Genome-wide association study identifies common and low-frequency variants at the AMHgene locus that strongly predict serum AMH levels in males

Perry, J. R.B., McMahon, G., Day, F. R., Ring, S. M., Nelson, S. M. and Lawlor, D. A. (2016) Genome-wide association study identifies common and low-frequency variants at the AMHgene locus that strongly predict serum AMH levels in males. Human Molecular Genetics, 25(2), pp. 382-388. (doi:10.1093/hmg/ddv465) (PMID:26604150) (PMCID:PMC4706112)

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Abstract

Anti-Müllerian hormone (AMH) is an essential messenger of sexual differentiation in the foetus and is an emerging biomarker of postnatal reproductive function in females. Due to a paucity of adequately sized studies, the genetic determinants of circulating AMH levels are poorly characterized. In samples from 2815 adolescents aged 15 from the ALSPAC study, we performed the first genome-wide association study of serum AMH levels across a set of ∼9 M ‘1000 Genomes Reference Panel’ imputed genetic variants. Genetic variants at the AMH protein-coding gene showed considerable allelic heterogeneity, with both common variants [rs4807216 (PMale = 2 × 10−49, Beta: ∼0.9 SDs per allele), rs8112524 (PMale = 3 × 10−8, Beta: ∼0.25)] and low-frequency variants [rs2385821 (PMale = 6 × 10−31, Beta: ∼1.2, frequency 3.6%)] independently associated with apparently large effect sizes in males, but not females. For all three SNPs, we highlight mechanistic links to AMH gene function and demonstrate highly significant sex interactions (PHet 0.0003–6.3 × 10−12), culminating in contrasting estimates of trait variance explained (24.5% in males versus 0.8% in females). Using these SNPs as a genetic proxy for AMH levels, we found no evidence in additional datasets to support a biological role for AMH in complex traits and diseases in men.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Nelson, Professor Scott
Authors: Perry, J. R.B., McMahon, G., Day, F. R., Ring, S. M., Nelson, S. M., and Lawlor, D. A.
College/School:College of Medical Veterinary and Life Sciences > School of Medicine, Dentistry & Nursing
Journal Name:Human Molecular Genetics
Publisher:Oxford University Press
ISSN:0964-6906
ISSN (Online):1460-2083
Published Online:24 November 2015
Copyright Holders:Copyright © 2015 The Authors
First Published:First published in Human Molecular Genetics 25(2):382-388
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
451351Maternal over nutrition and offspring fat mass, metabolic and vascular functionNaveed SattarNational Institute of Health (USA) (NIH(US))R01 DK077659-01RI CARDIOVASCULAR & MEDICAL SCIENCES