Leveraging Northern European population history: novel low-frequency variants for polycystic ovary syndrome.
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ABSTRACT:
SUBMITTER: Tyrmi JS
PROVIDER: S-EPMC8804330 | biostudies-literature | 2022 Jan
REPOSITORIES: biostudies-literature
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Leveraging Northern European population history: novel low-frequency variants for polycystic ovary syndrome.
Tyrmi Jaakko S JS Arffman Riikka K RK Pujol-Gualdo Natàlia N Kurra Venla V Morin-Papunen Laure L Sliz Eeva E Piltonen Terhi T TT Laisk Triin T Kettunen Johannes J Laivuori Hannele H
Human reproduction (Oxford, England) 20220101 2
<h4>Study question</h4>Can we identify novel variants associated with polycystic ovary syndrome (PCOS) by leveraging the unique population history of Northern Europe?<h4>Summary answer</h4>We identified three novel genome-wide significant associations with PCOS, with two putative independent causal variants in the checkpoint kinase 2 (CHEK2) gene and a third in myosin X (MYO10).<h4>What is known already</h4>PCOS is a common, complex disorder with unknown aetiology. While previous genome-wide ass ...[more]
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Project description:ContextA genome-wide association study has identified three loci (five independent signals) that confer risk for polycystic ovary syndrome (PCOS) in Han Chinese women. Replication is necessary to determine whether the same variants confer risk for PCOS in women of European ancestry.ObjectiveThe objective of the study was to test whether these PCOS risk variants in Han Chinese women confer risk for PCOS in women of European ancestry.DesignThis was a case-control study.SettingThe study was conducted at deCODE Genetics in Iceland and two academic medical centers in the United States.PatientsCases were 376 Icelandic women and 565 and 203 women from Boston, MA, and Chicago, IL, respectively, all diagnosed with PCOS by the National Institutes of Health criteria. Controls were 16,947, 483, and 189 women not known to have PCOS from Iceland, Boston, and Chicago, respectively.InterventionThere were no interventions.Main outcomesMain outcomes were allele frequencies for seven variants in PCOS cases and controls.ResultsTwo strongly correlated Han Chinese PCOS risk variants on chromosome 9q33.3, rs10986105[C], and rs10818854[A], were replicated in samples of European ancestry with odds ratio of 1.68 (P = 0.00033) and odds ratio of 1.53 (P = 0.0019), respectively. Other risk variants at 2p16.3 (rs13405728), 2p21 (rs12468394, rs12478601, and rs13429458), and 9q33.3 (rs2479106), or variants correlated with them, did not associate with PCOS. The same allele of rs10986105 that increased the risk of PCOS also increased the risk of hyperandrogenism in women without PCOS from Iceland and demonstrated a stronger risk for PCOS defined by the National Institutes of Health criteria than the Rotterdam criteria.ConclusionsWe replicated one of the five Chinese PCOS association signals, represented by rs10986105 and rs10818854 on 9q33, in individuals of European ancestry. Examination of the subjects meeting at least one of the Rotterdam criteria for PCOS suggests that the variant may be involved in the hyperandrogenism and possibly the irregular menses of PCOS.
| S-EPMC3387396 | biostudies-literature
Project description:Polycystic ovary syndrome (PCOS) is a complex endocrine disorder with a strong familial component. PCOS is characterised by hyperandrogenaemia and irregular menses. A recent genome-wide association study (GWAS) of PCOS in a Chinese cohort identified three reproducible PCOS susceptibility loci mapping to 2p16.3 (luteinising hormone/choriogonadotropin receptor; LHCGR), 2p21 (thyroid associated protein; THADA), and 9q33.3 (DENN/MADD domain containing 1A; DENNDIA). The impact of these loci in non-Chinese PCOS cohorts remains to be determined.The study tested association with PCOS of seven single nucleotide polymorphisms mapping to the three Chinese PCOS loci in two European derived PCOS cohorts (cohort A = 939 cases and 957 controls; cohort B = 535 cases and 845 controls). Cases fulfilled the National Institute of Child Health & Human Development criteria for PCOS. Variation in DENND1A was strongly associated with PCOS in the study cohort (p(combined cohorts)=10(-8)); multiple variants in THADA were also associated with PCOS, while there was no significant evidence for association of LHCGR variation with PCOS. The present study had >80% power to detect an effect of similar size as was observed by Chen et al for DENND1A and THADA, but reduced power (at <40%) for LHCGR at p=0.0001. The study had sufficient power (57-88%) for LHCGR at p=0.01.At least two of the PCOS susceptibility loci identified in the Chinese PCOS GWAS (DENND1A and THADA) are also associated with PCOS in European derived populations, and are therefore likely to be important in the aetiology of PCOS regardless of ethnicity. The analysis of the LHCGR gene was not sufficiently powered to detect modest effects.
