Pathogenic Anti-Müllerian Hormone Variants in Polycystic Ovary Syndrome

Gorsic, Lidija K.; Kosova, Gülüm; Werstein, Brian; Sisk, Ryan; Legro, Richard S.; Hayes, M. Geoffrey; Teixeira, Jose; Dunaif, Andrea; Urbanek, Margrit

doi:10.1210/jc.2017-00612

Cited by 94 publications

(61 citation statements)

References 46 publications

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“…Collectively, these results make BMPR1B a 477 compelling candidate gene in PCOS pathogenesis. These findings also support our 478 sequencing studies that have implicated pathogenic variants in the AMH signaling pathway 479 in PCOS (61,62). 480…”

Section: Subtypes In Pcos Families 398supporting

confidence: 67%

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

Dapas¹,

Lin²,

Nadkarni

et al. 2019

Preprint

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AD) 20 ghayes@northwestern.edu (MGH) 21 22 DISCLOSURE STATEMENT: The authors have nothing to disclose. 23 metabolic subtype (KCNH7/FIGN, P=1.0×10 -8 ). We have previously reported that rare 47 variants in DENND1A, a gene regulating androgen biosynthesis, were associated with PCOS 48 quantitative traits in a family-based whole genome sequencing analysis. We classified the 49 reproductive and metabolic subtypes in this family-based PCOS cohort and found that the 50 subtypes tended to cluster in families and that carriers of rare DENND1A variants were 51 significantly more likely to have the reproductive subtype of PCOS. Limitations of our study 52 were that only PCOS cases of European ancestry diagnosed by NIH criteria were included, 53 the sample sizes for the subtype GWAS were small, and the GWAS findings were not 54 replicated. 55 56 Conclusions 57In conclusion, we have found stable reproductive and metabolic subtypes of PCOS. Further, 58 these subtypes were associated with novel susceptibility loci. Our results suggest that these 59 subtypes are biologically relevant since they have distinct genetic architectures. This study 60 demonstrates how precise phenotypic delineation can be more powerful than increases in 61 sample size for genetic association studies. 62 63Understanding the genetic architecture of complex diseases is a central challenge in 64 human genetics (1-3). Often defined according to arbitrary diagnostic criteria, complex 65 diseases can represent the phenotypic convergence of numerous genetic etiologies (4)(5)(6)(7)(8). 66Recent studies in type 2 diabetes support the concept that there are disease subtypes with 67 distinct genetic architecture (7,8). Identifying and addressing genetic heterogeneity in 68 complex diseases could increase power to detect causal variants and improve treatment 69 efficacy (9). 70Polycystic ovary syndrome (PCOS) is a highly heritable, complex genetic disorder 71 affecting up to 15% of reproductive-age women worldwide, depending on the diagnostic 72 criteria applied (10). It is characterized by a variable constellation of reproductive and 73 metabolic abnormalities (Fig 1). It is the leading cause of anovulatory infertility and a major 74 risk factor for type 2 diabetes (T2D) in women (11). Despite these substantial morbidities, 75 the etiology(ies) of PCOS remains unknown (12). Accordingly, the commonly-used 76 diagnostic criteria for PCOS, the National Institutes of Health (NIH) criteria (13) and the 77 Rotterdam criteria (14,15), are based on expert opinion, rather than mechanistic insights, and 78 are designed to account for the diverse phenotypic presentations of PCOS. The NIH criteria 79 require the presence of hyperandrogenism (HA) and chronic oligo/anovulation or ovarian 80 dysfunction (OD) (13). The Rotterdam criteria include polycystic ovarian morphology 81 (PCOM) and require the presence of at least two of these three key reproductive traits, 82 resulting in three different affected phenotypes: HA and OD with or without PCOM, also 83 known as NIH PCOS, as w...

