Genome-wide association study of anti-Müllerian hormone levels in pre-menopausal women of late reproductive age and relationship with genetic determinants of reproductive lifespan

Kate S Ruth, Ana Goncalves Soares, Carolina Borges, A. Heather Eliassen, Susan E. Hankinson, Michael E. Jones, Peter Kraft, Hazel B. Nichols, Dale P. Sandler, Minouk J. Schoemaker, Jack A. Taylor, Anne Zeleniuch-Jacquotte, Debbie Lawlor, Anthony J. Swerdlow, Anna Murray

Research output: Contribution to journalArticle (Academic Journal)peer-review

4 Citations (Scopus)
111 Downloads (Pure)

Abstract

Anti-Müllerian hormone (AMH) is required for sexual differentiation in the fetus, and in adult females AMH is produced by growing ovarian follicles. Consequently, AMH levels are correlated with ovarian reserve, declining towards menopause when the oocyte pool is exhausted. A previous genome-wide association study identified three genetic variants in and around the AMH gene that explained 25% of variation in AMH levels in adolescent males but did not identify any genetic associations reaching genome-wide significance in adolescent females. To explore the role of genetic variation in determining AMH levels in women of late reproductive age, we carried out a genome-wide meta-analysis in 3344 pre-menopausal women from five cohorts (median age 44-48 years at blood draw). A single genetic variant, rs16991615, previously associated with age at menopause, reached genome-wide significance at P = 3.48 × 10-10, with a per allele difference in age-adjusted inverse normal AMH of 0.26 standard deviations (SD) (95% confidence interval (CI) [0.18,0.34]). We investigated whether genetic determinants of female reproductive lifespan were more generally associated with pre-menopausal AMH levels. Genetically-predicted age at menarche had no robust association but genetically-predicted age at menopause was associated with lower AMH levels by 0.18 SD (95% CI [0.14,0.21]) in age-adjusted inverse normal AMH per one-year earlier age at menopause. Our findings provide genetic support for the well-established use of AMH as a marker of ovarian reserve.

Original languageEnglish
Pages (from-to)1392-1401
Number of pages10
JournalHuman Molecular Genetics
Volume28
Issue number8
Early online date14 Jan 2019
DOIs
Publication statusPublished - 15 Apr 2019

Bibliographical note

© The Author(s) 2019. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Keywords

  • alles
  • menopause
  • adolescent
  • hormones
  • adult
  • fetus
  • genes
  • genome
  • menarche
  • oocytes
  • ovarian follicle
  • phlebotomy
  • reproductive physiological process
  • sex differentiation
  • genetics
  • mullerian-inhibiting hormone
  • genome-wide association study
  • life span
  • ovarian research

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