Elucidating the genetic architecture of early menopause in the Tehran cardiometabolic genetic study

Abstract

Background

Population studies elucidating the genetic architecture of early menopause have mainly focused on European ancestries, leaving a gap in understanding of the genetic influences in non-European populations. This study seeks to identify potential genetic variants linked to early menopause in Iranian women.

Research design and methods

We conducted a genome-wide association study on early menopause involving a discovery group of 3421 women, comprising 3145 individuals with normal age at menopause and 276 with early menopause. Additionally, a confirmation group included 1015 women, consisting of 208 individuals with a poor ovarian reserve and 807 with normal ovarian reserve, all drawn from an Iranian cohort. We analyzed over 9 million variants using the Genome-wide Complex Trait Analysis tool, followed by thorough bioinformatics evaluations and functional annotations.

Results

We identified specific genetic variants associated with early menopause, notably the rs9943588 variant of the GALNT18 gene; the variant significantly increases the risk of early menopause [OR = 1.93; p = 2.54E-8]. In our confirmatory population, this variant was associated with a 35 % increased risk of poor ovarian reserve (OR = 1.35, p < 0.0001). Furthermore, epigenomics data suggest that rs9943588 may influence a regulatory motif for the ETS transcription factor in women.

Conclusions

The rs9943588 variant of the GALNT18 gene is associated with an elevated risk of early menopause among Iranian women. Moreover, our results show significant differences in allele frequencies between Iranian and European variants, emphasizing the advantages and challenges of large-scale trans-ethnic strategies to inform personalized approaches to women's health.