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Genome-wide association of polycystic ovary syndrome implicates alterations in gonadotropin secretion in European ancestry populations.

ABSTRACT: Polycystic ovary syndrome (PCOS) is a common, highly heritable complex disorder of unknown aetiology characterized by hyperandrogenism, chronic anovulation and defects in glucose homeostasis. Increased luteinizing hormone relative to follicle-stimulating hormone secretion, insulin resistance and developmental exposure to androgens are hypothesized to play a causal role in PCOS. Here we map common genetic susceptibility loci in European ancestry women for the National Institutes of Health PCOS phenotype, which confers the highest risk for metabolic morbidities, as well as reproductive hormone levels. Three loci reach genome-wide significance in the case-control meta-analysis, two novel loci mapping to chr 8p23.1 [Corrected] and chr 11p14.1, and a chr 9q22.32 locus previously found in Chinese PCOS. The same chr 11p14.1 SNP, rs11031006, in the region of the follicle-stimulating hormone B polypeptide (FSHB) gene strongly associates with PCOS diagnosis and luteinizing hormone levels. These findings implicate neuroendocrine changes in disease pathogenesis.

SUBMITTER: Hayes MG

PROVIDER: S-EPMC4557132 | biostudies-literature | 2015 Aug

REPOSITORIES: biostudies-literature

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Genome-wide association of polycystic ovary syndrome implicates alterations in gonadotropin secretion in European ancestry populations.

Hayes M Geoffrey MG Urbanek Margrit M Ehrmann David A DA Armstrong Loren L LL Lee Ji Young JY Sisk Ryan R Karaderi Tugce T Barber Thomas M TM McCarthy Mark I MI Franks Stephen S Lindgren Cecilia M CM Welt Corrine K CK Diamanti-Kandarakis Evanthia E Panidis Dimitrios D Goodarzi Mark O MO Azziz Ricardo R Zhang Yi Y James Roland G RG Olivier Michael M Kissebah Ahmed H AH Stener-Victorin Elisabet E Legro Richard S RS Dunaif Andrea A

Nature communications 20150818

Polycystic ovary syndrome (PCOS) is a common, highly heritable complex disorder of unknown aetiology characterized by hyperandrogenism, chronic anovulation and defects in glucose homeostasis. Increased luteinizing hormone relative to follicle-stimulating hormone secretion, insulin resistance and developmental exposure to androgens are hypothesized to play a causal role in PCOS. Here we map common genetic susceptibility loci in European ancestry women for the National Institutes of Health PCOS ph ...[more]

PMID: 26284813

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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.

Project description:Women with polycystic ovary syndrome (PCOS) demonstrate gonadotropin-releasing hormone (GnRH) pulse generator resistance to suppression with 7 days of progesterone and estradiol administration. It remains unknown whether such women demonstrate impairments in acute progesterone negative feedback on LH pulse frequency or progesterone positive feedback on gonadotropin release. This was a randomized, double-blind, placebo-controlled crossover study designed to test the hypothesis that acute, progesterone-related suppression of LH pulse frequency and progesterone-related augmentation of gonadotropin release are impaired in PCOS. Twelve normally cycling women and 12 women with PCOS completed study. Volunteers were pretreated with transdermal estradiol (0.2 mg/day) for 3 days and then underwent a frequent blood sampling study (20:00-20:00 h), during which they received micronized progesterone (100 mg) or placebo at 06:00 h. In a second study admission, volunteers received the intervention they did not receive during the first admission, but the protocol was otherwise identical. The primary outcome measures were LH secretory characteristics and circulating gonadotropin concentrations. Exogenous progesterone did not reduce LH pulse frequency in either group. Mean LH, pulsatile LH secretion, LH pulse mass, and mean FSH increased more with progesterone compared to placebo in both groups. Although trends toward less pronounced changes in LH pulse mass and pulsatile LH secretion were observed in the PCOS group, these differences were not statistically significant. In summary, exogenous progesterone did not suppress LH pulse frequency within 12 hours in estradiol-pretreated women, and the positive feedback effect of progesterone on gonadotropin release was not demonstrably impaired in PCOS. NEW & NOTEWORTHY: This study indicated that exogenous progesterone does not reduce LH pulse frequency within 12 h in women with PCOS, but progesterone acutely increased gonadotropin in these women. This study suggested that progesterone-related augmentation of gonadotropin release may be impaired in PCOS compared to normally cycling women, but this finding was not statistically significant.

Project description:Are 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?One 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.Three 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.The 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).Women 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.A 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.The 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.This 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.The 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.NCT00166569.

Project description:BackgroundAt present, a number of clinical trials have been carried out on GLP-1 receptor agonist liraglutide in the treatment of polycystic ovary syndrome (PCOS). However, the effect of liraglutide on follicle development and its specific mechanism are still unclear.MethodsRNA sequencing was used to explore the molecular characteristics of granulosa cells from patients with PCOS treated with liraglutide. The levels of C-X-C motif chemokine ligand 10 (CXCL10) in follicular fluid were detected by ELISA, the expression levels of ovulation related genes and inflammatory factor genes in follicles and granulosa cells were detected by qPCR and the protein levels of connexin 43 (Cx43), Janus Kinase 2 (JAK2) and phosphorylated JAK2 were detected by Western blot. The mouse ovarian follicles culture system in vitro was used to detect the status of follicle development and ovulation.ResultsIn the present study, we found that liraglutide inhibited the secretion of inflammatory factors in PCOS granulosa cells, among which CXCL10 was the most significant. In addition, CXCL10 was significantly higher in granulosa cells and follicular fluid in PCOS patients than in non-PCOS patients. We applied in vitro follicle culture and other techniques to carry out the mechanism exploration which revealed that CXCL10 disrupted the homeostasis of gap junction protein alpha 1 (GJA1) between oocyte and granulosa cells before physiological ovulation, thus inhibiting follicular development and ovulation. Liraglutide inhibited CXCL10 secretion in PCOS granulosa cells by inhibiting the JAK signaling pathway and can improved dehydroepiandrosterone (DHEA)-induced follicle development disorders, which is reversed by CXCL10 supplementation.ConclusionsThe present study suggests that liraglutide inhibits CXCL10 secretion in granulosa cells through JAK signaling pathway, thereby improving the homeostasis of GJA1 between oocyte and granulosa cells before physiological ovulation and ultimately improving the follicular development and ovulation of PCOS, which provides more supportive evidence for the clinical application of liraglutide in the treatment of ovulatory disorders in PCOS.Trial registrationNot applicable.

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Genome-wide association of polycystic ovary syndrome implicates alterations in gonadotropin secretion in European ancestry populations.

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Genome-wide association of polycystic ovary syndrome implicates alterations in gonadotropin secretion in European ancestry populations.

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