학술논문
Metabolome-wide Mendelian randomization for age at menarche and age at natural menopause.
Document Type
Academic Journal
Author
Yazdanpanah M; Research Center of the Sainte-Justine University Hospital, Université de Montréal, 3175 Côte-Sainte-Catherine, Montréal, Québec, H3T 1C5, Canada.; Yazdanpanah N; Research Center of the Sainte-Justine University Hospital, Université de Montréal, 3175 Côte-Sainte-Catherine, Montréal, Québec, H3T 1C5, Canada.; Gamache I; Research Center of the Sainte-Justine University Hospital, Université de Montréal, 3175 Côte-Sainte-Catherine, Montréal, Québec, H3T 1C5, Canada.; Ong K; MRC Epidemiology Unit, School of Clinical Medicine, Wellcome-MRC Institute of Metabolic Science, University of Cambridge, Cambridge, CB2 0QQ, UK.; Perry JRB; MRC Epidemiology Unit, School of Clinical Medicine, Wellcome-MRC Institute of Metabolic Science, University of Cambridge, Cambridge, CB2 0QQ, UK.; Metabolic Research Laboratory, School of Clinical Medicine, Wellcome-MRC Institute of Metabolic Science, University of Cambridge, Cambridge, CB2 0QQ, UK.; Manousaki D; Research Center of the Sainte-Justine University Hospital, Université de Montréal, 3175 Côte-Sainte-Catherine, Montréal, Québec, H3T 1C5, Canada. despina.manousaki@umontreal.ca.; Departments of Pediatrics, Biochemistry and Molecular Medicine, Université de Montréal, Montreal, Canada. despina.manousaki@umontreal.ca.
Source
Publisher: BioMed Central Country of Publication: England NLM ID: 101475844 Publication Model: Electronic Cited Medium: Internet ISSN: 1756-994X (Electronic) Linking ISSN: 1756994X NLM ISO Abbreviation: Genome Med Subsets: MEDLINE
Subject
Language
English
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.
(© 2024. The Author(s).)
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.
(© 2024. The Author(s).)