Research Center of the Sainte-Justine University Hospital, Université de Montréal, 3175 Côte-Sainte-Catherine, Montréal, Québec, H3T 1C5, Canada.
MRC Epidemiology Unit, School of Clinical Medicine, Wellcome-MRC Institute of Metabolic Science, University of Cambridge, Cambridge, CB2 0QQ, UK.
Genome Med. 2024 May 28;16(1):69. doi: 10.1186/s13073-024-01322-7.
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).
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).
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.
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.
代谢在女性人群中初潮年龄（AAM）和自然绝经年龄（ANM）变化中的作用尚不完全清楚。我们旨在使用孟德尔随机化（MR）研究循环代谢物在 AAM 和 ANM 中的因果作用。
我们将 MR 与遗传共定位相结合，研究了 658 种代谢物与 AAM 之间以及 684 种代谢物与 ANM 之间的潜在因果关联。我们从四个关于循环代谢物的全基因组关联研究（GWAS）中提取了我们暴露的遗传工具，并在 ReproGen 联盟的两项大型 GWAS 中查询了这些变体对结果的影响。此外，我们评估了这些关联中 BMI 的中介作用，确定了与 AAM 和 ANM 相关的代谢途径，并在阿冯纵向父母与子女研究（ALSPAC）中对选定的代谢物进行了验证。
我们的分析确定了 10 种候选代谢物与 AAM 相关，但没有一种与 AAM 共定位。对于 ANM，有 76 种代谢物被优先考虑（经 FDR 调整的 MR P 值≤0.05），其中 17 种代谢物与 ANM 共定位，主要集中在甘油磷酸胆碱类，包括 ω-3 脂肪酸和磷脂酰胆碱（PC）类别。通路分析和在 ALSPAC 母亲中的验证也突出了 ω 和多不饱和脂肪酸水平在延迟绝经年龄中的作用。
我们的研究表明，甘油磷酸胆碱和脂肪酸家族的代谢物在初潮和绝经时间上都起着因果作用。这突显了特定代谢途径在女性生殖寿命生物学中的重要性。
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