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Meta-analysis identifies five novel loci associated with endometriosis highlighting key genes involved in hormone metabolism.

ABSTRACT: Endometriosis is a heritable hormone-dependent gynecological disorder, associated with severe pelvic pain and reduced fertility; however, its molecular mechanisms remain largely unknown. Here we perform a meta-analysis of 11 genome-wide association case-control data sets, totalling 17,045 endometriosis cases and 191,596 controls. In addition to replicating previously reported loci, we identify five novel loci significantly associated with endometriosis risk (P<5 × 10-8), implicating genes involved in sex steroid hormone pathways (FN1, CCDC170, ESR1, SYNE1 and FSHB). Conditional analysis identified five secondary association signals, including two at the ESR1 locus, resulting in 19 independent single nucleotide polymorphisms (SNPs) robustly associated with endometriosis, which together explain up to 5.19% of variance in endometriosis. These results highlight novel variants in or near specific genes with important roles in sex steroid hormone signalling and function, and offer unique opportunities for more targeted functional research efforts.

SUBMITTER: Sapkota Y

PROVIDER: S-EPMC5458088 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature

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Meta-analysis identifies five novel loci associated with endometriosis highlighting key genes involved in hormone metabolism.

Sapkota Yadav Y Steinthorsdottir Valgerdur V Morris Andrew P AP Fassbender Amelie A Rahmioglu Nilufer N De Vivo Immaculata I Buring Julie E JE Zhang Futao F Edwards Todd L TL Jones Sarah S O Dorien D Peterse Daniëlle D Rexrode Kathryn M KM Ridker Paul M PM Schork Andrew J AJ MacGregor Stuart S Martin Nicholas G NG Becker Christian M CM Adachi Sosuke S Yoshihara Kosuke K Enomoto Takayuki T Takahashi Atsushi A Kamatani Yoichiro Y Matsuda Koichi K Kubo Michiaki M Thorleifsson Gudmar G Geirsson Reynir T RT Thorsteinsdottir Unnur U Wallace Leanne M LM Yang Jian J Velez Edwards Digna R DR Nyegaard Mette M Nyegaard Mette M Low Siew-Kee SK Zondervan Krina T KT Missmer Stacey A SA D'Hooghe Thomas T Montgomery Grant W GW Chasman Daniel I DI Stefansson Kari K Tung Joyce Y JY Nyholt Dale R DR

Nature communications 20170524

Endometriosis is a heritable hormone-dependent gynecological disorder, associated with severe pelvic pain and reduced fertility; however, its molecular mechanisms remain largely unknown. Here we perform a meta-analysis of 11 genome-wide association case-control data sets, totalling 17,045 endometriosis cases and 191,596 controls. In addition to replicating previously reported loci, we identify five novel loci significantly associated with endometriosis risk (P<5 × 10<sup>-8</sup>), implicating g ...[more]

PMID: 28537267

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Project description:Abstract Background Schizophrenia is a highly heritable psychiatric disorder. In the past 30 years, thousands of case-control and family-designed association studies have examined candidate genes for schizophrenia. To assist the field in interpreting this large volume of gene-association studies, the online SzGene database was created and included meta analyses for 287 polymorphisms at the time of its final update in 2010. However, since then more than one-thousand new gene-association studies in schizophrenia have been conducted. As such, we have conducted an updated systematic review and meta-analysis of all gene-association studies in schizophrenia published before March 2017. Methods Studies published between January 2010 and March 2017 were identified using a customized querying strategy. Identified gene-association studies were included in the review and meta-analysis if they: 1) were case-control or family-designed studies with polymorphisms detected in schizophrenia or schizoaffective patients, 2) provide sufficient data to perform meta-analysis, and 3) were not genome-wide association studies (GWAS). Random-effects meta-analysis was performed on polymorphisms with four or more independent studies. Results Raw data of 1711 studies included in the SzGene database were integrated with 1368 studies identified from our systematic literature search. Random-effects meta-analysis were applied to 540 polymorphisms with at least four studies and 89 of these polymorphisms were nominally associated with SZ (unadjusted p < 0.05). After bonferroni correction, 12 polymorphisms remained statistically significant, including five associations not reported in the most recent Psychiatric Genomics Consortium schizophrenia GWAS: 1) rs11098403, p = 1.45e-10, odds ratio = 0.65; 2) rs12807809, p = 7.04e-06, odds ratio = 0.91; 3) rs910694 in PDE4B: p = 1.05e-05, odds ratio = 0.77; 4) rs1801133 in MTHFR: p = 2.99e-05, odds ratio = 1.13 and 5) rs1602565: p = 7.73e-05, odds ratio = 1.11. Discussion Our results provide a comprehensive and up-to-date review of candidate gene association studies in schizophrenia. Findings complement results from GWASs in schizophrenia but also expand the current list of candidate loci for schizophrenia.

Project description:Circulating homocysteine levels (tHcy), a product of the folate one carbon metabolism pathway (FOCM) through the demethylation of methionine, are heritable and are associated with an increased risk of common diseases such as stroke, cardiovascular disease (CVD), cancer and dementia. The FOCM is the sole source of de novo methyl group synthesis, impacting many biological and epigenetic pathways. However, the genetic determinants of elevated tHcy (hyperhomocysteinemia), dysregulation of methionine metabolism and the underlying biological processes remain unclear. We conducted independent genome-wide association studies and a meta-analysis of methionine metabolism, characterized by post-methionine load test tHcy, in 2,710 participants from the Framingham Heart Study (FHS) and 2,100 participants from the Vitamin Intervention for Stroke Prevention (VISP) clinical trial, and then examined the association of the identified loci with incident stroke in FHS. Five genes in the FOCM pathway (GNMT [p = 1.60 × 10(-63)], CBS [p = 3.15 × 10(-26)], CPS1 [p = 9.10 × 10(-13)], ALDH1L1 [p = 7.3 × 10(-13)] and PSPH [p = 1.17 × 10(-16)]) were strongly associated with the difference between pre- and post-methionine load test tHcy levels (ΔPOST). Of these, one variant in the ALDH1L1 locus, rs2364368, was associated with incident ischemic stroke. Promoter analyses reveal genetic and epigenetic differences that may explain a direct effect on GNMT transcription and a downstream affect on methionine metabolism. Additionally, a genetic-score consisting of the five significant loci explains 13% of the variance of ΔPOST in FHS and 6% of the variance in VISP. Association between variants in FOCM genes with ΔPOST suggest novel mechanisms that lead to differences in methionine metabolism, and possibly the epigenome, impacting disease risk. These data emphasize the importance of a concerted effort to understand regulators of one carbon metabolism as potential therapeutic targets.

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Meta-analysis identifies five novel loci associated with endometriosis highlighting key genes involved in hormone metabolism.

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Meta-analysis identifies five novel loci associated with endometriosis highlighting key genes involved in hormone metabolism.

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