Shared genetics found between anti-Müllerian hormone and age at menopause

Shared genetics found between anti-Müllerian hormone and age at menopause | Image Credit: © ktsdesign - © ktsdesign - stock.adobe.com.

Anti-Müllerian (AMH) hormone has a shared genetic architecture with age at menopause, according to a recent study published in the American Journal of Obstetrics & Gynecology.¹

Menopause, linked to various health outcomes in women, occurs at a mean 51 years among European women. However, 5% of European women experience menopause before the age of 45 years and 1% before the age of 40 years.²

As a family history of early menopause increases the risk of early menopause in women, this condition may be influenced by genetic factors.¹ However, data about genetic factors linked to age at menopause remains lacking. AMH has been considered a contributing factor, but more data is necessary to determine its overlap with age at menopause.

Investigators conducted a study to assess shared genetic structures and core molecular pathways of AMH and age at menopause. Linkage disequilibrium score regression was used to conduct a genetic correlation analysis based on the linkage disequilibrium structure from the 1000 Genomes Project European reference panel.

Pleiotropic loci associated with complex traits were identified using genome-wide association study (GWAS) statistics. Pleiotropic variants were significant if they had a P value under 5x10.

Gene-level multimarker analyses of GenoMic annotation (MAGMA) were conducted using pleiotropic analysis under composite null hypothesis (PLACO) results. This allowed investigators to identify candidate pleiotropic genes within the pleiotropic loci.

The Kyoto Encyclopedia of Genes and Genomes Orthology-Based Annotation System (version 3.0) was used to evaluate pathway enrichment, and biological processes linked to AHM and age at menopause were identified using Gene Ontology (GO).

Through summary data-based Mendelian randomization (SMR), investigators accessed the causal association between gene expression and the phenotype. This allowed genes responsible for the association between AMH and age at menopause to be identified.

SMR analyses were conducted for various genetically enriched tissues with single nucleotide polymorphisms (SNPs) linked to AMH and age at menopause. Investigators also performed colocalization analysis and mendelian randomization (MR) analysis.

A liability-scale SNP heritability of 14.8% was reported for AMH vs 19.2% for age at menopause. This indicated a positive genetic correlation between these 2 characteristics, with an intercept of genetic covariance of 0.002.

During PLACO analysis, investigators identified 2686 single nucleotide variants with potential polymorphic variants. In comparison, 245 significant pleiotropic genes were identified during the MAGMA analysis. Pleiotropic effects of independent genomic risk loci were found for 42 chromosomal regions, with 10 potentially shared between AMH and age at menopause.

Within GO enrichment, there were 245 genes with multiple effects concentrated in DNA replication. Analysis of GWAS data highlighted 9 potentially shared causal risk genes. Of these, ADORA2B, SNX17, and ZNF98 were present in most of the enriched tissues.

MR analysis showed no effect of AMH on age at menopause, but an inverse relationship was discovered, highlighting the causality of age at menopause on AMH. This association was supported by heterogeneity and pleiotropy tests.

These results indicated a potential causal relationship between AMH levels and age at menopause. Investigators concluded this data should be used to conduct research developing therapeutic interventions to protect fertility in women.

References

1. Long P, Tan H, Chen B, et al. Dissecting the shared genetic architecture between anti-Müllerian hormone and age at menopause based on genome-wide association study. Am J Obstet Gynecol. 2024;231:634.e1-11. doi:10.1016/j.ajog.2024.06.050
2. Louwers YV, Visser JA. Shared genetics between age at menopause, early nenopause, POI and other traits. Front Genet. 2021;12:676546. doi:10.3389/fgene.2021.676546