Genome-wide association study identifies susceptibility loci for polycystic ovary syndrome on chromosome 2p16.3, 2p21 and 9q33.3

Chen, Zi‐Jiang; Zhao, Han; He, Lin; Shi, Yuhua; Qin, Yingying; Shi, Yongyong; Li, Zhiqiang; You, Li; Zhao, Junli; Liu, Jiayin; Liang, Xiaoyan; Zhao, Xiaoming; Zhao, Junzhao; Sun, Yingpu; Zhang, Bo; Jiang, Hong; Dong, Zhao; Bian, Yuehong; Gao, Xuan; Geng, Ling; Li, Yiran; Zhu, Dan; Sun, Xiaobo; Xu, Jing; Hao, Cuifang; Ren, Chune; Zhang, Yajie; Chen, Shiling; Zhang, Wei; Yang, Aijun; Yan, Junhao; Li, Yuan; Ma, Jinlong; Zhao, Yong

doi:10.1038/ng.732

Cited by 641 publications

(503 citation statements)

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“…The fact that most differentially expressed lncRNAs (n=74) were transcribed from chromosome 2 is remarkable. Notably, a recent genome-wide association study (GWAS) identified three of 11 susceptibility loci for PCOS on chromosome 2, including the 2p16.3 (rs13405728), 2p21 (rs13429458), and FSHR genes [1,43]. Our data and previously published studies suggest that the genes located on chromosome 2 play important roles in the development and progression of PCOS.…”

Section: Discussionsupporting

confidence: 66%

Aberrant expression of long noncoding RNAs in cumulus cells isolated from PCOS patients

Huang

Hao

Bao

et al. 2015

J Assist Reprod Genet

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Purpose To describe the long noncoding RNA (lncRNA) profiles in cumulus cells isolated from polycystic ovary syndrome (PCOS) patients by employing a microarray and in-depth bioinformatics analysis. This information will help us understand the occurrence and development of PCOS. Methods In this study, we used a microarray to describe lncRNA profiles in cumulus cells isolated from ten patients (five PCOS and five normal women). Several differentially expressed lncRNAs were chosen to validate the microarray results by quantitative RT-PCR (qRT-PCR). Then, the differentially expressed lncRNAs were classified into three subgroups (HOX loci lncRNA, enhancer-like lncRNA, and lincRNA) to deduce their potential features. Furthermore, a lncRNA/mRNA co-expression network was constructed by using the Cytoscape software (V2.8.3, http://www.cytoscape.org/). Results We observed that 623 lncRNAs and 260 messenger RNAs (mRNAs) were significantly up-or down-regulated (≥2-fold change), and these differences could be used to discriminate cumulus cells of PCOS from those of normal pat i e n t s . F i v e d i f f e r e n t i a l l y e x p r e s s e d l n c R N A s (XLOC_011402, ENST00000454271, ENST00000433673, ENST00000450294, and ENST00000432431) were selected to validate the microarray results using quantitative RT-PCR (qRT-PCR). The qRT-PCR results were consistent with the microarray data. Further analysis indicated that many differentially expressed lncRNAs were transcribed from chromosome 2 and may act as enhancers to regulate their neighboring protein-coding genes. Forty-three lncRNAs and 29 mRNAs were used to construct the coding-non-coding gene coexpression network. Most pairs positively correlated, and one mRNA correlated with one or more lncRNAs. Conclusions Our study is the first to determine genome-wide lncRNA expression patterns in cumulus cells isolated from PCOS patients by microarray. The results show that clusters of lncRNAs were aberrantly expressed in cumulus cells of PCOS patients compared with those of normal women, which revealed that lncRNAs differentially expressed in PCOS and normal women may contribute to the occurrence of PCOS and affect oocyte development.

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Section: Discussionsupporting

confidence: 66%

Aberrant expression of long noncoding RNAs in cumulus cells isolated from PCOS patients

Huang

Hao

Bao

et al. 2015

J Assist Reprod Genet

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“…Despite the semblance to an autosomal dominant inheritance, an oligogenic/polygenic model most likely contributes to the underlying pathophysiology (23,24). Incomplete penetrance, epigenetic modification, and environmental contributions have hindered attempts to clarify the underlying model of inheritance.…”

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confidence: 99%

“…The first genome-wide association studies (GWAS) and subsequent follow up performed on Han Chinese populations identified the following PCOS candidate loci: DENND1A, insulin receptor (INSR), YAP1, C9orf3, RAB5B, HMGA2, TOX3, SUMO1P1/ZNF217, THADA, follicle stimulating hormone receptor (FSHR), luteinizing hormone/choriogonadotropin receptor (LHCGR) (23,24). The identification of the DENND1A locus at 9q22.32 has been replicated in both Asian and European populations (26)(27)(28)(29), hence DENND1A has gained recognition as a strong PCOS susceptibility gene (30).…”

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confidence: 99%

Overexpression of a DENND1A isoform produces a polycystic ovary syndrome theca phenotype

