{"_id":"14258","acknowledgement":"This project was funded by an SNSF Eccellenza grant to M.R.R. (PCEGP3-181181) and by core funding from the Institute of Science and Technology Austria. K.L. and R.M. were supported by the Estonian Research Council grant 1911. Estonian Biobank computations were performed in the High-Performance Computing Center, University of Tartu. We thank Triin Laisk for her valuable insights and comments that helped greatly. We would like to acknowledge the participants and investigators of UK Biobank and Estonian Biobank studies. This project uses UK Biobank data under project number 35520.","publisher":"Elsevier","oa":1,"scopus_import":"1","page":"1549-1563","intvolume":"       110","external_id":{"pmid":["37543033"]},"publication":"American Journal of Human Genetics","date_published":"2023-09-07T00:00:00Z","oa_version":"Published Version","tmp":{"image":"/images/cc_by.png","short":"CC BY (4.0)","legal_code_url":"https://creativecommons.org/licenses/by/4.0/legalcode","name":"Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)"},"date_updated":"2024-01-30T13:21:05Z","article_processing_charge":"Yes (via OA deal)","has_accepted_license":"1","date_created":"2023-09-03T22:01:15Z","user_id":"2DF688A6-F248-11E8-B48F-1D18A9856A87","volume":110,"publication_status":"published","quality_controlled":"1","day":"07","ddc":["570"],"doi":"10.1016/j.ajhg.2023.07.006","language":[{"iso":"eng"}],"file":[{"success":1,"file_name":"2023_AJHG_Ojavee.pdf","date_updated":"2024-01-30T13:20:35Z","file_size":2551276,"file_id":"14912","date_created":"2024-01-30T13:20:35Z","checksum":"4108b031dc726ae6b4a5ae7e021ba188","creator":"dernst","access_level":"open_access","relation":"main_file","content_type":"application/pdf"}],"author":[{"last_name":"Ojavee","full_name":"Ojavee, Sven E.","first_name":"Sven E."},{"last_name":"Darrous","full_name":"Darrous, Liza","first_name":"Liza"},{"full_name":"Patxot, Marion","last_name":"Patxot","first_name":"Marion"},{"full_name":"Läll, Kristi","last_name":"Läll","first_name":"Kristi"},{"first_name":"Krista","full_name":"Fischer, Krista","last_name":"Fischer"},{"last_name":"Mägi","full_name":"Mägi, Reedik","first_name":"Reedik"},{"first_name":"Zoltan","last_name":"Kutalik","full_name":"Kutalik, Zoltan"},{"orcid":"0000-0001-8982-8813","last_name":"Robinson","full_name":"Robinson, Matthew Richard","first_name":"Matthew Richard","id":"E5D42276-F5DA-11E9-8E24-6303E6697425"}],"article_type":"original","month":"09","publication_identifier":{"issn":["0002-9297"],"eissn":["1537-6605"]},"status":"public","abstract":[{"lang":"eng","text":"There is currently little evidence that the genetic basis of human phenotype varies significantly across the lifespan. However, time-to-event phenotypes are understudied and can be thought of as reflecting an underlying hazard, which is unlikely to be constant through life when values take a broad range. Here, we find that 74% of 245 genome-wide significant genetic associations with age at natural menopause (ANM) in the UK Biobank show a form of age-specific effect. Nineteen of these replicated discoveries are identified only by our modeling framework, which determines the time dependency of DNA-variant age-at-onset associations without a significant multiple-testing burden. Across the range of early to late menopause, we find evidence for significantly different underlying biological pathways, changes in the signs of genetic correlations of ANM to health indicators and outcomes, and differences in inferred causal relationships. We find that DNA damage response processes only act to shape ovarian reserve and depletion for women of early ANM. Genetically mediated delays in ANM were associated with increased relative risk of breast cancer and leiomyoma at all ages and with high cholesterol and heart failure for late-ANM women. These findings suggest that a better understanding of the age dependency of genetic risk factor relationships among health indicators and outcomes is achievable through appropriate statistical modeling of large-scale biobank data."}],"issue":"9","year":"2023","citation":{"apa":"Ojavee, S. E., Darrous, L., Patxot, M., Läll, K., Fischer, K., Mägi, R., … Robinson, M. R. (2023). Genetic insights into the age-specific biological mechanisms governing human ovarian aging. <i>American Journal of Human Genetics</i>. Elsevier. <a href=\"https://doi.org/10.1016/j.ajhg.2023.07.006\">https://doi.org/10.1016/j.ajhg.2023.07.006</a>","ista":"Ojavee SE, Darrous L, Patxot M, Läll K, Fischer K, Mägi R, Kutalik Z, Robinson MR. 2023. Genetic insights into the age-specific biological mechanisms governing human ovarian aging. American Journal of Human Genetics. 110(9), 1549–1563.","ama":"Ojavee SE, Darrous L, Patxot M, et al. Genetic insights into the age-specific biological mechanisms governing human ovarian aging. <i>American Journal of Human Genetics</i>. 2023;110(9):1549-1563. doi:<a href=\"https://doi.org/10.1016/j.ajhg.2023.07.006\">10.1016/j.ajhg.2023.07.006</a>","chicago":"Ojavee, Sven E., Liza Darrous, Marion Patxot, Kristi Läll, Krista Fischer, Reedik Mägi, Zoltan Kutalik, and Matthew Richard Robinson. “Genetic Insights into the Age-Specific Biological Mechanisms Governing Human Ovarian Aging.” <i>American Journal of Human Genetics</i>. Elsevier, 2023. <a href=\"https://doi.org/10.1016/j.ajhg.2023.07.006\">https://doi.org/10.1016/j.ajhg.2023.07.006</a>.","ieee":"S. E. Ojavee <i>et al.</i>, “Genetic insights into the age-specific biological mechanisms governing human ovarian aging,” <i>American Journal of Human Genetics</i>, vol. 110, no. 9. Elsevier, pp. 1549–1563, 2023.","mla":"Ojavee, Sven E., et al. “Genetic Insights into the Age-Specific Biological Mechanisms Governing Human Ovarian Aging.” <i>American Journal of Human Genetics</i>, vol. 110, no. 9, Elsevier, 2023, pp. 1549–63, doi:<a href=\"https://doi.org/10.1016/j.ajhg.2023.07.006\">10.1016/j.ajhg.2023.07.006</a>.","short":"S.E. Ojavee, L. Darrous, M. Patxot, K. Läll, K. Fischer, R. Mägi, Z. Kutalik, M.R. Robinson, American Journal of Human Genetics 110 (2023) 1549–1563."},"title":"Genetic insights into the age-specific biological mechanisms governing human ovarian aging","license":"https://creativecommons.org/licenses/by/4.0/","pmid":1,"file_date_updated":"2024-01-30T13:20:35Z","type":"journal_article","department":[{"_id":"MaRo"}]}