Maternal polycystic ovary syndrome and offspring birth weight: a Mendelian randomization study

2021 ◽  
Author(s):  
Yuexin Gan ◽  
Donghao Lu ◽  
Chonghuai Yan ◽  
Jun Zhang ◽  
Jian Zhao
Keyword(s):  
Birth Weight ◽  
Polycystic Ovary Syndrome ◽  
Causal Relationship ◽  
Mendelian Randomization ◽  
Polycystic Ovary ◽  
Causal Effect ◽  
Sensitivity Analyses ◽  
European Ancestry ◽  
Ovary Syndrome ◽  
Genetic Instruments

Abstract Background Observational associations between maternal polycystic ovary syndrome (PCOS) and offspring birth weight (BW) have been inconsistent and the causal relationship is still uncertain. Objective We conducted a two-sample Mendelian randomization (MR) study to estimate the causal effect of maternal PCOS on offspring BW. Methods We constructed genetic instruments for PCOS with 14 single nucleotide polymorphisms (SNPs) which were identified in the genome-wide association study (GWAS) meta-analysis including 10,074 PCOS cases and 103,164 controls of European ancestry from seven cohorts. The genetic associations of these SNPs with the offspring BW were extracted from summary statistics estimated by the Early Growth Genetics (EGG) consortium (n = 406,063 European-ancestry individuals) using the weighted linear model (WLM), an approximation method of structural equation model (SEM), which separated maternal genetic effects from fetal genetic effects. We used a two-sample MR design to examine the causal relationship between maternal PCOS and offspring BW. Sensitivity analyses were conducted to assess the robustness of the MR results. Results We found little evidence for a causal effect of maternal PCOS on offspring BW (-6.1 g, 95% confidence interval [CI]: -16.8 g, 4.6 g). Broadly consistent results were found in the sensitivity analyses. Conclusion Despite the large scale of this study, our results suggested little causal effect of maternal PCOS on offspring BW. MR studies with a larger sample size of women with PCOS or more genetic instruments that would increase the variation of PCOS explained are needed in the future.

scholarly journals Assessment of Bidirectional Relationships Between Polycystic Ovary Syndrome and Periodontitis: Insights From a Mendelian Randomization Analysis

2021 ◽  
Vol 12 ◽  
Author(s):  
Pengfei Wu ◽  
Xinghao Zhang ◽  
Ping Zhou ◽  
Wan Zhang ◽  
Danyang Li ◽  
...  
Keyword(s):  
Polycystic Ovary Syndrome ◽  
Odds Ratio ◽  
Mendelian Randomization ◽  
Polycystic Ovary ◽  
Causal Effect ◽  
Sensitivity Analyses ◽  
Ovary Syndrome ◽  
Unit Increase ◽  
Log Odds ◽  
Mr Study

BackgroundObservational studies have indicated an association between polycystic ovary syndrome (PCOS) and periodontitis, but it is unclear whether the association is cofounded or causal. We conducted a two-sample Mendelian randomization (MR) study to investigate the bidirectional relationship between genetically predicted PCOS and periodontitis.MethodsFrom two genome-wide association studies we selected 13 and 7 single nucleotide polymorphisms associated with PCOS and periodontitis, respectively, as instrumental variables. We utilized publicly shared summary-level statistics from European-ancestry cohorts. To explore the causal effect of PCOS on periodontitis, 12,289 cases of periodontitis and 22,326 controls were incorporated, while 4,890 cases of PCOS and 20,405 controls in the reverse MR. Inverse-variance weighted method was employed in the primary MR analysis and multiple sensitivity analyses were implemented.ResultsGenetically determined PCOS was not causally associated with risk of periodontitis (odds ratio 0.97; 95% confidence interval 0.88–1.06; P = 0.50) per one-unit increase in the log-odds ratio of periodontitis. Similarly, no causal effect of periodontitis on PCOS was shown with the odds ratio for PCOS was 1.17 (95% confidence interval 0.91–1.49; P = 0.21) per one-unit increase in the log-odds ratio of periodontitis. Consistent results were yielded via additional MR methods. Sensitivity analyses demonstrated no presence of horizontal pleiotropy or heterogeneity.ConclusionThe bidirectional MR study couldn’t provide convincing evidence for the causal relationship between genetic liability to PCOS and periodontitis in the Europeans. Triangulating evidence across further observational and genetic-epidemiological studies is necessary.

