Genome-wide association study meta-analysis identifies three novel loci for circulating anti-Müllerian hormone levels in women.
Genome-wide association study meta-analysis identifies three novel loci for circulating anti-Müllerian hormone levels in women.
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全基因组关联研究荟萃分析确定了三个新的女性体内循环抗苗勒氏激素水平的基因座。
DOI：
10.1093/humrep/deac028
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发表时间：
2022-05-03
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通过包括绝经前女性大样本的全基因组关联研究 (GWAS) 荟萃分析，能否识别循环抗苗勒氏管激素 (AMH) 水平的其他遗传变异？我们确定了与 P < 5 × 10−8 的 AMH 水平相关的四个基因座：先前报道的 MCM8 基因座以及 AMH、TEX41 和 CDCA7 中或附近的三个新信号。 AMH 由女性窦期卵泡表达，年龄特异性循环 AMH 水平的变化与疾病结果相关。然而，这些 AMH 与疾病关联的生理机制在很大程度上尚不清楚。我们进行了 GWAS 荟萃分析，其中将之前 AMH GWAS 的汇总统计数据与来自三个不同队列的 3705 名其他女性的 GWAS 数据结合起来。总的来说，我们纳入了 7049 名欧洲血统绝经前女性参与者的数据。各队列研究参与者的中位年龄为 15.3 岁至 48 岁。使用不同的 ELISA 测定法测量血清或血浆样本中的循环 AMH 水平。研究特定分析根据采血年龄和人群分层进行调整，并使用标准误差加权方法对汇总统计数据进行荟萃分析。随后，我们对达到全基因组显着性的 GWAS 变异进行了功能注释 (P < 5 × 10−8)。我们还进行了基于基因的 GWAS、通路分析和连锁不平衡评分回归以及孟德尔随机化 (MR) 分析。我们确定了与 P < 5 × 10−8 的 AMH 水平相关的四个基因座：先前报道的 MCM8 基因座以及 AMH、TEX41 和 CDCA7 中或附近的三个新信号。最强的信号是 AMH 基因 (rs10417628) 中的错义变异。其他三个已确定位点的最优先基因涉及细胞周期调节。遗传相关分析表明，AMH 水平的单核苷酸多态性与绝经年龄之间存在很强的正相关性（rg = 0.82，FDR = 0.003）。探索性两样本 MR 分析并不支持 AMH 对乳腺癌或多囊卵巢综合征风险的因果影响，但应谨慎解释，因为它们可能动力不足，并且无法广泛探索遗传仪器的有效性。完整的 AMH GWAS 摘要统计数据将在 GWAS 目录发布后提供 (https://www.ebi.ac.uk/gwas/)。虽然这项研究将最近 GWAS 的样本量增加了一倍，但统计功效仍然相对较低。因此，我们可能仍然缺乏能力来识别更多的 AMH 基因变异，并确定 AMH 对乳腺癌等疾病的因果影响。此外，还需要开展后续研究来调查 AMH 基因信号是否是由某些检测方法检测到的 AMH 水平降低引起的，而不是实际较低的循环 AMH 水平。映射到 MCM8、TEX41 和 CDCA7 基因座的基因参与细胞周期和 DNA 复制和细胞凋亡等过程。它们与 AMH 相关的机制可能会影响卵巢卵泡池的大小。总而言之，我们的结果让我们更深入地了解 AMH 的生物学特性，从而更深入地了解卵巢衰老所涉及的生物过程。护士健康研究和护士健康研究 II 得到了美国国立卫生研究院 (CA172726、CA186107、CA50385、CA87969、CA49449、CA67262、CA178949) 的研究经费的支持。英国医学研究理事会和 Wellcome (217065/Z/19/Z) 以及布里斯托大学为 ASPAC 提供核心支持。本出版物是所列作者的作品，他们将作为本文内容的担保人。 ALSPAC 网站 (http://www.bristol.ac.uk/alspac/external/documents/grant-acknowledgements.pdf) 上提供了完整的赠款清单。此处使用的基因型和表型数据收集的资金由英国心脏基金会 (SP/07/008/24066)、Wellcome (WT092830M 和 WT08806) 和英国医学研究委员会 (G1001357) 提供。 M.C.B.、A.L.G.S.和 D.A.L.在布里斯托大学和英国医学研究理事会 (MC_UU_00011/6) 资助的单位工作。 M.C.B. 对这项工作的贡献由英国医学研究理事会技能发展奖学金 (MR/P014054/1) 和 D.A.L. 资助。是国家健康研究所高级研究员 (NF-0616-10102)。 A.L.G.S.得到了心血管和代谢性非传染性疾病动态纵向暴露轨迹研究（H2020-SC1-2019-Single-Stage-RTD，项目 ID 874739）的支持。杜廷赫姆队列研究得到了荷兰卫生、福利和体育部的资助。资助者在研究设计、数据收集和分析、出版决定或手稿准备中没有任何作用。 Ansh Labs 免费为 Doetinchem 队列研究进行 AMH 测量。 Ansh Labs 没有参与数据分析、解释或报告，也没有在财务上参与该研究的任何方面。 R.M.G.V.由乌得勒支大学医学中心流行病学理学硕士荣誉课程资助，并获得荷兰科学研究组织 (NWO) (022.005.021) 的资助。全国妇女健康研究 (SWAN) 得到了美国国立卫生研究院 (NIH)、DHHS、国家老龄化研究所 (NIA)、国家护理研究所 (NINR) 和 NIH 妇女健康研究办公室 (ORWH) 的资助 (U01NR004061; U01AG012505, U01AG012535, U01AG012531、U01AG012539、U01AG012546、U01AG012553、U01AG012554、U01AG012495）。 SWAN 基因组分析和 SWAN Legacy 得到了 NIA (U01AG017719) 的资助。这项世代研究由 Breast Cancer Now 和癌症研究所 (ICR) 资助。 ICR 感谢 NHS 对 NIHR 生物医学研究中心的资助。本手稿的内容完全由作者负责，并不一定代表资助者的官方观点。该姐妹研究由美国国立卫生研究院 (NIH)、国家环境健康科学研究所 (Z01-ES044005 至 D.P.S.) 的校内研究计划资助； AMH 检测得到了雅芳基金会 (02-2012-065 to H.B. Nichols and D.P.S.) 的支持。乳腺癌全基因组关联分析得到了加拿大政府通过 Genome Canada 和加拿大卫生研究院、“Minisère de l’Économie, de la Science et de l’Innovation du Québec”通过 Genome Québec 和 PSR-SIIRI-701、英国国立卫生研究院 (U19 CA148065、X01HG007492)、英国癌症研究中心的资助（C1287/A10118、C1287/A16563、C1287/A10710）和欧盟（HEALTH-F2-2009-223175 和 H2020 633784 和 634935）。所有研究和资助者都列在）中。 F.J.M.B.已收到 Merck Serono 和 Ferring BV 的费用和赠款支持。 D.A.L.已获得多个国家和国际政府和慈善资助者以及美敦力有限公司和罗氏诊断公司的财政支持，用于与本研究无关的研究。国家统计局是 Ansh 实验室的科学顾问。其他作者声明没有竞争利益。