| S-EPMC3536488 | biostudies-literature
Project description:ContextPolycystic ovary syndrome (PCOS), a common endocrine condition, is the leading cause of anovulatory infertility.ObjectiveGiven that common disease-susceptibility variants account for only a small percentage of the estimated PCOS heritability, we tested the hypothesis that rare variants contribute to this deficit in heritability.Design, setting, and participantsUnbiased whole-genome sequencing (WGS) of 80 patients with PCOS and 24 reproductively normal control subjects identified potentially deleterious variants in AMH, the gene encoding anti-Müllerian hormone (AMH). Targeted sequencing of AMH of 643 patients with PCOS and 153 control patients was used to replicate WGS findings.Main outcome measuresDual luciferase reporter assays measured the impact of the variants on downstream AMH signaling.ResultsWe found 24 rare (minor allele frequency < 0.01) AMH variants in patients with PCOS and control subjects; 18 variants were specific to women with PCOS. Seventeen of 18 (94%) PCOS-specific variants had significantly reduced AMH signaling, whereas none of 6 variants observed in control subjects showed significant defects in signaling. Thus, we identified rare AMH coding variants that reduced AMH-mediated signaling in a subset of patients with PCOS.ConclusionTo our knowledge, this study is the first to identify rare genetic variants associated with a common PCOS phenotype. Our findings suggest decreased AMH signaling as a mechanism for the pathogenesis of PCOS. AMH decreases androgen biosynthesis by inhibiting CYP17 activity; a potential mechanism of action for AMH variants in PCOS, therefore, is to increase androgen biosynthesis due to decreased AMH-mediated inhibition of CYP17 activity.
| S-EPMC5546867 | biostudies-literature
Project description:This was a prospective cross-sectional study in which 126 female students between the ages of 18 and 30 years were evaluated for the frequency of polycystic ovary syndrome (PCOS) through clinical interview, questionnaire, and anthropometric measurements. The diagnostic criteria of the US National Institutes of Health criteria were used. Menstrual irregularities (MI) were identified, and clinical hyperandrogenism was evaluated by self-assessment of hirsutism using modified Ferriman-Gallwey score. Blood analysis was done for measurement of prolactin, thyroid-stimulating hormone, and the androgen hormones. Of all the students, 37 (30.8%) had MI, 38 (31.7%) had clinical hirsutism, 37 (30.8%) had acne, and 76 (63.3%) had a family history of type 2 diabetes. The estimated frequency of PCOS was 18.33% according to the US National Institutes of Health definition. Hormonal analysis demonstrated a significant increase in androgens (total testosterone, dehydroepiandrosterone sulfate, and free testosterone), and a significant decrease in sex hormone-binding globulin in our PCOS group, with a P-value <0.05. This study revealed a higher level of the androgen hormones among PCOS subjects with a frequency of PCOS (18.33%) similar to the global estimates of 10%-20%.
