PCOS.[37] Naji et al. found that, compared to the mormo-androgenic individuals, miR-93 and miR-21 were present at significantly higher levels in the granulosa cells (GCs) of patients with HA, whereas a decrease in the levels of the follicular fluid and no changes in their serum samples were observed.[38] However, the sample size (n < 40) of this study was relatively small, which reduced the credibility of the results. Despite this limitation, a potential role of miRNAs in the molecular mechanism of the GCs has been indicated. Further studies should be conducted to elaborate on the specific role of miRNAs in the pathogenesis of PCOS.

Mitochondrial DNA hypermethylation

Studies have found that, in individuals with POCS, the number of mitochondria greatly increased in the oocytes and played critical roles during oocyte maturation and fertilization, which are the main characteristics of PCOS. Therefore, we can elucidate the presence of some association between them. The primary function of the mitochondrion is the production of ATP via the oxidative phosphorylation (OXPHOS) pathway. Mammalian mitochondrial DNA (mtDNA) is approximately 16 kb in size and encodes 13 proteins which are subunits of the OXPHOS complexes, 22 transfer RNAs, and 2 ribosomal RNAs. mtDNA was found to be involved in epigenetic modifications and can, thus, contribute to mitochondrial dysfunction.[39] Although mtDNA has not been researched as thoroughly as nuclear DNA, its association and role in the occurrence of PCOS were first studied by Jia et al. They used cross-bred prepubertal gilts as experimental subjects. Interestingly, they found that the hypermethylation of mtDNA is associated with mitochondrial malfunction and poor quality of oocytes derived from the polycystic ovaries of the gilts. Although these findings were obtained mainly from association analysis and lacked information from a human-based experiment with a large sample size, it still provides a new insight to the pathogenesis of PCOS.[40]

Genes associated with fat mass obesity (FTO)

Obesity is a common feature of PCOS, and the obesity rate of patients with PCOS is approximately 50%.[41],[42] FTO is located on chromosome 16q12.2, which has been associated with body mass index, weight gain, T2DM, inflammation, and other factors in different populations.[43] These are common clinical features of PCOS, and hence, it can be assumed that FTO, which is related to fat content and obesity, may also be one of the susceptible genes involved in the occurrence of PCOS. In a study in which the relationship between FTO (rs9926289A/G, rs79206939A/G, rs8050136A/T, and rs9930506A/G) and PCOS was evaluated, it was found that SNPs in the FTO rs8050136A/C and rs1588413C/T were associated with susceptibility to PCOS and people with the susceptibility gene were more likely to be obese. Among these, rs8050136 A may be a risk allele for PCOS, and rs8050136 and rs1588413 were also found to be associated with the follicular number and embryo transfer rate, respectively.[43] The correlation between FTO and PCOS has been suggested, but further studies are needed to determine the specific relationship between the FTO gene and PCOS.


  Conclusions Top


In this article, we have summarized the recent progress in research associated with PCOS. Despite new findings, there are no genes or biomarkers that can be used singularly as exact indicators for the diagnosis of PCOS. Furthermore, information on the genes responsible for PCOS susceptibility is often controversial in some respect, and no effective methods are available to predict those involved in the occurrence of PCOS. Not only genetic factors but epigenetics, environment, and other attributes also affect the pathogenesis of PCOS. Besides, this review was limited to incomplete literature collection, and some studies that were published at the time of writing have not been included. However, we can conclude that some new insights related to PCOS have been found in recent years. More importantly, there is still a long way to go before we can fully understand the pathogenesis of PCOS and apply the suggested therapies clinically to improve the life of women.

Acknowledgments

The authors are grateful to the authors of the studies from which data were used for this review.

Financial support and sponsorship

This work was supported by the National Natural Science Foundation of China project (Nos. 81674018, 81874484).

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Deepika M, Reddy KR, Yashwanth A, Rani VU, Latha KP, Jahan P. TNF-αhaplotype association with polycystic ovary syndrome-a South Indian study. J Assist Reprod Genet 2013;30:1493-503. doi: 10.1007/s10815-013-0080-4.  Back to cited text no. 1
    
2.
Ji SY, Liu XM, Li BT, Zhang YL, Liu HB, Zhang YC, et al. The polycystic ovary syndrome-associated gene Yap1 is regulated by gonadotropins and sex steroid hormones in hyperandrogenism-induced oligo-ovulation in mouse. Mol Hum Reprod 2017;23:698-707. doi: 10.1093/molehr/gax046.  Back to cited text no. 2
    
