scholarly journals Family-Based Quantitative Trait Meta-Analysis Implicates Rare Noncoding Variants in DENND1A in Polycystic Ovary Syndrome

2019 ◽  
Vol 104 (9) ◽  
pp. 3835-3850 ◽  
Author(s):  
Matthew Dapas ◽  
Ryan Sisk ◽  
Richard S Legro ◽  
Margrit Urbanek ◽  
Andrea Dunaif ◽  
...  
Keyword(s):  
Polycystic Ovary Syndrome ◽  
Quantitative Trait ◽  
Rare Variants ◽  
Polycystic Ovary ◽  
Association Studies ◽  
Meta Analysis ◽  
Premenopausal Women ◽  
Endocrine Disorders ◽  
Genome Wide Association Studies ◽  
Ovary Syndrome

AbstractContextPolycystic ovary syndrome (PCOS) is among the most common endocrine disorders of premenopausal women, affecting 5% to15% of this population depending on the diagnostic criteria applied. It is characterized by hyperandrogenism, ovulatory dysfunction, and polycystic ovarian morphology. PCOS is highly heritable, but only a small proportion of this heritability can be accounted for by the common genetic susceptibility variants identified to date.ObjectiveThe objective of this study was to test whether rare genetic variants contribute to PCOS pathogenesis.Design, Patients, and MethodsWe performed whole-genome sequencing on DNA from 261 individuals from 62 families with one or more daughters with PCOS. We tested for associations of rare variants with PCOS and its concomitant hormonal traits using a quantitative trait meta-analysis.ResultsWe found rare variants in DENND1A (P = 5.31 × 10−5, adjusted P = 0.039) that were significantly associated with reproductive and metabolic traits in PCOS families.ConclusionsCommon variants in DENND1A have previously been associated with PCOS diagnosis in genome-wide association studies. Subsequent studies indicated that DENND1A is an important regulator of human ovarian androgen biosynthesis. Our findings provide additional evidence that DENND1A plays a central role in PCOS and suggest that rare noncoding variants contribute to disease pathogenesis.

scholarly journals Family-based quantitative trait meta-analysis implicates rare noncoding variants in DENND1A in pathogenesis of polycystic ovary syndrome

2018 ◽  
Author(s):  
Matthew Dapas ◽  
Ryan Sisk ◽  
Richard S. Legro ◽  
Margrit Urbanek ◽  
Andrea Dunaif ◽  
...  
Keyword(s):  
Polycystic Ovary Syndrome ◽  
Quantitative Trait ◽  
Rare Variants ◽  
Polycystic Ovary ◽  
Association Studies ◽  
Meta Analysis ◽  
Premenopausal Women ◽  
Endocrine Disorders ◽  
Genome Wide Association Studies ◽  
Ovary Syndrome

ABSTRACTPolycystic ovary syndrome (PCOS) is among the most common endocrine disorders of premenopausal women, affecting 5-15% of this population depending on the diagnostic criteria applied. It is characterized by hyperandrogenism, ovulatory dysfunction and polycystic ovarian morphology. PCOS is a leading risk factor for type 2 diabetes in young women. PCOS is highly heritable, but only a small proportion of this heritability can be accounted for by the common genetic susceptibility variants identified to date. To test the hypothesis that rare genetic variants contribute to PCOS pathogenesis, we performed whole-genome sequencing on DNA from 62 families with one or more daughters with PCOS. We tested for associations of rare variants with PCOS and its concomitant hormonal traits using a quantitative trait meta-analysis. We found rare variants in DENND1A (P=5.31×10−5, Padj=0.019) that were significantly associated with reproductive and metabolic traits in PCOS families. Common variants in DENND1A have previously been associated with PCOS diagnosis in genome-wide association studies. Subsequent studies indicated that DENND1A is an important regulator of human ovarian androgen biosynthesis. Our findings provide additional evidence that DENND1A plays a central role in PCOS and suggest that rare noncoding variants contribute to disease pathogenesis.

scholarly journals Non‐alcoholic fatty liver disease in premenopausal women with polycystic ovary syndrome: A systematic review and meta‐analysis