Can additional genetic variants for circulating anti-Müllerian hormone (AMH) levels be identified through a genome-wide association study (GWAS) meta-analysis including a large sample of premenopausal women? We identified four loci associated with AMH levels at P < 5 × 10−8: the previously reported MCM8 locus and three novel signals in or near AMH, TEX41 and CDCA7. AMH is expressed by antral stage ovarian follicles in women, and variation in age-specific circulating AMH levels has been associated with disease outcomes. However, the physiological mechanisms underlying these AMH-disease associations are largely unknown. We performed a GWAS meta-analysis in which we combined summary statistics of a previous AMH GWAS with GWAS data from 3705 additional women from three different cohorts. In total, we included data from 7049 premenopausal female participants of European ancestry. The median age of study participants ranged from 15.3 to 48 years across cohorts. Circulating AMH levels were measured in either serum or plasma samples using different ELISA assays. Study-specific analyses were adjusted for age at blood collection and population stratification, and summary statistics were meta-analysed using a standard error-weighted approach. Subsequently, we functionally annotated GWAS variants that reached genome-wide significance (P < 5 × 10−8). We also performed a gene-based GWAS, pathway analysis and linkage disequilibrium score regression and Mendelian randomization (MR) analyses. We identified four loci associated with AMH levels at P < 5 × 10−8: the previously reported MCM8 locus and three novel signals in or near AMH, TEX41 and CDCA7. The strongest signal was a missense variant in the AMH gene (rs10417628). Most prioritized genes at the other three identified loci were involved in cell cycle regulation. Genetic correlation analyses indicated a strong positive correlation among single nucleotide polymorphisms for AMH levels and for age at menopause (rg = 0.82, FDR = 0.003). Exploratory two-sample MR analyses did not support causal effects of AMH on breast cancer or polycystic ovary syndrome risk, but should be interpreted with caution as they may be underpowered and the validity of genetic instruments could not be extensively explored. The full AMH GWAS summary statistics will made available after publication through the GWAS catalog (https://www.ebi.ac.uk/gwas/). Whilst this study doubled the sample size of the most recent GWAS, the statistical power is still relatively low. As a result, we may still lack power to identify more genetic variants for AMH and to determine causal effects of AMH on, for example, breast cancer. Also, follow-up studies are needed to investigate whether the signal for the AMH gene is caused by reduced AMH detection by certain assays instead of actual lower circulating AMH levels. Genes mapped to the MCM8, TEX41 and CDCA7 loci are involved in the cell cycle and processes such as DNA replication and apoptosis. The mechanism underlying their associations with AMH may affect the size of the ovarian follicle pool. Altogether, our results provide more insight into the biology of AMH and, accordingly, the biological processes involved in ovarian ageing. Nurses’ Health Study and Nurses’ Health Study II were supported by research grants from the National Institutes of Health (CA172726, CA186107, CA50385, CA87969, CA49449, CA67262, CA178949). The UK Medical Research Council and Wellcome (217065/Z/19/Z) and the University of Bristol provide core support for ALSPAC. This publication is the work of the listed authors, who will serve as guarantors for the contents of this article. A comprehensive list of grants funding is available on the ALSPAC website (http://www.bristol.ac.uk/alspac/external/documents/grant-acknowledgements.pdf). Funding for the collection of genotype and phenotype data used here was provided by the British Heart Foundation (SP/07/008/24066), Wellcome (WT092830M and WT08806) and UK Medical Research Council (G1001357). M.C.B., A.L.G.S. and D.A.L. work in a unit that is funded by the University of Bristol and UK Medical Research Council (MC_UU_00011/6). M.C.B.’s contribution to this work was funded by a UK Medical Research Council Skills Development Fellowship (MR/P014054/1) and D.A.L. is a National