Genome-wide association study identifies common and low-frequency variants at the AMH gene locus that strongly predict serum AMH levels in males
Human Molecular Genetics
Oxford University Press
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Perry, J., McMahon, G., Day, F., Ring, S. M., Nelson, S. M., & Lawlor, D. A. (2015). Genome-wide association study identifies common and low-frequency variants at the AMH gene locus that strongly predict serum AMH levels in males. Human Molecular Genetics, 25 382-388. https://doi.org/10.1093/hmg/ddv465
Anti-Müllerian hormone (AMH) is an essential messenger of sexual differentiation in the fetus 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 characterised. In samples from 2815 children aged 15 from the ALSPAC study, we performed the first genome-wide association study of serum AMH levels across a set of ~9M ‘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=2x10⁻⁴⁹, Beta: ~0.9 SDs per allele], rs8112524 [PMale=3x10⁻⁸, Beta: ~0.25]) and low-frequency variants (rs2385821 [PMale=6x10⁻³¹, 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 to 6.3x10⁻¹²), culminating in contrasting estimates of trait variance explained (24.5% in males vs 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.
The UK Medical Research Council and the Wellcome Trust (Grant ref: 102215/2/13/2) and the University of Bristol provide core support for ALSPAC. The work in this paper is funded by a grant from the US National Institute of Health (R01 DK077659). DAL, SMR and GM work in a Unit that receives funds from the UK Medical Research Council (MC_UU_12013/5) and the University of Bristol. DAL is a UK NIHR Senior Investigator (NF-SI-0611-10196).
Wellcome Trust (091310/Z/10/Z)
Medical Research Council (MC_U106179472)
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External DOI: https://doi.org/10.1093/hmg/ddv465
This record's URL: https://www.repository.cam.ac.uk/handle/1810/252617
Attribution 2.0 UK: England & Wales
Licence URL: http://creativecommons.org/licenses/by/2.0/uk/