3.
Ricardo A. PCOS in 2015: New insights into the genetics of polycystic ovary syndrome. Nat Rev Endocrinol 2016;12:74-5. doi: 10.1038/nrendo.2015.230.  Back to cited text no. 3
    
4.
Fu LL, Xu Y, Li DD, Dai XW, Xu X, Zhang JS, et al. Expression profiles of mRNA and long noncoding RNA in the ovaries of letrozole-induced polycystic ovary syndrome rat model through deep sequencing. Gene 2018;8:19-29. doi: 10.1016/j.gene.2018.03.002.  Back to cited text no. 4
    
5.
Liu AL, Liao HQ, Zhou J, Nie YL, Zhou CL, Li ZL, et al. The role of FTO variants in the susceptibility of polycystic ovary syndrome and in vitro fertilization outcomes in Chinese women. Gene 2018;8:101649-58. doi: 10.1080/09513590.2018.1441397.  Back to cited text no. 5
    
6.
Andrea D. Perspectives in polycystic ovary syndrome: From hair to eternity. J Clin Endocrinol Metab 2016;101:759-68. doi: 10.1210/jc. 2015-3780.  Back to cited text no. 6
    
7.
Cooper HE, Spellacy WE, Prem KA, Cohen WD. Hereditary factors in Stein–Leventhal syndrome. Am J Obstet Gynecol 1968;100:371-82. doi: 10.1016/S0002-9378(15)33704-2.  Back to cited text no. 7
    
8.
Govind A, Obhrai MS, Clayton RN. Polycystic ovaries are inherited as an autosomal dominant trait: Analysis of 29 polycystic ovary syndrome and 10 control families. J Clin Endocrinol Metab 1999;84:38-43. doi: 10.1210/jcem.84.1.5382.  Back to cited text no. 8
    
9.
Carey AH, Chan KL, Short F, White D, Williamson R, Franks S. Evidence for a single gene effect causing polycystic ovaries and male pattern baldness. Clin Endocrinol (Oxf) 1993;38:653-8. doi: 10.1111/j. 1365-2265.1993.tb02150.x.  Back to cited text no. 9
    
10.
Jahanfar S, Eden JA, Warren P, Seppala M, Nguyen TV. A twin study of polycystic ovary syndrome. Fertil Steril 1995;63:478-86. doi: 10.1016/S0015-0282(16)57412-3.  Back to cited text no. 10
    
11.
Stewart DR, Dombroski BA, Urbanek MA, Ewens W, Wood KG, Legro JR, 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;91:4112-7. doi: 10.1210/jc. 2006-0951.  Back to cited text no. 11
    
12.
Hickey TE, Legro RS, Norman RJ. Epigenetic modification of the X chromosome influences susceptibility to polycystic ovary syndrome. J Clin Endocrinol Metab 2006;91:2789-91. doi: 10.1210/jc.2006-0069.  Back to cited text no. 12
    
13.
Domecq JP, Prutsky G, Mullan RJ, Hazem A, Sundaresh V, Elamin MB, et al. Lifestyle modification programs in polycystic ovary syndrome: systematic review and meta-analysis. J Clin Endocrinol Metab 2013;98:4655-63. doi: 10.1210/jc.2013-2385.  Back to cited text no. 13
    
14.
Zhao H, Lv Y, Li L, Chen ZJ. Genetic studies on polycystic ovary syndrome. Best Pract Res Clin Obstet Gynaecol 2016;37:56-65. doi: 10.1016/j.bpobgyn.2016.04.002.  Back to cited text no. 14
    
15.
Shi Y, Zhao H, Shi Y, Cao Y, Yang D, Li Z, et al. Genome-wide association study identifies eight new risk loci for polycystic ovary syndrome. Nat Genet 2012;44:1020. doi: 10.1038/ng.2384.  Back to cited text no. 15
    
16.
Chen ZJ, Zhao H, He L, Shi Y, Qin Y, Shi Y, et al. Genome-wide association study identifies susceptibility loci for polycystic ovary syndrome on chromosome 2p16.3, 2p21 and 9q33.3. Nat Genet 2011;43:55-9. doi: 10.1038/ng.732.  Back to cited text no. 16
    
17.
Lee H, Oh JY, Sung YA, Chung H, Kim HL, Kim GS, et al. Genome-wide association study identified new susceptibility loci for polycystic ovary syndrome. Hum Reprod 2015;30:723-31. doi: 10.1093/humrep/deu352.  Back to cited text no. 17
    