JGH Open ◽  
2021 ◽  
Vol 5 (4) ◽  
pp. 434-445
Author(s):  
Mohamed Shengir ◽  
Tianyan Chen ◽  
Elena Guadagno ◽  
Agnihotram V Ramanakumar ◽  
Peter Ghali ◽  
...  
Keyword(s):  
Systematic Review ◽  
Liver Disease ◽  
Polycystic Ovary Syndrome ◽  
Fatty Liver Disease ◽  
Polycystic Ovary ◽  
Meta Analysis ◽  
Premenopausal Women ◽  
Ovary Syndrome ◽  
Alcoholic Fatty Liver ◽  
Alcoholic Fatty Liver Disease

scholarly journals Understanding Polycystic Ovary Syndrome: A Multifactorial Endocrine Disorder

2021 ◽  
Author(s):  
Surankita Sukul ◽  
Pushkal Sinduvadi Ramesh ◽  
Narahari Agasti
Keyword(s):  
Polycystic Ovary Syndrome ◽  
Genetic Markers ◽  
Polycystic Ovary ◽  
Association Studies ◽  
Reproductive Age ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Ovary Syndrome ◽  
Endocrine Disorder ◽  
Genome Wide

Polycystic Ovary Syndrome (PCOS) is a common endocrine disorder affecting a significant population of women of reproductive age group worldwide. Due to the complex pathophysiology and overlapping symptoms, this disorder is often difficult to diagnose. Genome-wide association studies have identified several new risk loci and candidate genes for PCOS. However, currently, there are no standard genetic markers for PCOS susceptibility testing owing to the inconsistent findings. Despite the advent of the genomic era, the challenge to identify and pinpoint the heritable genetic basis of PCOS still exists. This mini-review explores the basic definition and phenotypes of PCOS, the different criteria for the diagnosis, the incidence, gestational complications associated with it, the basis of genetic heritability, and the influence of various gene polymorphisms. Also, this review briefly summarises the reports of genome-wide association studies conducted to identify candidate genetic markers to aid in understanding the complex pathophysiology of PCOS.

scholarly journals Pathogenesis of polycystic ovary syndrome: multifactorial assessment from the foetal stage to menopause

Reproduction ◽  
2015 ◽  
Vol 150 (1) ◽  
pp. R11-R24 ◽  
Author(s):  
Anderson Sanches de Melo ◽  
Sabrine Vilan Dias ◽  
Ricardo de Carvalho Cavalli ◽  
Viviane Cunha Cardoso ◽  
Heloisa Bettiol ◽  
...  
Keyword(s):  
Environmental Factors ◽  
Polycystic Ovary Syndrome ◽  
Structural Changes ◽  
Polycystic Ovary ◽  
Association Studies ◽  
Visceral Obesity ◽  
Developmental Programming ◽  
Postnatal Life ◽  
Genome Wide Association Studies ◽  
Ovary Syndrome

Polycystic ovary syndrome (PCOS) is a multifactorial disorder that arises from interactions between genetic, environmental and intra-uterine factors. Small-for-gestational-age (SGA) babies and the daughters of mothers with PCOS represent possible postnatal clinical targets for developmental programming by steroid excess. The presence of excess glucocorticoids and/or androgens during foetal organogenesis and growth might promote changes in gene expression, and these changes might be related to an increase in the risk of PCOS-like reproductive and metabolic disorders in postnatal life, such as rapid growth and weight gain during the first 2 years of life (only in SGA babies), hyperinsulinaemia, adipocyte dysfunction and childhood visceral obesity, premature pubarche and adrenarche (only in SGA babies) and PCOS. In the fourth decade of life, women who have PCOS may be at higher risk for type 2 diabetes mellitus, dyslipidaemia and systemic arterial hypertension, which suggests that these women are also at higher risk for cardiovascular disease during menopause. However, PCOS can also occur in women who were born at appropriate weight for GA or in newborns of women without PCOS, which suggests that genetic variation and environmental factors play important roles in the development and maintenance of PCOS in a population. Genome-wide association studies based on adequate population samples have shown a higher frequency of genetic polymorphisms of the LHCGR, THADA and DENND1A genes in women with PCOS. Genetic studies of PCOS have also included analyses of structural changes in the chromosome based on an assessment of telomere length in single, cross-sectional evaluations, and these studies have produced controversial results. The present narrative review assesses the multifactorial origins of PCOS (including environmental, genetic and intra-uterine factors) and the development of conditions associated with this disorder. It is concluded that although PCOS might originate in the intra-uterine environment through developmental programming by steroid excess, the interaction between genetic and environmental factors is crucial for its appearance. Follow-up studies should be conducted to assess the same populations over their entire lifespans while taking into account different aspects of the pathogenesis of PCOS.

scholarly journals Scientific Statement on the Diagnostic Criteria, Epidemiology, Pathophysiology, and Molecular Genetics of Polycystic Ovary Syndrome

