Dataset Information

Association between genetically predicted polycystic ovary syndrome and ovarian cancer: a Mendelian randomization study.

ABSTRACT: BACKGROUND:Polycystic ovary syndrome (PCOS) is a complex endocrine disorder with an estimated prevalence of 4-21% in reproductive aged women. Recently, the Ovarian Cancer Association Consortium (OCAC) reported a decreased risk of invasive ovarian cancer among women with self-reported PCOS. However, given the limitations of self-reported PCOS, the validity of these observed associations remains uncertain. Therefore, we sought to use Mendelian randomization with genetic markers as a proxy for PCOS, to examine the association between PCOS and ovarian cancer. METHODS:Utilizing 14 single nucleotide polymorphisms (SNPs) previously associated with PCOS we assessed the association between genetically predicted PCOS and ovarian cancer risk, overall and by histotype, using summary statistics from a previously conducted genome-wide association study (GWAS) of ovarian cancer among European ancestry women within the OCAC (22 406 with invasive disease, 3103 with borderline disease and 40 941 controls). RESULTS:An inverse association was observed between genetically predicted PCOS and invasive ovarian cancer risk: odds ratio (OR)=0.92 [95% confidence interval (CI)=0.85-0.99; P?=?0.03]. When results were examined by histotype, the strongest inverse association was observed between genetically predicted PCOS and endometrioid tumors (OR?=?0.77; 95% CI?=?0.65-0.92; P?=?0.003). Adjustment for individual-level body mass index, oral contraceptive use and parity did not materially change the associations. CONCLUSION:Our study provides evidence for a relationship between PCOS and reduced ovarian cancer risk, overall and among specific histotypes of invasive ovarian cancer. These results lend support to our previous observational study results. Future studies are needed to understand mechanisms underlying this association.

SUBMITTER: Harris HR

PROVIDER: S-EPMC6659359 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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Association between genetically predicted polycystic ovary syndrome and ovarian cancer: a Mendelian randomization study.

Harris Holly R HR Cushing-Haugen Kara L KL Webb Penelope M PM Nagle Christina M CM Jordan Susan J SJ Risch Harvey A HA Rossing Mary Anne MA Doherty Jennifer A JA Goodman Marc T MT Modugno Francesmary F Ness Roberta B RB Moysich Kirsten B KB Kjær Susanne K SK Høgdall Estrid E Jensen Allan A Schildkraut Joellen M JM Berchuck Andrew A Cramer Daniel W DW Bandera Elisa V EV Rodriguez Lorna L Wentzensen Nicolas N Kotsopoulos Joanne J Narod Steven A SA McLaughlin John R JR Anton-Culver Hoda H Ziogas Argyrios A Pearce Celeste L CL Wu Anna H AH Lindström Sara S Terry Kathryn L KL

International journal of epidemiology 20190601 3

<h4>Background</h4>Polycystic ovary syndrome (PCOS) is a complex endocrine disorder with an estimated prevalence of 4-21% in reproductive aged women. Recently, the Ovarian Cancer Association Consortium (OCAC) reported a decreased risk of invasive ovarian cancer among women with self-reported PCOS. However, given the limitations of self-reported PCOS, the validity of these observed associations remains uncertain. Therefore, we sought to use Mendelian randomization with genetic markers as a proxy ...[more]

PMID: 31211375

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Project description:Study questionWhat are the causal relationships between polycystic ovary syndrome (PCOS) and body mass index (BMI)?Summary answerBidirectional Mendelian randomization analyses suggest that increased BMI is causal for PCOS while the reverse is not the case.What is known alreadyThe contribution of obesity to the pathogenesis of PCOS is controversial. To date, published genetic studies addressing this question have generated conflicting results and have not utilized the full extent of known single nucleotide polymorphisms associated with body mass index (BMI).Study design, size, durationThis cross-sectional Mendelian randomization (MR) and genetic association study was conducted in 750 individuals of European origin and with PCOS and 1567 BMI-matched controls.Participants/materials, setting, methodsCases and controls were matched for BMI as well as for distribution of weight categories (normal weight, overweight, obese). Two-sample MR using inverse variance weighting (IVW) was conducted using a 92-SNP instrument variable for BMI with PCOS as the outcome, followed by two-sample MR with a 16-SNP instrument variable for PCOS with BMI as the outcome. Sensitivity analyses included MR-Egger and maximum likelihood methods. Secondary analyses assessed associations of genetic risk scores and individual SNPs with PCOS, BMI and quantitative androgen-related and glucose homeostasis-related traits.Main results and the role of chanceEach standard deviation genetically higher BMI was associated with a 4.89 (95% CI 1.46-16.32) higher odds of PCOS. Conversely, genetic risk of PCOS did not influence BMI. Sensitivity analyses yielded directionally consistent results. The genetic risk score of 92 BMI SNPs was associated with the diagnosis of PCOS (OR 1.043, 95% CI 1.009-1.078, P = 0.012). Of the 92 BMI risk variants evaluated, none were associated individually with PCOS after considering multiple testing. The association of FTO SNP rs1421085 with BMI was stronger in women with PCOS (β = 0.071, P = 0.0006) than in controls (β = 0.046, P = 0.065).Limitations, reasons for cautionThe current sample size, while providing good power for MR and genetic risk score analyses, had limited power to demonstrate association of individual SNPs with PCOS. Cases and controls were not matched for age; however, this was mitigated by adjusting analyses for age. Dietary and lifestyle data, which could have been used to explore the greater association of the FTO SNP with BMI in women with PCOS, was not available.Wider implications of the findingsIncreasing BMI appears to be causal for PCOS but having PCOS does not appear to affect BMI. This study used the most comprehensive set of SNPs for BMI currently available. Prior studies using fewer SNPs had yielded conflicting results and may have been confounded because cases and controls were not matched for weight categories. The current results highlight the potential utility of weight management in the prevention and treatment of PCOS.Study funding/competing interest(s)National Institutes of Health Grants R01-HD29364 and K24-HD01346 (to R.A.), Grant R01-DK79888 (to M.O.G.), Grant U54-HD034449 (to R.S.L.), Grant U19-HL069757 (to R.M.K.). The funders had no influence on the data collection, analyses or conclusions of the study. No conflict of interests to declare.Trial registration numberN/A.

Dataset Information

Association between genetically predicted polycystic ovary syndrome and ovarian cancer: a Mendelian randomization study.

Publications

Association between genetically predicted polycystic ovary syndrome and ovarian cancer: a Mendelian randomization study.

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