scholarly journals Polycystic ovary syndrome susceptibility loci inform disease etiological heterogeneity

2021 ◽  
Author(s):  
Yanfei Zhang ◽  
Vani C. Movva ◽  
Marc S Williams ◽  
Ming Ta Michael Lee
Keyword(s):  
Polycystic Ovary Syndrome ◽  
Clustering Analysis ◽  
Mendelian Randomization ◽  
Polycystic Ovary ◽  
Causal Effect ◽  
Sex Hormone Binding Globulin ◽  
Model Assessment ◽  
Ovary Syndrome ◽  
Insulin Resistant ◽  
Disease Outcomes

Purpose Polycystic ovary syndrome (PCOS) is a complex disorder with heterogenous phenotypes and unclear etiology. A recent phenotypic clustering study identified metabolic and reproductive subtypes of PCOS. We attempted to deconstruct the PCOS heterogeneity from a genetic perspective. Methods We applied k-means clustering to categorize the genome-wide significant PCOS variants into clusters based on their associations with selected quantitative traits that likely reflect PCOS etiological pathways. We evaluated the association of each cluster with PCOS related traits and disease outcomes. We then applied Mendelian randomization to estimate the causal effect of the traits on PCOS and PCOS on disease outcomes. Results Clustering analysis suggested three categories of variants: adiposity, insulin resistant, and reproductive. Significant associations were observed for variants in the adiposity cluster with body mass index (BMI), waist circumference and breast cancer, and variants in insulin resistant cluster with fasting insulin and glucose values, and homeostatic model assessment of insulin resistance (HOMA-IR). Sex hormone binding globulin (SHBG) has strong association with all three clusters. Mendelian randomization supported the causal role of BMI and SHBG on PCOS. No causal associations were observed for PCOS on disease outcomes. Main Conclusions Our study provides genetic evidence for the heterogeneity in PCOS etiologies, corresponding to the reported phenotypic subtypes. Such studies will improve the current PCOS diagnosis criteria that do not distinguish the heterogeneity. Classification of women with PCOS to inform appropriate treatment will be more accurate in the future with improvements in clustering analysis for PCOS.

scholarly journals Investigating the causal relationship between physical activity and chronic back pain: a bidirectional two-sample Mendelian randomization study

2021 ◽  
Author(s):  
Shaowei Gao ◽  
Huaqiang Zhou ◽  
Siyu Luo ◽  
Xiaoying Cai ◽  
Fang Ye ◽  
...  
Keyword(s):  
Physical Activity ◽  
Back Pain ◽  
Causal Relationship ◽  
Mendelian Randomization ◽  
Chronic Back Pain ◽  
Vigorous Physical Activity ◽  
Sensitivity Analyses ◽  
European Ancestry ◽  
Genome Wide Association Studies ◽  
Genetic Instruments

