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Hum Mol Genet. 2019 Apr 15;28(8):1392-1401. doi: 10.1093/hmg/ddz015.

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.

Author information

1
Genetics of Complex Traits, University of Exeter Medical School, University of Exeter, Exeter, UK.
2
MRC Integrative Epidemiology Unit at the University of Bristol, Bristol, UK.
3
Population Health Science, Bristol Medical School, University of Bristol, Bristol, UK.
4
Department of Epidemiology, Harvard T.H. Chan School of Public Health, and Channing Division of Network Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
5
Department of Biostatistics and Epidemiology, School of Public Health and Health Sciences, University of Massachusetts, Amherst, MA, USA.
6
Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK.
7
Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
8
Department of Epidemiology, University of North Carolina, Chapel Hill, NC, USA.
9
Epidemiology Branch, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA.
10
Epigenetic and Stem Cell Biology Laboratory, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, NC, USA.
11
Department of Population Health and Perlmutter Cancer Center, New York University School of Medicine, New York, NY, USA.
12
National Institute for Health Research Bristol Biomedical Research Centre, University Hospitals Bristol NHS Foundation Trust and University of Bristol, Bristol, UK.
13
Division of Breast Cancer Research, The Institute of Cancer Research, London, UK.

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.

PMID:
30649302
PMCID:
PMC6452199
[Available on 2020-04-15]
DOI:
10.1093/hmg/ddz015
[Indexed for MEDLINE]

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