Functional Genetic Variation in the Anti-Müllerian Hormone Pathway in Women With Polycystic Ovary Syndrome

Gorsic, Lidija K.; Dapas, Matthew; Legro, Richard S.; Hayes, M. Geoffrey; Urbanek, Margrit

doi:10.1210/jc.2018-02178

Cited by 70 publications

(37 citation statements)

References 67 publications

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“…Collectively, these results make BMPR1B a compelling candidate gene in PCOS pathogenesis. These findings also support our sequencing studies that have implicated pathogenic variants in the AMH signaling pathway in PCOS [63,64].…”

Section: Plos Medicinesupporting

confidence: 90%

Distinct subtypes of polycystic ovary syndrome with novel genetic associations: An unsupervised, phenotypic clustering analysis

et al. 2020

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Background Polycystic 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 findings Using biochemical and genotype data from a previously published PCOS genome-wide association study (GWAS), we investigated whether there were reproducible phenotypic subtypes of PCOS with subtype-specific genetic associations. Unsupervised hierarchical cluster analysis was performed on quantitative anthropometric, reproductive, and metabolic traits in a genotyped cohort of 893 PCOS cases (median and interquartile range [IQR]: age = 28 [25-32], body mass index [BMI] = 35.4 [28.2-41.5]). The clusters were replicated in an independent, ungenotyped cohort of 263 PCOS cases (median and IQR: age = 28 [24-33], BMI = 35.7 [28.4-42.3]). The clustering revealed 2 distinct PCOS subtypes: a "reproductive" group (21%-23%), characterized by higher luteinizing hormone (LH) and sex hormone binding globulin (SHBG) levels with relatively low BMI and insulin levels, and a "metabolic" group

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Section: Plos Medicinesupporting

confidence: 90%

Distinct subtypes of polycystic ovary syndrome with novel genetic associations: An unsupervised, phenotypic clustering analysis

et al. 2020

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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

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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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“…Familial clustering and twin studies have shown that PCOS has a strong heritable component [117]. Polymorphisms in both AMH and AMHR2 have been identified in women with PCOS [118–120]. However, the polymorphisms identified in the AMH signaling pathway and in other genes do not explain the frequency of the disease [121], suggesting that environmental and epigenetic mechanisms may play far greater roles in the onset of PCOS.…”

Section: Amh Relevance To Polycystic Ovary Syndrome (Pcos)mentioning

confidence: 99%

Emerging Roles of Anti-Müllerian Hormone in Hypothalamic-Pituitary Function

et al. 2019

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Since its initial discovery in the 1940s, research into the physiological actions of anti-Müllerian hormone (AMH), from its eponymous role in male developmental biology to its routine clinical use in female reproductive health, has undergone a paradigm shifting change. With several exciting studies recently reporting hitherto unforeseen AMH actions at all levels in the hypogonadal-pituitary-gonadal axis, the importance of this hormone for both hypothalamic and pituitary reproductive control is finding increasing support and significance. In this review, we will briefly summarize what is known about the traditional roles and biology of AMH and how this could be integrated with new findings of AMH actions at the level of the hypothalamic-pituitary axis. We also synthesize the important findings from these new studies and discuss their potential impact and significance to our understanding of one of the most common reproductive disorders currently affecting women, polycystic ovary syndrome.

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Functional Genetic Variation in the Anti-Müllerian Hormone Pathway in Women With Polycystic Ovary Syndrome

Cited by 70 publications

References 67 publications

Distinct subtypes of polycystic ovary syndrome with novel genetic associations: An unsupervised, phenotypic clustering analysis

Distinct subtypes of polycystic ovary syndrome with novel genetic associations: An unsupervised, phenotypic clustering analysis

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

Emerging Roles of Anti-Müllerian Hormone in Hypothalamic-Pituitary Function

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