Reproductive longevity is essential for fertility and influences healthy ageing in women(1,2), but insights into its underlying biological mechanisms and treatments to preserve it are limited. Here... Show moreReproductive longevity is essential for fertility and influences healthy ageing in women(1,2), 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 in approximately 200,000 women of European ancestry. These common alleles were associated with clinical extremes of age at natural menopause; women in the top 1% of genetic susceptibility have an equivalent risk of premature ovarian insufficiency to those carrying monogenic FMR1 premutations(3). 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. Show less
We provide a new observational test for a key prediction of the ΛCDM cosmological model: the contributions of mergers with different halo-to-main-cluster mass ratios to cluster-sized halo growth.... Show moreWe provide a new observational test for a key prediction of the ΛCDM cosmological model: the contributions of mergers with different halo-to-main-cluster mass ratios to cluster-sized halo growth. We perform this test by dynamically analyzing 7 galaxy clusters, spanning the redshift range 0.13 < z c < 0.45 and caustic mass range 0.4-1.5 $10^{15}, h_{0.73}^{-1}$ M ☉, with an average of 293 spectroscopically confirmed bound galaxies to each cluster. The large radial coverage (a few virial radii), which covers the whole infall region, with a high number of spectroscopically identified galaxies enables this new study. For each cluster, we identify bound galaxies. Out of these galaxies, we identify infalling and accreted halos and estimate their masses and their dynamical states. Using the estimated masses, we derive the contribution of different mass ratios to cluster-sized halo growth. For mass ratios between ~0.2 and ~0.7, we find a ~1σ agreement with ΛCDM expectations based on the Millennium simulations I and II. At low mass ratios, lesssim 0.2, our derived contribution is underestimated since the detection efficiency decreases at low masses, ~2 × 1014 $h_{0.73}^{-1}$ M ☉. At large mass ratios, gsim 0.7, we do not detect halos probably because our sample, which was chosen to be quite X-ray relaxed, is biased against large mass ratios. Therefore, at large mass ratios, the derived contribution is also underestimated. Show less
