---
_id: '14258'
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.
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.
article_processing_charge: Yes (via OA deal)
article_type: original
author:
- first_name: Sven E.
  full_name: Ojavee, Sven E.
  last_name: Ojavee
- first_name: Liza
  full_name: Darrous, Liza
  last_name: Darrous
- first_name: Marion
  full_name: Patxot, Marion
  last_name: Patxot
- first_name: Kristi
  full_name: Läll, Kristi
  last_name: Läll
- first_name: Krista
  full_name: Fischer, Krista
  last_name: Fischer
- first_name: Reedik
  full_name: Mägi, Reedik
  last_name: Mägi
- first_name: Zoltan
  full_name: Kutalik, Zoltan
  last_name: Kutalik
- first_name: Matthew Richard
  full_name: Robinson, Matthew Richard
  id: E5D42276-F5DA-11E9-8E24-6303E6697425
  last_name: Robinson
  orcid: 0000-0001-8982-8813
citation:
  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>
  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>
  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.
  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.
  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.
date_created: 2023-09-03T22:01:15Z
date_published: 2023-09-07T00:00:00Z
date_updated: 2024-01-30T13:21:05Z
day: '07'
ddc:
- '570'
department:
- _id: MaRo
doi: 10.1016/j.ajhg.2023.07.006
external_id:
  pmid:
  - '37543033'
file:
- access_level: open_access
  checksum: 4108b031dc726ae6b4a5ae7e021ba188
  content_type: application/pdf
  creator: dernst
  date_created: 2024-01-30T13:20:35Z
  date_updated: 2024-01-30T13:20:35Z
  file_id: '14912'
  file_name: 2023_AJHG_Ojavee.pdf
  file_size: 2551276
  relation: main_file
  success: 1
file_date_updated: 2024-01-30T13:20:35Z
has_accepted_license: '1'
intvolume: '       110'
issue: '9'
language:
- iso: eng
month: '09'
oa: 1
oa_version: Published Version
page: 1549-1563
pmid: 1
publication: American Journal of Human Genetics
publication_identifier:
  eissn:
  - 1537-6605
  issn:
  - 0002-9297
publication_status: published
publisher: Elsevier
quality_controlled: '1'
scopus_import: '1'
status: public
title: Genetic insights into the age-specific biological mechanisms governing human
  ovarian aging
tmp:
  image: /images/cc_by.png
  legal_code_url: https://creativecommons.org/licenses/by/4.0/legalcode
  name: Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)
  short: CC BY (4.0)
type: journal_article
user_id: 2DF688A6-F248-11E8-B48F-1D18A9856A87
volume: 110
year: '2023'
...