18.
Hayes MG, Urbanck M, Ehrmann DA, Armstrong LL, Lee JY, Sisk R, et al. Genome-wide association of polycystic ovary syndrome implicates alterations in gonadotropin secretion in European ancestry population. Nat Commun 2015;6:7502. doi: 10.1038/ncomms8502.  Back to cited text no. 18
    
19.
Hayes MG, Urbanck M, Ehrmann DA, Armstrong LL, Lee JY, Sisk R, et al. Corrigendum: Genome-wide association of polycystic ovary syndrome implicates alterations in gonadotropin secretion in European ancestry populations. Nat Commun 2016;7:10762. doi: 10.1038/ncomms10762.  Back to cited text no. 19
    
20.
Jones MR, Goodarzi MO. Genetic determinants of polycystic ovary syndrome: Progress and future directions. Fertil Steril 2016;1:25-32. doi: 10.1016/j.fertnstert.2016.04.040.  Back to cited text no. 20
    
21.
Cui L, Zhao H, Zhang B, Qu Z, Liu J, Liang X, et al. Genotype–phenotype correlations of PCOS susceptibility SNPs identified by: GWAS in a large cohort of Han Chinese women. Hum Reprod 2013;28:538-44. doi: 10.1093/humrep/des424.  Back to cited text no. 21
    
22.
Chen L, Hu LM, Wang YF, Yang HY, Huang XY, Zhou W, et al. Genome-wide association study for SNPs associated with PCOS in human patients. Exp Ther Med 2017;14:4896-900. doi: 10.3892/etm. 2017.5113.  Back to cited text no. 22
    
23.
Meier RK. Polycystic ovary syndrome. Nurs Clin North Am 2018;3:407-20. doi: 10.1383/medc.2005.33.11.38.  Back to cited text no. 23
    
24.
Liu H, Zhao H, Chen ZJ. Genome-wide association studies for polycystic ovary syndrome. Semin Reprod Med 2016;4:224-9. doi: 10.1055/s-0036-1585403.  Back to cited text no. 24
    
25.
Shim U. Kim HN, LeeH, Oh JY, Sung YA, Kim HL. Pathway analysis based on a genome-wide association study of polycystic ovary syndrome. PLoS One 2015;8:11. doi: 10.1371/journal.pone.0136609.  Back to cited text no. 25
    
26.
Segars JH, DeCherney AH. Is there a genetic basis for polycystic ovary syndrome? J Clin Endocrinol Metab 2010;95:2058. doi: 10.1210/jc. 2010-0518.  Back to cited text no. 26
    
27.
Bartel DP. MicroRNAs: Genomics, biogenesis, mechanism, and function. Cell 2004;116:281-97. doi: 10.1016/S0092-8674(04)00045-5.  Back to cited text no. 27
    
28.
Lewis BP, Burge CB, Bartel DP. Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets. Cell 2005;120:15. doi: 10.1016/j.cell.2004.12.035.  Back to cited text no. 28
    
29.
Xue Y, Lv J, Xu P, Gu L, Cao J, Xu L, et al. Identification of microRNAs and genes associated with hyperandrogenism in the follicular fluid of women with polycystic ovary syndrome. J Cell Biochem 2018;119:3913-21. doi: 10.1002/jcb.26531.  Back to cited text no. 29
    
30.
McAllister JM, Modi B, Miller BA, Biegler J, Bruggeman R, Legro RS, et al. Overexpression of a DENND1A isoform produces a polycystic ovary syndrome theca phenotype. Proc Natl Acad Sci U S A 2014;111:E1519-27. doi: 10.1073/pnas.1400574111.  Back to cited text no. 30
    
31.
Anastasia K, Koika V, Roupas ND, Armeni A, Marioli D, Panidis D, et al. Association of Calpain (CAPN) 10 (UCSNP-43, rs3792267) gene polymorphism with elevated serum androgens in young women with the most severe phenotype of polycystic ovary syndrome (PCOS). Gynecol Endocrinol 2015;31:630-4. doi: 10.3109/09513590.2015.1032932.  Back to cited text no. 31
    
32.
Kim JJ, Choi YM, Hong MA, Chae SJ, Hwang K, Yoon SH, et al. FSH receptor gene p. Thr307Ala and p. Asn680Ser polymorphisms are associated with the risk of polycystic ovary syndrome. J Assist Reprod Genet 2017;34:1-7. doi: 10.1007/s10815-017-0953-z.  Back to cited text no. 32
    