Background Recent observational studies have reported a negative association between physical activity and chronic back pain (CBP), but the causality of the association remains unknown. We introduce bidirectional Mendelian randomization (MR) to assess potential causal inference between physical activity and CBP. Methods The two-sample MR was used with independent genetic variants associated with physical activity phenotypes and CBP as genetic instruments from large genome-wide association studies (GWASs) on individuals of European ancestry. The effects of both directions (physical activity to CBP and CBP to physical activity) were examined. Inverse variance-weighted meta-analysis and alternate methods (weighted median and MR-Egger) were used to combine the MR estimates of the genetic instruments. Multiple sensitivity analyses were conducted to examine the robustness of the results. Results For primary analysis, instrumental variables were extracted from 337,234 participants for physical activity (the same as the outcome cohort) and 158,025 participants (29,531 cases) for CBP, while the outcome cohort for CBP included 117,404 participants (80,588 cases). No evidence of a causal relationship was found in the direction of physical activity to CBP (odds ratio [OR], 0.98; 95% CI, 0.85-1.13; P = 0.81). In contrast, a negative causal relationship in the direction of CBP to physical activity was detected (β = -0.07; 95% CI, -0.12 to -0.01; P = 0.02), implying a reduction in moderate-vigorous physical activity (approximately 146 MET-minutes/week) for participants with CBP relative to controls. Conclusions The negative relationship between physical activity and CBP is probably derived from the reduced physical activity of patients experiencing CBP rather than the protective effect of physical activity on CBP.

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

2019 ◽  
Vol 48 (3) ◽  
pp. 822-830 ◽  
Author(s):  
Holly R Harris ◽  
Kara L Cushing-Haugen ◽  
Penelope M Webb ◽  
Christina M Nagle ◽  
Susan J Jordan ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cancer Risk ◽  
Polycystic Ovary Syndrome ◽  
Mendelian Randomization ◽  
Polycystic Ovary ◽  
European Ancestry ◽  
Ovarian Cancer Risk ◽  
Inverse Association ◽  
Ovary Syndrome ◽  
Study Results

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.

scholarly journals The Association Between Genetically Predicted Systemic Inflammatory Regulators and Polycystic Ovary Syndrome: A Mendelian Randomization Study

2021 ◽  
Vol 12 ◽  
Author(s):  
Hanxiao Chen ◽  
Yaoyao Zhang ◽  
Shangwei Li ◽  
Yuanzhi Tao ◽  
Rui Gao ◽  
...  
Keyword(s):  
Polycystic Ovary Syndrome ◽  
Genome Wide Association Study ◽  
Metabolic Diseases ◽  
Mendelian Randomization ◽  
Polycystic Ovary ◽  
Meta Analysis ◽  
Reproductive Age ◽  
European Ancestry ◽  
Ovary Syndrome ◽  
Increased Risk

Polycystic ovary syndrome (PCOS) is one of the most common endocrine and metabolic diseases among women of reproductive age. Inflammation may be involved in the pathogenesis of PCOS, but its exact relationship with PCOS remains unclear. Herein, we investigate the causal association between systemic inflammatory regulators and PCOS risk through a two-sample Mendelian randomization (MR) approach based on the latest and largest genome-wide association study (GWAS) of 41 systemic inflammatory regulators in 8293 Finnish participants and a GWAS meta-analysis consisting of 10,074 PCOS cases and 103,164 controls of European ancestry. Our results suggest that higher levels of IL-17 and SDF1a, as well as lower levels of SCGFb and IL-4, are associated with an increased risk of PCOS (OR = 1.794, 95% CI = 1.150 – 2.801, P = 0.010; OR = 1.563, 95% CI = 1.055 – 2.315, P = 0.026; OR = 0.838, 95% CI = 0.712 – 0.986, P = 0.034; and OR = 0.637, 95% CI = 0.413 – 0.983, P = 0.042, respectively). In addition, genetically predicted PCOS is related to increased levels of IL-2 and VEGF (OR = 1.257, 95% CI = 1.022 – 1.546, P = 0.030 and OR = 1.112, 95% CI = 1.006 – 1.229, P = 0.038, respectively). Our results indicate the essential role of cytokines in the pathogenesis of PCOS. Further studies are warranted to assess the possibility of these biomarkers as targets for PCOS prevention and treatment.

scholarly journals Phenotypic clustering reveals distinct subtypes of polycystic ovary syndrome with novel genetic associations