| S-EPMC5179205 | biostudies-literature
Project description:Study questionAre PCOS risk variants identified in women of Han Chinese ethnicity also associated with risk of PCOS or the phenotypic features of PCOS in European women?Summary answerOne variant, rs2268361-T, in the intron of FSHR was associated with PCOS and lower FSH levels, while another variant rs705702-G near the RAB5B and SUOX genes was associated with insulin and glucose levels after oral glucose testing in women with PCOS of European ethnicity.What is known alreadyThree of the eleven variants associated with PCOS in the Han Chinese genome-wide association studies were also associated with PCOS in at least one European population when corrected for multiple testing (DENND1A, THADA and YAP1). However, additional replication is needed to establish the importance of these variants in European women and to determine the relationship to PCOS phenotypic traits.Study design, size, durationThe study was a case-control examination in a discovery cohort of women with PCOS (n = 485) and controls (n = 407) from Boston (Boston 1). Replication was performed in women from Greece (cases n = 884 and controls n = 311) and an additional cohort from Boston (Boston electronic medical record (EMR); n = 350 cases and n = 1258 controls).Participants/materials, settings, methodsWomen had PCOS defined by the National Institutes of Health criteria in Boston 1 and Greece (n = 783), with additional subjects fulfilling the Rotterdam criteria (hyperandrogenism, polycystic ovary morphology and regular menses) in Greece (n = 101). Controls in Boston and Greece had regular menstrual cycles and no hyperandrogenism. The second cohort from Boston was defined using the EMR and natural language processing. Allele frequencies for variants associated with PCOS in Han Chinese women were examined in PCOS cases and controls, along with the relationship to quantitative traits.Main results and the role of chanceA variant rs2268361-T in an intron of FSHR was associated with PCOS (0.84 [0.76-0.93], OR [95% CI]; P = 0.002). The rs2268361-T was associated with lower FSH levels (-0.15 ± 0.05; P = 0.0029). A variant rs705702-G near RAB5B and SUOX was associated with insulin (-0.16 ± 0.05, P = 0.0029) and glucose levels (-0.20 ± 0.05, P = 0.0002) 120 min after an oral glucose test.Limitations, reasons for cautionThe study was large and contained replication cohorts, but was limited by a small number of controls in the Greek cohort and a small number of cases in the second Boston cohort. The second Boston group was identified using electronic medical record review, but was validated for the cardinal features of PCOS.Wider implications of the findingsThis study demonstrates a cross-ethnic PCOS risk locus in FSHR in women of European ancestry with PCOS. The variant may influence FSH receptor responsiveness as suggested by the associated change in FSH levels. The relationship between a variant near RAB5B and SUOX and glucose stimulated insulin and glucose levels suggests an influence of one of these genes on glucose tolerance, but the absence of a relationship with PCOS points to potential differences in the international PCOS patient populations.Study funding/competing interestsThe project was supported by Award Number R01HD065029 from the Eunice Kennedy Shriver National Institute Of Child Health & Human Development, Award Number 1 UL1 RR025758, Harvard Clinical and Translational Science Center, from the National Center for Research Resources, award 1-10-CT-57 from the American Diabetes Association and the Partners Healthcare Center for Personalized Genetics Project Grant. C.K.W. is a consultant for Takeda Pharmaceuticals.Trial registration numberNCT00166569.
| S-EPMC4498224 | biostudies-literature
Project description:OBJECTIVE:To date, little is known about differences in the knowledge, diagnosis making and treatment strategies of health care providers regarding polycystic ovary syndrome (PCOS) across different disciplines in countries with similar health care systems. To inform guideline translation, we aimed to study physician reported awareness, diagnosis and management of PCOS and to explore differences between medical disciplines in the Nordic countries and Estonia. METHODS:This cross-sectional survey was conducted among 382 endocrinologists and obstetrician-gynaecologists in the Nordic countries and Estonia in 2015-2016. Of the participating physicians, 43% resided in Finland, 18% in Denmark, 16% in Norway, 13% in Estonia, and 10% in Sweden or Iceland, and 75% were obstetrician-gynaecologists. Multivariable logistic regression models were run to identify health care provider characteristics for awareness, diagnosis and treatment of PCOS. RESULTS:Clinical features, lifestyle management and comorbidity were commonly recognized in women with PCOS, while impairment in psychosocial wellbeing was not well acknowledged. Over two-thirds of the physicians used the Rotterdam diagnostic criteria for PCOS. Medical endocrinologists more often recommended lifestyle management (OR = 3.6, CI 1.6-8.1) or metformin (OR = 5.0, CI 2.5-10.2), but less frequently OCP (OR = 0.5, CI 0.2-0.9) for non-fertility concerns than general obstetrician-gynaecologists. The physicians aged <35 years were 2.2 times (95% CI 1.1-4.3) more likely than older physicians to recommend lifestyle management for patients with PCOS for fertility concerns. Physicians aged 46-55 years were less likely to recommend oral contraceptive pills (OCP) for patients with PCOS than physicians aged >56 (adjusted odds ratio (OR) = 0.4, 95% CI 0.2-0.8). CONCLUSION:Despite well-organized healthcare, awareness, diagnosis and management of PCOS is suboptimal, especially in relation to psychosocial comorbidities, among physicians in the Nordic countries and Estonia. Physicians need more education on PCOS and evidence-based information on Rotterdam diagnostic criteria, psychosocial features and treatment of PCOS, with the recently published international PCOS guideline well needed and welcomed.
