A genome-wide association study of anti-Müllerian hormone (AMH) levels in Samoan women.

Abstract

Study question: Can a genome-wide association study (GWAS) and transcriptome-wide association study (TWAS) help identify genetic variation or genes associated with circulating anti-Müllerian hormone (AMH) levels in Samoan women?

Summary answer: We identified eleven genome-wide suggestive loci (strongest association signal in ARID3A 19-946163-G-C [ p = 2.32 × 10⁻⁷]) and seven transcriptome-wide significant genes ( GINS2, SENP3, USP7, TUSC3, MAFA, METTL4, NDFIP1 [all with a p < 2.50 × 10⁻⁶]) associated with circulating AMH levels in Samoan women.

What is known already: Three prior GWASs of AMH levels identified eight loci in premenopausal women of European ancestry (AMH, MCM8, TEX41 , CHECK2, CDCA7 , EIF4EBP1, BMP4 and an uncharacterized non-coding RNA gene CTB-99A3.1 ), among which the MCM8 locus was shared among all three studies.

Study design size duration: We included a sample of 1,185 women from two independently recruited samples: a family study ( n = 212; [age: 18 to 40 years]) recruited in 2002-03 from Samoa and American Samoa; and the Soifua Manuia Study ( n = 973; age: 25 to 51 years), a crosssectional population-based study recruited in 2010 from Samoa.

Participants/materials setting methods: Serum AMH levels were measured using enzyme linked immunosorbent assays (ELISA). We performed GWASs in the two participant samples using a Cox mixed-effects model to account for AMH levels below detectable limits and adjusted for centered age, centered age², polity, and kinship via kinship matrix. The summary statistics were then meta-analyzed using a fixed-effect model. We annotated the variants with p < 1 × 10⁻⁵ and calculated posterior probability of causality for prioritization. We further annotated variants using FUMA and performed colocalization and transcriptome-wide association analysis. We also assessed whether any previously reported loci were replicated in our GWAS.

Main results and the role of chance: We identified eleven novel genome-wide suggestive loci ( p < 1 × 10⁻⁵) associated with AMH levels and replicated EIF4EBP1, a previously reported AMH locus, in the GWAS. The lead variant in ARID3A , 19-946163-G-C is in high linkage disequilibrium ( r ² = 0.79) with the known age-at-menopause variant 19-950694-G-A. Nearby KISS1R is a biologically plausibility causal gene in the region; kisspeptin regulates ovarian follicle development and has been linked to AMH levels. Further investigation of the ARID3A locus is warranted.

Limitations reasons for caution: The main limitations of our study are the small sample size for a GWAS and the use of the transcription model trained on mostly European samples from the Genotype Tissue Expression (GTEx) project, which may have led to reduced power to detect genotype-expression associations. Our findings need to be validated in larger Polynesian cohorts.

Wider implications of the findings: In addition to replicating one of the eight previously discovered AMH loci, we identified new suggestive associations. It is known that the inclusion of founder populations aids in the discovery of novel loci. These findings could enhance our understanding of AMH and AMH-related reproductive phenotypes (ovarian reserve, age at menopause, premature ovarian failure, and polycystic ovary syndrome) and help build a screening approach for women at risk for these phenotypes using genetically predicted AMH levels.

Study funding/competing interests: This work was funded by NIH grants R01-HL093093 (PI: S.T.M.), R01-HL133040 (PI: R.L.M.), and T90-DE030853 (PI: C.S. Sfeir). Molecular data for the Trans-Omics in Precision Medicine (TOPMed) Program was supported by the National Heart, Lung and Blood Institute (NHLBI). The content is solely the responsibility of the authors and does not represent the official views of the National Institutes of Health.