Genome-Wide Association Study Meta-Analysis Identifies Three Novel Loci For Circulating Anti-Mullerian Hormone Levels In Women

Anti-Mullerian hormone (AMH) is expressed by antral stage ovarian follicles in women. Consequently, circulating AMH levels are detectable until menopause. Variation in age-specific AMH levels has been associated with breast cancer and polycystic ovary syndrome (PCOS), amongst other diseases. Identification of genetic variants underlying variation in AMH levels could provide clues about the physiological mechanisms that explain these AMH-disease associations. To date, only one variant in MCM8 has been identified to be associated with circulating AMH levels in women. We aimed to identify additional variants for AMH through a GWAS meta-analysis including data from 7049 premenopausal women of European ancestry, which more than doubles the sample size of the largest previous GWAS. We identified four loci associated with AMH levels at p < 5x10-8: 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 SNPs for AMH levels and for age at menopause (rg= 0.82, FDR=0.003). Exploratory Mendelian randomization analyses did not support a causal effect of AMH on breast cancer or PCOS risk, but should be interpreted with caution as they may be underpowered and the validity of genetic instruments could not be extensively explored. In conclusion, we identified a variant in the AMH gene and three other loci that may affect circulating AMH levels in women. ### Competing Interest Statement FJMB has received fees and grant support from Merck Serono, Gedeon Richter, Ferring BV, and Roche. DAL 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. NS is scientific consultant for Ansh Laboratories. The other authors declare no competing interests. ### Funding Statement 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 (Grant ref: 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 paper. 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). MCB, ALS and DAL work in a Unit that is funded by the University of Bristol and UK Medical Research Council (MC\_UU\_00011/6). MCB is funded by a UK Medical Research Council Skills Development Fellowship (MR/P014054/1) and DAL is a National Institute of Health Research Senior Investigator (NF-0616-10102). The Doetinchem Cohort Study is 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. RMGV is funded by the Honours Track of MSc Epidemiology, University Medical Center Utrecht with a grant from the Netherlands Organization for Scientific Research (NWO) (Grant number: 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) (Grants U01NR004061; U01AG012505, U01AG012535, U01AG012531, U01AG012539, U01AG012546, U01AG012553, U01AG012554, U01AG012495). The SWAN Genomic Analyses and SWAN Legacy has grant support from the NIA (U01AG017719). The Generations Study is 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 DP Sandler); the AMH assays were supported by the Avon Foundation (02-2012-065) to H.B. Nichols and D.P. Sandler). The breast c