| S-EPMC6932801 | biostudies-literature
Project description:Polycystic ovary syndrome (PCOS) affects 5-10 percent of all fertile women and is associated with anovulation/oligoovulation, hyperandrogenism, and polycystic ovaries. Pharmacological treatment is often effective but associated with unwanted side effects. Acupuncture treatments have been shown to improve menstrual bleeding patterns and ovulation as well as hyperandrogenism, without side effects. The purpose of the present study was to describe the experience of acupuncture for women diagnosed with PCOS.Eight women with PCOS living in western Sweden, were interviewed following repeated acupuncture treatments. Data was analyzed using systematic text condensation as described by Malterud.The experience of acupuncture for women diagnosed with PCOS can be described in five categories; the experience of hope, getting results, feelings of responsibility, skepticism and proof of effect, and feeling normal.Since acupuncture is a promising treatment for the symptoms of the common syndrome PCOS, the present study adds to the knowledge base by providing the important experiences of patients receiving the treatment. Acupuncture provides a possibility for patients to gain hope as the treatment shows results. The results show that acupuncture empowers the patients to take responsibility for their future well-being, although they may have been initially skeptical to the treatment. Because the syndrome had affected them for some time, even small changes offered a chance for them to feel that their bodies were capable of normal function.
| S-EPMC3365875 | biostudies-literature
Project description:BackgroundPolycystic ovary syndrome (PCOS) is a common and complex multisystemic genetic disease. Previous genome-wide association study (GWAS) of PCOS has found several potentially causative single nucleotide polymorphisms (SNPs) in Han Chinese population. The goal of present investigation was to assess the potential association between rs1121980, rs1421085, rs1558902, rs8050136 SNPs and PCOS. In order to make a better elucidation of this disease, further investigations of association between SNPs susceptibility and PCOS become necessary.MethodsIn the present study, we enrolled 212 patients with PCOS and 198 control subjects. Four polymorphisms of FTO gene (rs1121980, rs1421085, rs1558902, rs8050136) were genotyped by Taqman-MGB method, and their relationship with PCOS was speculated.ResultsThe allele frequency has no significant difference between the PCOS group and the controls. Genotype frequencies of the four SNPs in the additive, dominant and recessive models showed no significant difference between PCOS cases and controls.ConclusionsOur results demonstrate that FTO gene has little association in PCOS development.
| S-EPMC4680510 | biostudies-literature
Project description:Polycystic ovary syndrome (PCOS) is a reproductive endocrine disease, and results to opsomenorrhea or amenorrhea, hairy, acne, acanthosis, infertility, abortion. In the long term, PCOS may also increase the risk of endometrial cancer, diabetes, hypertension, dyslipidemia and other diseases. Till now there is no specific drug for PCOS due to the unclearness of the cause and pathogenesis, as current treatments for PCOS only target certain symptoms. Quercetin (QUR) is a flavonoid drug widely found in Chinese herbal medicines, fruits, leaves, vegetables, seeds and plants roots. Studies on other diseases have found that QUR has anti-oxidant, anti-inflammatory, anti-insulin resistance, anti-cancer and other effects. Some studies have shown that serum testosterone (T), luteinizing hormone (LH), the LH/follicule-stimulating hormone (FSH) ratio, fasting glucose, fasting insulin, HOMA-IR and lipid levels are reduced in PCOS patients with QUR treatment. However, the mechanisms of QUR in PCOS patients have not been completely elucidated. In this review, we retrospect the basic characteristics of QUR, and in vitro studies, animal experiments and clinical trials of QUR and plant extracts containing QUR in the treatment of PCOS. We also summarized the effects and mechanism of QUR in ovarian cells in vitro and PCOS model rats, the changes in relevant parameters after QUR administration in PCOS patients, and its potentially therapeutic applications.
| S-EPMC9800798 | biostudies-literature
Project description:Polycystic ovary syndrome (PCOS) is one of the most common endocrinopathies in women of fertile age. Obesity is encountered in 30-70% of PCOS-affected women, and its presence significantly modifies both clinical and laboratory expression of the syndrome. Obesity increases the risk of co-morbidities associated with PCOS, such as impaired glucose tolerance and type 2 diabetes mellitus, hyperlipidemia and arterial hypertension. The etiopathogenesis of obesity in PCOS has not yet been exactly clarified. There clearly is a vicious circle of abdominal obesity, insulin resistance, and hyperadrogenemia. Differences in ghrelin and neuropeptide Y levels between PCOS patients and those with simple obesity were also described. Weight loss is the first choice recommendation for the treatment of clinical manifestations of PCOS, such as menstrual cycle irregularities, infertility or hirsutism. However, the best treatment approach in obese PCOS patients remains to be defined. Studies concerning different weight loss regimens, antiobesity drugs, bariatric surgery, insulin sensitizers, and hormonal therapy are reviewed.
| S-EPMC6444522 | biostudies-literature