A Genome-Wide Association Study of Anti-Müllerian Hormone (AMH) Levels in Samoan Women.

Background/

Objectives

The anti-Müllerian hormone (AMH) is a key biomarker of the ovarian reserve, correlating with ovarian follicle count, fertility outcomes, and menopause timing. Understanding its genetic determinants has broad implications for female reproductive health. However, prior genome-wide association studies (GWASs) have focused exclusively on women of European ancestry, limiting insights into diverse populations.

Methods

We conducted a GWAS to identify genetic loci associated with circulating AMH levels in a sample of 1185 Samoan women from two independently recruited samples. Using a Cox mixed-effects model we accounted for AMH levels below detectable limits and meta-analysed the summary statistics using a fixed-effect model. To prioritize variants and genes, we used FUMA and performed colocalization and transcriptome-wide association analysis (TWAS). We also assessed whether any previously reported loci were replicated in our GWAS.

Results

We identified eleven genome-wide suggestive loci, with the strongest signal at ARID3A (19-946163-G-C; p = 2.32 × 10-7) and replicated rs10093345 near EIF4EBP1. The gene-based testing revealed ARID3A and R3HDM4 as significant genes. Integrating GWAS results with expression quantitative trait loci via TWAS, we detected seven transcriptome-wide significant genes. The lead variant in ARID3A is in high linkage disequilibrium (r2 = 0.79) with the known age-at-menopause variant 19-950694-G-A. Nearby KISS1R is a biologically plausible candidate gene that encodes the kisspeptin receptor, a regulator of ovarian follicle development linked to AMH levels.

Conclusions

This study expands our understandings of AMH genetics by focusing on Samoan women. While these findings may be particularly relevant to Pacific Islanders, they hold broader implications for reproductive phenotypes such as the ovarian reserve, menopause timing, and polycystic ovary syndrome.