2019 ◽  
Author(s):  
Matthew Dapas ◽  
Frederick T. J. Lin ◽  
Girish N. Nadkarni ◽  
Ryan Sisk ◽  
Richard S. Legro ◽  
...  
Keyword(s):  
Polycystic Ovary Syndrome ◽  
Diagnostic Criteria ◽  
Polycystic Ovary ◽  
Reproductive Age ◽  
European Ancestry ◽  
Sequencing Analysis ◽  
Ovary Syndrome ◽  
Biologically Relevant ◽  
Insulin Levels ◽  
Family Based

AbstractBackgroundPolycystic ovary syndrome (PCOS) is a common, complex genetic disorder affecting up to 15% of reproductive age women worldwide, depending on the diagnostic criteria applied. These diagnostic criteria are based on expert opinion and have been the subject of considerable controversy. The phenotypic variation observed in PCOS is suggestive of an underlying genetic heterogeneity, but a recent meta-analysis of European ancestry PCOS cases found that the genetic architecture of PCOS defined by different diagnostic criteria was generally similar, suggesting that the criteria do not identify biologically distinct disease subtypes. We performed this study to test the hypothesis that there are biologically relevant subtypes of PCOS.Methods and FindingsUnsupervised hierarchical cluster analysis was performed on quantitative anthropometric, reproductive, and metabolic traits in a genotyped discovery cohort of 893 PCOS cases and an ungenotyped validation cohort of 263 PCOS cases. We identified two PCOS subtypes: a “reproductive” group (21-23%) characterized by higher luteinizing hormone (LH) and sex hormone binding globulin (SHBG) levels with relatively low body mass index (BMI) and insulin levels; and a “metabolic” group (37-39%), characterized by higher BMI, glucose, and insulin levels with lower SHBG and LH levels. We performed a GWAS on the genotyped cohort, limiting the cases to either the reproductive or metabolic subtypes. We identified alleles in four novel loci that were associated with the reproductive subtype at genome-wide significance (PRDM2/KAZN1, P=2.2×10-10; IQCA1, P=2.8×10-9; BMPR1B/UNC5C, P=9.7×10-9; CDH10, P=1.2×10-8) and one locus that was significantly associated with the metabolic subtype (KCNH7/FIGN, P=1.0×10-8). We have previously reported that rare variants in DENND1A, a gene regulating androgen biosynthesis, were associated with PCOS quantitative traits in a family-based whole genome sequencing analysis. We classified the reproductive and metabolic subtypes in this family-based PCOS cohort and found that the subtypes tended to cluster in families and that carriers of rare DENND1A variants were significantly more likely to have the reproductive subtype of PCOS. Limitations of our study were that only PCOS cases of European ancestry diagnosed by NIH criteria were included, the sample sizes for the subtype GWAS were small, and the GWAS findings were not replicated.ConclusionsIn conclusion, we have found stable reproductive and metabolic subtypes of PCOS. Further, these subtypes were associated with novel susceptibility loci. Our results suggest that these subtypes are biologically relevant since they have distinct genetic architectures. This study demonstrates how precise phenotypic delineation can be more powerful than increases in sample size for genetic association studies.

Obesity, hormonal and metabolic abnormalities in adolescent girls with polycystic ovary syndrome

2013 ◽  
Vol 154 (31) ◽  
pp. 1226-1234
Author(s):  
László Ságodi ◽  
Béla Lombay ◽  
Ildikó Vámosi ◽  
László Barkai
Keyword(s):  
Insulin Resistance ◽  
Metabolic Syndrome ◽  
Body Mass Index ◽  
Birth Weight ◽  
Low Birth Weight ◽  
Polycystic Ovary Syndrome ◽  
Adolescent Girls ◽  
Polycystic Ovary ◽  
Metabolic Abnormalities ◽  
Ovary Syndrome