33.
Prabhu YD, Sekar N, Abilash VG. Screening of polymorphisms of transcription factor 7-like 2 gene in polycystic ovary syndrome using polymerase chain reaction-restriction fragment length polymorphism analysis. J Hum Reprod Sci 2018;11:137-41. doi: 10.4103/jhrs.JHRS_123_15.  Back to cited text no. 33
[PUBMED]  [Full text]  
34.
Azziz R. PCOS in 2015: New insights into the genetics of polycystic ovary syndrome. Nat Rev Endocrinol 2016;12:74-5. doi: 10.1038/nrendo.2015.230.  Back to cited text no. 34
    
35.
Zhang YJ, Li L, Wang ZJ, Zhang XJ, Zhao H, Zhao Y, et al. Association study between variants in LHCGR DENND1A and THADA with preeclampsia risk in Han Chinese populations. J Matern Fetal Neonatal Med 2019;32:3801-5. doi: 10.1080/14767058.2018.1472228.  Back to cited text no. 35
    
36.
Fahimeh K, Sahar M, Yousef M, Saeideh M, Mojtaba F, Haleh R, et al. Preliminary study showing no association between G238A (rs361525) tumor necrosis factor-α (TNF-α) gene polymorphism and its serum level, hormonal and biochemical aspects of polycystic ovary syndrome. BMC Med Genet 2018;19:149. doi: 10.1186/s12881-018-0662-1.  Back to cited text no. 36
    
37.
Selbach M, Schwanhäusser B, Thierfelder N, Fang Z, Khanin R, Rajewsky N, et al. Widespread changes in protein synthesis induced by microRNAs. Nature 2008;455:58-63. doi: 10.1038/nature07228.  Back to cited text no. 37
    
38.
Naji M. Aleyasin A, Nekoonam S, Arefian E, Mahdian R, Amidi F. Differential expression of miR-93 and miR-21 in granulosa cells and follicular fluid of polycystic ovary syndrome associating with different phenotypes. Sci Rep 2017;7:14671. doi: 10.1038/s41598-017-13250-1.  Back to cited text no. 38
    
39.
Shaughnessy DT, McAllister K, Worth L, Haugen AC, Meyer JN, Domann FE, et al. Mitochondria, energetics, epigenetics, and cellular responses to stress. Environ Health Persp 2014;122:1271-8. doi: 10.1289/ehp.1408418.  Back to cited text no. 39
    
40.
Jia L, Li J, He B, Jia Y, Niu Y, Wang C, et al. Abnormally activated one-carbon metabolic pathway is associated with mtDNA hypermethylation and mitochondrial malfunction in the oocytes of polycystic gilt ovaries. Sci Rep 2016;6:19436. doi: 10.1038/srep19436.  Back to cited text no. 40
    
41.
Marciniak A, Nawrocka Rutkowska J, Brodowska A, Wiśniewska B, Starczewski A. Cardiovascular system diseases in patients with polycystic ovary syndrome – The role of inflammation process in this pathology and possibility of early diagnosis and prevention. Ann Agric Environ Med 2016;23:537-41. doi: 10.5604/12321966.1226842.  Back to cited text no. 41
    
42.
Unfer V, Nestler JE, Kamenov ZA, Prapas N, Facchinetti F. Effects of inositol(s) in women with PCOS: A Systematic review of randomized controlled trials. Int J Endocrinol 2016;2016:1849162. doi: 10.1155/2016/1849162.  Back to cited text no. 42
    
43.
Chedraui P, Perez-Lopez FR, Escobar GS, Espinoza-Caicedo JA, Montt-Guevara M, Genazzani AR, et al. Polymorphisms of the FTO and MTHFR genes and vascular, inflammatory and metabolic marker levels in postmenopausal women. J Endocrinol Invest 2016;39:885-90. doi: 10.1007/s40618-016-0443-7.  Back to cited text no. 43
    




 

Top
 
 
  Search
 
Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
 Related articles
Access Statistics
Email Alert *
Add to My List *
* Registration required (free)

 
  In this article
Abstract
Introduction
Previous Knowledge
What Was Discove...
Other Genes Asso...
Conclusions
References

 Article Access Statistics
    Viewed131    
    Printed8    
    Emailed0    
    PDF Downloaded195    
    Comments [Add]    

Recommend this journal


[TAG2]
[TAG3]
[TAG4]