Institute of Health Research Senior Investigator (NF-0616-10102). A.L.G.S. was supported by the study of Dynamic longitudinal exposome trajectories in cardiovascular and metabolic non-communicable diseases (H2020-SC1-2019-Single-Stage-RTD, project ID 874739). The Doetinchem Cohort Study was financially supported by the Ministry of Health, Welfare and Sports of the Netherlands. The funder had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. Ansh Labs performed the AMH measurements for the Doetinchem Cohort Study free of charge. Ansh Labs was not involved in the data analysis, interpretation or reporting, nor was it financially involved in any aspect of the study. R.M.G.V. was funded by the Honours Track of MSc Epidemiology, University Medical Center Utrecht with a grant from the Netherlands Organization for Scientific Research (NWO) (022.005.021). The Study of Women's Health Across the Nation (SWAN) has grant support from the National Institutes of Health (NIH), DHHS, through the National Institute on Aging (NIA), the National Institute of Nursing Research (NINR) and the NIH Office of Research on Women’s Health (ORWH) (U01NR004061; U01AG012505, U01AG012535, U01AG012531, U01AG012539, U01AG012546, U01AG012553, U01AG012554, U01AG012495). The SWAN Genomic Analyses and SWAN Legacy have grant support from the NIA (U01AG017719). The Generations Study was funded by Breast Cancer Now and the Institute of Cancer Research (ICR). The ICR acknowledges NHS funding to the NIHR Biomedical Research Centre. The content of this manuscript is solely the responsibility of the authors and does not necessarily represent official views of the funders. The Sister Study was funded by the Intramural Research Program of the National Institutes of Health (NIH), National Institute of Environmental Health Sciences (Z01-ES044005 to D.P.S.); the AMH assays were supported by the Avon Foundation (02-2012-065 to H.B. Nichols and D.P.S.). The breast cancer genome-wide association analyses were supported by the Government of Canada through Genome Canada and the Canadian Institutes of Health Research, the ‘Ministère de l’Économie, de la Science et de l’Innovation du Québec’ through Genome Québec and grant PSR-SIIRI-701, The National Institutes of Health (U19 CA148065, X01HG007492), Cancer Research UK (C1287/A10118, C1287/A16563, C1287/A10710) and The European Union (HEALTH-F2-2009-223175 and H2020 633784 and 634935). All studies and funders are listed in). F.J.M.B. has received fees and grant support from Merck Serono and Ferring BV. D.A.L. has received financial support from several national and international government and charitable funders as well as from Medtronic Ltd and Roche Diagnostics for research that is unrelated to this study. N.S. is scientific consultant for Ansh Laboratories. The other authors declare no competing interests.
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影响因子：
30.8
作者：
Bulik-Sullivan, Brendan K.;Loh, Po-Ru;Finucane, Hilary K.;Ripke, Stephan;Yang, Jian;Patterson, Nick;Daly, Mark J.;Price, Alkes L.;Neale, Benjamin M.
通讯作者：
Neale, Benjamin M.
影响因子：
7
作者：
Boyle AP;Hong EL;Hariharan M;Cheng Y;Schaub MA;Kasowski M;Karczewski KJ;Park J;Hitz BC;Weng S;Cherry JM;Snyder M
通讯作者：
Snyder M
影响因子：
30.8
作者：
Kircher, Martin;Witten, Daniela M.;Jain, Preti;O'Roak, Brian J.;Cooper, Gregory M.;Shendure, Jay
通讯作者：
Shendure, Jay
影响因子：
30.8
作者：
He, Chunyan;Kraft, Peter;Chen, Constance;Buring, Julie E.;Pare, Guillaume;Hankinson, Susan E.;Chanock, Stephen J.;Ridker, Paul M.;Hunter, David J.;Chasman, Daniel I.
通讯作者：
Chasman, Daniel I.
影响因子：
30.8
作者：
Bulik-Sullivan B;Finucane HK;Anttila V;Gusev A;Day FR;Loh PR;ReproGen Consortium;Psychiatric Genomics Consortium;Genetic Consortium for Anorexia Nervosa of the Wellcome Trust Case Control Consortium 3;Duncan L;Perry JR;Patterson N;Robinson EB;Daly MJ;Price AL;Neale BM
通讯作者：
Neale BM