title: Genome-wide association study identifies common and low-frequency variants at the AMH gene locus that strongly predict serum AMH levels in males.
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 (P(Male) = 2 × 10(-49), Beta: ∼0.9 SDs per allele), rs8112524 (P(Male) = 3 × 10(-8), Beta: ∼0.25)] and low-frequency variants [rs2385821 (P(Male) = 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 (P(Het) 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.
authors.affiliation: MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Box 285 Institute of Metabolic Science, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK, john.perry@mrc-epid.cam.ac.uk d.a.lawlor@bristol.ac.uk.
authors.forename: John R B
authors.initials: JR
authors.lastname: Perry
authors.affiliation: MRC Integrative Epidemiology Unit at the University of Bristol, Bristol BS8 2BN, UK, School of Social and Community Medicine, University of Bristol, Oakfield House, Oakfield Grove, Bristol BS8 2BN, UK and.
authors.forename: George
authors.initials: G
authors.lastname: McMahon
authors.affiliation: MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Box 285 Institute of Metabolic Science, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK.
authors.forename: Felix R
authors.initials: FR
authors.lastname: Day
authors.affiliation: MRC Integrative Epidemiology Unit at the University of Bristol, Bristol BS8 2BN, UK, School of Social and Community Medicine, University of Bristol, Oakfield House, Oakfield Grove, Bristol BS8 2BN, UK and.
authors.forename: Susan M
authors.initials: SM
authors.lastname: Ring
authors.affiliation: School of Medicine, University of Glasgow, Glasgow G31 2ER, UK.
authors.forename: Scott M
authors.initials: SM
authors.lastname: Nelson
authors.affiliation: MRC Integrative Epidemiology Unit at the University of Bristol, Bristol BS8 2BN, UK, School of Social and Community Medicine, University of Bristol, Oakfield House, Oakfield Grove, Bristol BS8 2BN, UK and john.perry@mrc-epid.cam.ac.uk d.a.lawlor@bristol.ac.uk.
authors.forename: Debbie A
authors.initials: DA
authors.lastname: Lawlor
mesh_terms: D000293:Adolescent; D000483:Alleles; D054304:Anti-Mullerian Hormone / Q000097:blood / Q000235:genetics*; D005260:Female; D005796:Genes; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D020641:Polymorphism, Single Nucleotide; D012737:Sex Factors
chemical_list: D054304:Anti-Mullerian Hormone