Genetic insights into biological mechanisms governing human ovarian ageing.
Ruth KS, Day FR, Hussain J et al.
Publication Details
Comprehensive information about this research publication
Authors
Abstract
Summary of the research findings
Reproductive longevity is essential for fertility and influences healthy ageing in women1,2, but insights into its underlying biological mechanisms and treatments to preserve it are limited. Here we identify 290 genetic determinants of ovarian ageing, assessed using normal variation in age at natural menopause (ANM) in about 200,000 women of European ancestry. These common alleles were associated with clinical extremes of ANM; women in the top 1% of genetic susceptibility have an equivalent risk of premature ovarian insufficiency to those carrying monogenic FMR1 premutations3. The identified loci implicate a broad range of DNA damage response (DDR) processes and include loss-of-function variants in key DDR-associated genes. Integration with experimental models demonstrates that these DDR processes act across the life-course to shape the ovarian reserve and its rate of depletion. Furthermore, we demonstrate that experimental manipulation of DDR pathways highlighted by human genetics increases fertility and extends reproductive life in mice. Causal inference analyses using the identified genetic variants indicate that extending reproductive life in women improves bone health and reduces risk of type 2 diabetes, but increases the risk of hormone-sensitive cancers. These findings provide insight into the mechanisms that govern ovarian ageing, when they act, and how they might be targeted by therapeutic approaches to extend fertility and prevent disease.
201,323 European ancestry individuals
Study Statistics
Key metrics and study information
Analysis
Comprehensive review of health and genetic findings
Important Disclaimer: This review has been performed semi-automatically and is provided for informational purposes only. While we strive for accuracy, this analysis may contain errors, omissions, or misinterpretations of the original research. DNA Genics disclaims all liability for any inaccuracies, errors, or consequences arising from the use of this information. Users should independently verify all information and consult original research publications before making any decisions based on this content. This analysis is not intended as a substitute for professional scientific review or medical advice.
Analysis In Progress
Our analysis of this publication is currently being prepared. Please check back soon for comprehensive insights into the health and genetic findings discussed in this research.
Summary
Key Findings
Health Insights
Disease Analysis
Genetic Trait Analysis
Clinical Relevance
Scientific Assessment
Related Publications
Other publications that may be of interest
A saturated map of common genetic variants associated with human height.
Yengo L
Nature
Height
GWAS and meta-analysis identifies 49 genetic variants underlying critical COVID-19.
Pairo-Castineira E
Nature
COVID-19 (critical illness vs population)
Genetic diversity fuels gene discovery for tobacco and alcohol use.
Saunders GRB
Nature
Smoking initiation
Genetic drivers of heterogeneity in type 2 diabetes pathophysiology.
Suzuki K
Nature
Type 2 diabetes
Locus for severity implicates CNS resilience in progression of multiple sclerosis.
International Multiple Sclerosis Genetics Consortium
Nature
Age-related multiple sclerosis severity score
Explore More Research
Discover the latest findings in health and genetic research