McAllister

Modi

Miller³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

192

157

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Polycystic ovary syndrome (PCOS), characterized by increased ovarian androgen biosynthesis, anovulation, and infertility, affects 5-7% of reproductive-age women. Genome-wide association studies identified PCOS candidate loci that were replicated in subsequent reports, including DENND1A, which encodes a protein associated with clathrin-coated pits where cell-surface receptors reside. However, these studies provided no information about functional roles for DENND1A in the pathogenesis of PCOS. DENND1A protein was located in the cytoplasm as well as nuclei of theca cells, suggesting a possible role in gene regulation. DENND1A immunostaining was more intense in the theca of PCOS ovaries. Using theca cells isolated and propagated from normal cycling and PCOS women, we found that DENND1A variant 2 (DENND1A.V2) protein and mRNA levels are increased in PCOS theca cells. Exosomal DENND1A.V2 RNA was significantly elevated in urine from PCOS women compared with normal cycling women. Forced overexpression of DENND1A.V2 in normal theca cells resulted in a PCOS phenotype of augmented CYP17A1 and CYP11A1 gene transcription, mRNA abundance, and androgen biosynthesis. Knock-down of DENND1A.V2 in PCOS theca cells reduced androgen biosynthesis and CYP17A1 and CYP11A1 gene transcription. An IgG specific to DENND1A.V2 also reduced androgen biosynthesis and CYP17 and CYP11A1 mRNA when added to the medium of cultured PCOS theca cells. We conclude that the PCOS candidate gene, DENND1A, plays a key role in the hyperandrogenemia associated with PCOS. These observations have both diagnostic and therapeutic implications for this common disorder. P olycystic ovary syndrome (PCOS) is one of the most common endocrinopathies affecting 5-7% of reproductive age women world-wide (1). PCOS is associated with hyperandrogenemia/ hyperandrogenism, anovulation, infertility, and a characteristic ovarian morphology consisting of multiple small subcortical follicular "cysts" embedded in bilaterally enlarged ovaries (2-5). The presence of elevated circulating concentrations of testosterone results primarily from increased production of androgens by the ovaries, and is a classic endocrine phenotype of women with PCOS. Although there has been debate about the diagnostic criteria for PCOS, hyperandrogenemia/hyperandrogenism and anovulation, not explained by other causes, is a hallmark of the disorder, and is included as a key element in all "consensus" diagnosis schemes (6-10).There is consensus that the ovarian theca cells are the primary source of excess androgen biosynthesis in women with PCOS (11-13). Studies on freshly isolated thecal tissue or cultures of theca cells derived from normal and PCOS women have demonstrated that PCOS theca secretes greater amounts of androgen than theca tissue or cells from regularly ovulating women (12,(14)(15)(16)(17)(18)(19). Increased androgen biosynthesis in PCOS theca cells results from increased expression of the key enzymes involved in androgen biosynthesis, steroid-17-α-hydroxylase/17,20 lyase (encoded by the CYP17...

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“…40 A recent GWAS and replication study identified three new susceptibility loci on chromosome 2p16.3, 2p21 and 9q33.3 and a novel YAP1 gene for PCOS in Han Chinese. 10,41 We also evaluated the significance in the previously reported 7 genome-wide significant loci for PCOS (rs13405728 at 2p16.3; rs12468394, rs13429458 and rs12478601 at 2p21; rs10818854, rs2479106 and rs10986105 at 9q33.3). Except for rs2479106 in DENND1A, the six of seven SNPs had a significant P-value between 2 Â 10 À2 and 8 Â 10 À4 .…”

Section: Resultsmentioning

confidence: 99%

“…5,6 However, because of differential diagnostic criteria and unclear etiology of PCOS, it can be difficult to find reproducible associations from diverse racial and ethnic background. [7][8][9] Although a recent genome-wide association study (GWAS) has contributed to susceptibility genes or loci discovery for PCOS, 10 identifying a major determinants underlying variation in primary metabolism would be more valuable. [11][12][13] PCOS and T2D are obesity-related conditions that share epidemiological and pathophysiological factors.…”

Section: Introductionmentioning

confidence: 99%

Genome-wide association study identifies GYS2 as a novel genetic factor for polycystic ovary syndrome through obesity-related condition

Hwang

Lee

et al. 2012

J Hum Genet

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To investigate the role of genetic predisposition in the pathogenesis of polycystic ovary syndrome (PCOS) in relation to obesity, we performed a genome-wide association study of PCOS in Koreans (n ¼ 1741). PCOS is a heterogeneous endocrinal disorder of uncertain etiology. Obesity is one of the well-known risk factors for PCOS. Genome-wide association study. Women with or without PCOS. A total of 1881 samples were genotyped using Illumina HumanOmni1 Quad v1 and processed by R packages. The PCOS patients were divided into two subgroups according to PCOS diagnostic criteria (Rotterdam and National Institutes of Health (NIH)). For PCOS-associated loci in the two definitions, we successfully confirmed significant associations of GYS2 for body mass index in the discovery stage. We further replicated pleiotropic associations of GYS2 in a childhood obesity study (n ¼ 482) and in a gestational diabetes study (n ¼ 1710), respectively. Our study provides a preliminary framework upon diverse genetic effects underlying PCOS in Korean women. A newly identified GYS2 gene as a predisposing factor of PCOS might expand understanding of the biological pathways in metabolic and endocrine regulation.

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Genome-wide association study identifies susceptibility loci for polycystic ovary syndrome on chromosome 2p16.3, 2p21 and 9q33.3

Cited by 641 publications

References 32 publications

Aberrant expression of long noncoding RNAs in cumulus cells isolated from PCOS patients

Aberrant expression of long noncoding RNAs in cumulus cells isolated from PCOS patients

Overexpression of a DENND1A isoform produces a polycystic ovary syndrome theca phenotype

Genome-wide association study identifies GYS2 as a novel genetic factor for polycystic ovary syndrome through obesity-related condition

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