Introduction: Polycystic ovary syndrome is associated with metabolic abnormalities, such as dyslipidemia, obesity, glucose intolerance, which are also components of the metabolic syndrome. Central obesity and insulin resistance appear to play an important role in the pathogenesis of polycystic ovary syndrome, perhaps via subsequent steroidogenic dysregulation. Aim: The aim of the authors was to assess metabolic and hormonal abnormalities in adolescent girls with polycystic ovary syndrome. Method: The study included 52 adolescents diagnosed with polycystic ovary syndrome based on the Rotterdam criteria. Anthropometric, hormonal and metabolic parameters were evaluated among all subjects. 20 healthy, age-matched, non-obese, regularly menstruating girls were used as controls. Of the 52 patients, 15 patients were born with low-birth-weight and 37 patients were born with normal birth weight. Oral glucose tolerance test was performed in all patients and controls. The age of patients was 16.8±3.1 years, and the age of controls was 16.95±2.1 years. Results: Among patients with polycystic ovary syndrome the prevalence of overweight and obesity was 35% (n = 18), while impaired fasting glucose occurred in one patient, impaired glucose tolerance in 8 patients, insulin resistance in 25 patients and metabolic syndrome in 12 patients. Serum triglyceride levels in patients and controls were 1.4±0.8 and 0.9±0.3 mmol/l, respectively (p<0.05), while fasting blood glucose, total cholesterol, HDL and LDL cholesterol were not different in the two groups. Metabolic abnormalities and obesity were more severe and more frequent in patients with low-birth-weight compared to those born with normal weight. There was a negative correlation between birth weight and body mass index SDS values and a positive correlation between fasting insulin levels and body mass index SDS (r = 0.37) in patients born with low-birth-weight. Conclusions: Abnormal glucose metabolism is frequently present in adolescents with polycystic ovary syndrome. It is possible that early diagnosis of polycystic ovary syndrome in adolescences may prevent some of the long-term complications associated with this syndrome. Orv. Hetil., 2013, 154, 1226–1234.

Fertility and Pregnancy Outcomes in Women with Polycystic Ovary Syndrome Following Bariatric Surgery

2020 ◽  
Vol 105 (9) ◽  
pp. e3384-e3391
Author(s):  
Estela Benito ◽  
Jesús M Gómez-Martin ◽  
Belén Vega-Piñero ◽  
Pablo Priego ◽  
Julio Galindo ◽  
...  
Keyword(s):  
Bariatric Surgery ◽  
Birth Weight ◽  
Polycystic Ovary Syndrome ◽  
Live Birth ◽  
Polycystic Ovary ◽  
Premenopausal Women ◽  
Obese Women ◽  
Ovary Syndrome ◽  
Birth Rates ◽  
Live Birth Rates

Abstract Context Restoration of ovulation is quite common in women with polycystic ovary syndrome (PCOS) after surgically induced weight loss. Whether or not this results in an improvement of PCOS-associated infertility is uncertain. Objective To study fertility and gestational outcomes in women with PCOS after bariatric surgery. Design Unicenter cohort study. Setting Academic hospital. Patients Two hundred and sixteen premenopausal women were screened for PCOS before bariatric surgery. Women were followed-up after the intervention until mid-2019 regardless of having or not PCOS. Interventions All participants underwent bariatric surgery from 2005 to 2015. Main outcome measures Pregnancy and live birth rates in the PCOS and control groups. Results In women seeking fertility, pregnancy rates were 95.2% in PCOS and 76.9% in controls (P = 0.096) and live birth rates were 81.0% and 69.2%, respectively (P = 0.403). The time to achieve the first pregnancy after surgery was 34 ± 28 months in women with PCOS and 32 ± 25 months in controls. Albeit the mean birth weight was lower (P = 0.040) in newborns from women with PCOS (2763 ± 618 g) compared with those from controls (3155 ± 586 g), the number of newborns with low birth weight was similar in both groups (3 in the PCOS group and 1 in the controls, P = 0.137). Maternal (17.6% in PCOS and 22.2% in controls, P = 0.843) and neonatal (23.5% in PCOS and 14.8% in controls, P = 0.466) complications were rare, showing no differences between groups. Conclusions Pregnancy and fertility rates in very obese women with PCOS after bariatric surgery were high, with few maternal and neonatal complications.

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