2015 ◽  
Vol 36 (5) ◽  
pp. 487-525 ◽  
Author(s):  
Daniel A. Dumesic ◽  
Sharon E. Oberfield ◽  
Elisabet Stener-Victorin ◽  
John C. Marshall ◽  
Joop S. Laven ◽  
...  
Keyword(s):  
Polycystic Ovary Syndrome ◽  
Diagnostic Criteria ◽  
Polycystic Ovary ◽  
Association Studies ◽  
Metabolic Phenotype ◽  
Genome Wide Association Studies ◽  
Polycystic Ovaries ◽  
Ovary Syndrome ◽  
Gonadotropin Secretion ◽  
Functional Changes

Polycystic ovary syndrome (PCOS) is a heterogeneous and complex disorder that has both adverse reproductive and metabolic implications for affected women. However, there is generally poor understanding of its etiology. Varying expert-based diagnostic criteria utilize some combination of oligo-ovulation, hyperandrogenism, and the presence of polycystic ovaries. Criteria that require hyperandrogenism tend to identify a more severe reproductive and metabolic phenotype. The phenotype can vary by race and ethnicity, is difficult to define in the perimenarchal and perimenopausal period, and is exacerbated by obesity. The pathophysiology involves abnormal gonadotropin secretion from a reduced hypothalamic feedback response to circulating sex steroids, altered ovarian morphology and functional changes, and disordered insulin action in a variety of target tissues. PCOS clusters in families and both female and male relatives can show stigmata of the syndrome, including metabolic abnormalities. Genome-wide association studies have identified a number of candidate regions, although their role in contributing to PCOS is still largely unknown.

scholarly journals Cross-Ethnic Meta-Analysis of Genetic Variants for Polycystic Ovary Syndrome

2013 ◽  
Vol 98 (12) ◽  
pp. E2006-E2012 ◽  
Author(s):  
Yvonne V. Louwers ◽  
Lisette Stolk ◽  
André G. Uitterlinden ◽  
Joop S. E. Laven
Keyword(s):  
Polycystic Ovary Syndrome ◽  
Genetic Variants ◽  
Polycystic Ovary ◽  
Meta Analysis ◽  
The United States ◽  
European Ancestry ◽  
P Value ◽  
Genome Wide Association Studies ◽  
Ovary Syndrome ◽  
Northern European

Context: Genome-wide association studies (GWAS) have revealed new susceptibility loci for Chinese patients with polycystic ovary syndrome (PCOS). Because ethnic background adds to phenotypic diversities in PCOS, it seems plausible that genetic variants associated with PCOS act differently in various ethnic populations. Objective: We studied cross-ethnic effects of Chinese PCOS loci (ie, LHCGR, THADA, DENND1A, FSHR, c9orf3, YAP1, RAB5B/SUOX, HMGA2, TOX3, INSR, SUMO1P1) in patients of Northern European descent. Design: This study was a genetic association study conducted at an University Medical Center. Patients: Association was studied in 703 Dutch PCOS patients and 2164 Dutch controls. To assess the cross-ethnic effect, we performed a meta-analysis of the Dutch data combined with results of previously published studies in PCOS patients from China (n = 2254) and the United States (n = 2618). Adjusted for multiple testing, a P value <3.1 × 10−3 was considered statistically significant. Results: Meta-analysis of the Chinese, US, and Dutch data resulted in 12 significant variants mapping to the YAP1 (P value = 1.0× 10−9), RAB5B/SUOX (P value = 3.8 × 10−11), LHCGR (P value = 4.1 × 10−4), THADA (P value = 2.2 × 10−4 and P value = 1.3 × 10−3), DENND1A (P value = 2.3 × 10−3 and P value = 2.5 × 10−3), FSHR (P value = 3.8 × 10−5 and P value = 3.6 × 10−4), c9orf3 (P value = 2.0 × 10−6 and P value = 9.2 × 10−6), SUMO1P1 (P value = 2.3 × 10−3) loci with odds ratios ranging from 1.19 to 1.45 and 0.79 to 0.87. Conclusions: Overall, we observed for 12 of 17 genetic variants mapping to the Chinese PCOS loci similar effect size and identical direction in PCOS patients from Northern European ancestry, indicating a common genetic risk profile for PCOS across populations. Therefore, it is expected that large GWAS in PCOS patients from Northern European ancestry will partly identify similar loci as the GWAS in Chinese PCOS patients.

Sign in / Sign up

Export Citation Format

Share Document