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

Dapas, Matthew; Sisk, Ryan; Legro, Richard S.; Urbanek, Margrit; Dunaif, Andrea; Hayes, M. Geoffrey

doi:10.1210/jc.2018-02496

Cited by 57 publications

(49 citation statements)

References 105 publications

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“…BMPR1B 472 has been found to mediate the AMH response in ovine granulosa cells (58), and BMPR1B-473 deficient mice are infertile and suffer from a variety of functional defects in the 474 ovary (59,60). One of the BMPR1B ligand genes, BMP6, had the 3 rd strongest gene-level 475 association with altered hormonal levels (P=4.00×10 -3 ) out of 339 genes tested in our rare 476 variant association study in PCOS families (29). Collectively, these results make BMPR1B a 477 compelling candidate gene in PCOS pathogenesis.…”

Section: Subtypes In Pcos Families 398mentioning

confidence: 77%

“…However, the aforementioned functional evidence for several of the loci-particularly for 507 PRDM2 and BMPR1B-support the validity of their associations. Also, the fact that one of 508 the genes associated with the reproductive subtype, PRDM2, was associated with PCOS 509 quantitative traits in our family-based analysis (29) does represent a replication of this signal 510 by an independent analytical approach. Nevertheless, our genetic association results should 511 be considered preliminary.…”

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confidence: 82%

Section: Subjects 136mentioning

confidence: 99%

“…The association signal on chr1 appeared downstream of and 458 within the same TAD as the PRDM2 gene (Figs 8a, 9), which is an estrogen receptor co-459 activator (49) that is highly expressed in the ovary (50) and pituitary gland (51). In an 460 independent rare variant association study in PCOS families, PRDM2 demonstrated the 5 th 461 strongest gene-level association with altered hormonal levels in PCOS families (P=6.92×10 -3 ) 462 out of 339 genes tested (29). PRDM2 binds with ligand bound estrogen receptor alpha (ERα) 463 to open chromatin at ERα target genes (49,52).…”

Section: Subtypes In Pcos Families 398mentioning

confidence: 99%

“…An independent, 147 ungenotyped cohort of 263 women with PCOS was used for clustering replication. A family-148 based whole-genome sequencing cohort of 73 women with PCOS was used for investigating 149 subtype clustering in families and for rare variant analysis (29). 150Population-based control DNA samples for the GWAS Stage 1 cohort were obtained 151 from the NUgene biobank (31) from women of European ancestry, ages 18-97 years.…”

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confidence: 99%

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

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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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