Genetic insights into biological mechanisms governing human ovarian ageing
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 natura...
| Main Authors: | , , , , , , , , , |
|---|---|
| Format: | Journal article |
| Language: | English |
| Published: |
Springer Nature
2021
|
| _version_ | 1826266822314295296 |
|---|---|
| author | Ruth, KS Day, FR Hussain, J Walters, R Lin, K Kartsonaki, C Hunter, D Chen, Z Perry, JRB et al |
| author_facet | Ruth, KS Day, FR Hussain, J Walters, R Lin, K Kartsonaki, C Hunter, D Chen, Z Perry, JRB et al |
| author_sort | Ruth, KS |
| collection | OXFORD |
| description | 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. |
| first_indexed | 2024-03-06T20:44:47Z |
| format | Journal article |
| id | oxford-uuid:358397d8-2631-4df3-ab63-97fb2860a50d |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-06T20:44:47Z |
| publishDate | 2021 |
| publisher | Springer Nature |
| record_format | dspace |
| spelling | oxford-uuid:358397d8-2631-4df3-ab63-97fb2860a50d2022-03-26T13:32:28ZGenetic insights into biological mechanisms governing human ovarian ageingJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:358397d8-2631-4df3-ab63-97fb2860a50dEnglishSymplectic ElementsSpringer Nature2021Ruth, KSDay, FRHussain, JWalters, RLin, KKartsonaki, CHunter, DChen, ZPerry, JRBet alReproductive 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. |
| spellingShingle | Ruth, KS Day, FR Hussain, J Walters, R Lin, K Kartsonaki, C Hunter, D Chen, Z Perry, JRB et al Genetic insights into biological mechanisms governing human ovarian ageing |
| title | Genetic insights into biological mechanisms governing human ovarian ageing |
| title_full | Genetic insights into biological mechanisms governing human ovarian ageing |
| title_fullStr | Genetic insights into biological mechanisms governing human ovarian ageing |
| title_full_unstemmed | Genetic insights into biological mechanisms governing human ovarian ageing |
| title_short | Genetic insights into biological mechanisms governing human ovarian ageing |
| title_sort | genetic insights into biological mechanisms governing human ovarian ageing |
| work_keys_str_mv | AT ruthks geneticinsightsintobiologicalmechanismsgoverninghumanovarianageing AT dayfr geneticinsightsintobiologicalmechanismsgoverninghumanovarianageing AT hussainj geneticinsightsintobiologicalmechanismsgoverninghumanovarianageing AT waltersr geneticinsightsintobiologicalmechanismsgoverninghumanovarianageing AT link geneticinsightsintobiologicalmechanismsgoverninghumanovarianageing AT kartsonakic geneticinsightsintobiologicalmechanismsgoverninghumanovarianageing AT hunterd geneticinsightsintobiologicalmechanismsgoverninghumanovarianageing AT chenz geneticinsightsintobiologicalmechanismsgoverninghumanovarianageing AT perryjrb geneticinsightsintobiologicalmechanismsgoverninghumanovarianageing AT etal geneticinsightsintobiologicalmechanismsgoverninghumanovarianageing |