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Genetic insights into the biological mechanisms governing human ovarian ageing

ABSTRACT: Reproductive longevity is critical for fertility and impacts healthy ageing in women, yet insights into the 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 ~200,000 women of European ancestry. These common alleles influence 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 premutations. Identified loci implicate a broad range of DNA damage response (DDR) processes and include loss-of-function variants in key DDR 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 increase fertility and extend reproductive life in mice. Causal inference analyses using the identified genetic variants indicates that extending reproductive life in women improves bone health and reduces risk of type 2 diabetes, but increases risks of hormone-sensitive cancers. These findings provide insight into the mechanisms governing ovarian ageing, when they act across the life-course, and how they might be targeted by therapeutic approaches to extend fertility and prevent disease.

PROVIDER: EGAS00001004947 | EGA |

REPOSITORIES: EGA

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Project description:Our modern era is witnessing an increasing infertility rate worldwide. Although some of the causes can be attributed to our modern lifestyle (eg. persistent organic polluants, late pregnancy), our knowledge of the human ovarian tissue has remained limited and insufficient to reverse the infertility statistics. Indeed, all efforts have been focused on the endocrine and cellular function in support of the cell theory that dates back to the 18th century, while the human ovarian matrisome is still under-described. Therefore, hereby we provide the first systematic study focusing on the human ovarian matrisome and its remodeling during a woman lifetime, from prepuberty til menopause. We apply our matrisome tailored fractionation method, the DC-MaP strategy and mass spectrometry-based quantitative proteomics using TMT pro 16-plex isobaric labeling to delineate proteome-wide and ECM-specific shifts between prepubertal, reproductive-age and menopausal stages. Post-translational modifications, namely proline hydroxylation and advanced glycation ends products have also been detected at different intensities according to age. Matrisome age-biomarkers have been validated with lightsheet microscopy-based-3D imaging, following immunofluorescence and tissue clearing with an ovary-tailored protocol. We used machine learning and statistics to build a neural network that can predict predict the probability of a specific ovarian tissue matrisome to resemble to prepubertal, reproductive-age or menopausal tissue and potentially conclude its fertility potency or evaluate in the future the efficiency of ovarian rejuvenation treatments. We also used NLP medscan technology for advanced literature text-mining to predict all possible-connections between the extra- and intra-cellular compartments and how chemo-radiotherapy, known for its gonadotoxicity can also affect key matrisome proteins.This comprehensive proteomics analysis represents the ovarian proteomic codex and contributes to an improved understanding of the critical roles that ECM plays throughout ovarian life span. By publishing our proteomic data, we hope to open new avenues in fertility restoration, ovarian rejuvenation and reproductive tissue engineering

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Genetic insights into the biological mechanisms governing human ovarian ageing

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