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. 2024 May 28;16(1):69.
doi: 10.1186/s13073-024-01322-7.

Metabolome-wide Mendelian randomization for age at menarche and age at natural menopause

Mojgan Yazdanpanah  1 , Nahid Yazdanpanah  1 , Isabel Gamache  1 , Ken Ong  2 , John R B Perry  2   3 , Despoina Manousaki  4   5
Affiliations

Metabolome-wide Mendelian randomization for age at menarche and age at natural menopause

Mojgan Yazdanpanah et al. Genome Med. .

Abstract

Background: The role of metabolism in the variation of age at menarche (AAM) and age at natural menopause (ANM) in the female population is not entirely known. We aimed to investigate the causal role of circulating metabolites in AAM and ANM using Mendelian randomization (MR).

Methods: We combined MR with genetic colocalization to investigate potential causal associations between 658 metabolites and AAM and between 684 metabolites and ANM. We extracted genetic instruments for our exposures from four genome-wide association studies (GWAS) on circulating metabolites and queried the effects of these variants on the outcomes in two large GWAS from the ReproGen consortium. Additionally, we assessed the mediating role of the body mass index (BMI) in these associations, identified metabolic pathways implicated in AAM and ANM, and sought validation for selected metabolites in the Avon Longitudinal Study of Parents and Children (ALSPAC).

Results: Our analysis identified 10 candidate metabolites for AAM, but none of them colocalized with AAM. For ANM, 76 metabolites were prioritized (FDR-adjusted MR P-value ≤ 0.05), with 17 colocalizing, primarily in the glycerophosphocholines class, including the omega-3 fatty acid and phosphatidylcholine (PC) categories. Pathway analyses and validation in ALSPAC mothers also highlighted the role of omega and polyunsaturated fatty acids levels in delaying age at menopause.

Conclusions: Our study suggests that metabolites from the glycerophosphocholine and fatty acid families play a causal role in the timing of both menarche and menopause. This underscores the significance of specific metabolic pathways in the biology of female reproductive longevity.

Keywords: ALSPAC; Menarche; Mendelian randomization; Menopause; Metabolites.

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Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Flow chart of study design. Representation of the analytical steps and of the main results for both studied outcomes. Orange boxes refer to AAM, while green boxes refer to ANM
Fig. 2
Fig. 2
MR-prioritized metabolites for AAM (A) or ANM (B). Estimates (betas) express changes in years in AAM and ANM per SD increase in the circulating level of each metabolite. The results are grouped based on the main class of the metabolites
Fig. 3
Fig. 3
Shared MR-prioritized metabolites between AAM and ANM. Comparison of the effects of shared metabolites between AAM and ANM on the two outcomes. Estimates (betas) express changes in years in AAM and ANM per SD increase in the circulating level of each metabolite. The results are grouped based on the main class of the metabolites
Fig. 4
Fig. 4
Pathway analysis of colocalized metabolites with ANM using GeneMANIA. Each circle represents a gene and its diverse interactions across the network. Pie-chart for each gene represents specific functions associated with lipid metabolism
See this image and copyright information in PMC

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