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Section: Subtypes In Pcos Families 398supporting

confidence: 67%

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

Dapas¹,

Lin²,

Nadkarni

et al. 2019

Preprint

Self Cite

View full text Add to dashboard Cite

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“…PCOS is strongly familial [14][15][16] and highly heritable [17], with~60% of daughters born to women with PCOS manifesting their own PCOS phenotype during adolescence and young adulthood [18]. Mounting evidence suggests, however, that heritable defects leading to ovarian hyperandrogenism contribute to the manifestation of PCOS [19].…”

Section: Pcos and Its Potential Originsmentioning

confidence: 99%

Naturally Occurring and Experimentally Induced Rhesus Macaque Models for Polycystic Ovary Syndrome: Translational Gateways to Clinical Application

et al. 2019

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Indian rhesus macaque nonhuman primate models for polycystic ovary syndrome (PCOS) implicate both female hyperandrogenism and developmental molecular origins as core components of PCOS etiopathogenesis. Establishing and exploiting macaque models for translational impact into the clinic, however, has required multi-year, integrated basic-clinical science collaborations. Paradigm shifting insight has accrued from such concerted investment, leading to novel mechanistic understanding of PCOS, including hyperandrogenic fetal and peripubertal origins, epigenetic programming, altered neural function, defective oocytes and embryos, adipogenic constraint enhancing progression to insulin resistance, pancreatic decompensation and type 2 diabetes, together with placental compromise, all contributing to transgenerational transmission of traits likely to manifest in adult PCOS phenotypes. Our recent demonstration of PCOS-related traits in naturally hyperandrogenic (High T) female macaques additionally creates opportunities to employ whole genome sequencing to enable exploration of gene variants within human PCOS candidate genes contributing to PCOS-related traits in macaque models. This review will therefore consider Indian macaque model contributions to various aspects of PCOS-related pathophysiology, as well as the benefits of using macaque models with compellingly close homologies to the human genome, phenotype, development and aging.

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“…Gorsic et al . found that 18 rare AMH variants are specific to women with PCOS and that 17 of them significantly reduce AMH signaling . On the other hand, Wang et al .…”

Section: Polycystic Ovarian Syndromementioning

confidence: 99%

Clinical application of serum anti‐Müllerian hormone as an ovarian reserve marker: A review of recent studies

Iwase

Osuka

Goto

et al. 2018

J of Obstet and Gynaecol

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It has been more than 15 years since the measurement of serum anti-Müllerian hormone (AMH) first allowed the quantitative assessment of ovarian reserve. Meanwhile, the clinical implication of serum AMH has been expanding. The measurement of serum AMH has been applied in various clinical fields, including assisted reproduction, menopause, reproductive disorders and assessment of ovarian damage/toxicity. Well-known findings about the usefulness of serum AMH revealed by numerous studies executed in the early era include decline with aging, a good correlation with oocyte yield in assisted reproduction, upregulation in polycystic ovarian syndrome and a decrease on ovarian surgery and toxic treatment. More intensive research, including a meta-analysis, cutting-edge clinical trial and advances in AMH assays, has yielded newer findings and firmer clinical interpretations in serum AMH in the past few years. Variations in the AMH decline trajectory in the general population do not support the accurate prediction of menopause. The ability to predict pregnancy in infertility treatment and natural conception is poor, while a nomogram integrating serum AMH as a stimulation protocol is useful for avoiding poor and/or hyper-responses. On the other hand, improvements in measuring very low concentrations of serum AMH may be capable of distinguishing women with poor ovarian function. Age-independent standardization of AMH values may be helpful for comparing ovarian reserves among women at different ages.

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Pathogenic Anti-Müllerian Hormone Variants in Polycystic Ovary Syndrome

Cited by 94 publications

References 46 publications

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

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

Naturally Occurring and Experimentally Induced Rhesus Macaque Models for Polycystic Ovary Syndrome: Translational Gateways to Clinical Application

Clinical application of serum anti‐Müllerian hormone as an ovarian reserve marker: A review of recent studies

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