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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

View ORCID ProfileKatherine S. Ruth, Ana Luiza G. Soares, Maria-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, Deborah A. Lawlor, Anthony J. Swerdlow, Anna Murray
doi: https://doi.org/10.1101/487181
Katherine S. Ruth
1Genetics of Complex Traits, University of Exeter Medical School, University of Exeter, Exeter, UK.
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Ana Luiza G. Soares
2MRC Integrative Epidemiology Unit at the University of Bristol, Bristol, UK.
3Population Health Science, Bristol Medical School, University of Bristol, Bristol, UK.
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Maria-Carolina Borges
2MRC Integrative Epidemiology Unit at the University of Bristol, Bristol, UK.
3Population Health Science, Bristol Medical School, University of Bristol, Bristol, UK.
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A. Heather Eliassen
4Department 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.
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Susan E. Hankinson
4Department 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.
5Department of Biostatistics and Epidemiology, School of Public Health and Health Sciences, University of Massachusetts, Amherst, MA, USA.
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Michael E. Jones
6Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK.
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Peter Kraft
7Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
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Hazel B. Nichols
8Department of Epidemiology, University of North Carolina, Chapel Hill, NC, USA.
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Dale P. Sandler
9Epidemiology Branch, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA.
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Minouk J. Schoemaker
6Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK.
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Jack A. Taylor
10Epigenetic and Stem Cell Biology Laboratory, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, NC, USA.
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Anne Zeleniuch-Jacquotte
11Department of Population Health and Perlmutter Cancer Center, New York University School of Medicine, New York, NY, USA.
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Deborah A. Lawlor
2MRC Integrative Epidemiology Unit at the University of Bristol, Bristol, UK.
3Population Health Science, Bristol Medical School, University of Bristol, Bristol, UK.
12National Institute for Health Research Bristol Biomedical Research Centre, University Hospitals Bristol NHS Foundation Trust and University of Bristol, Bristol, UK.
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Anthony J. Swerdlow
6Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK.
13Division of Breast Cancer Research, The Institute of Cancer Research, London, UK.
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Anna Murray
1Genetics of Complex Traits, University of Exeter Medical School, University of Exeter, Exeter, UK.
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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 3,344 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 SD (95% 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 support the hypothesis that AMH is a valid measure of ovarian reserve in pre-menopausal women and suggest that the underlying biology of ovarian reserve results in a causal link between pre-menopausal AMH levels and menopause timing.

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Posted December 04, 2018.
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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
Katherine S. Ruth, Ana Luiza G. Soares, Maria-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, Deborah A. Lawlor, Anthony J. Swerdlow, Anna Murray
bioRxiv 487181; doi: https://doi.org/10.1101/487181
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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
Katherine S. Ruth, Ana Luiza G. Soares, Maria-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, Deborah A. Lawlor, Anthony J. Swerdlow, Anna Murray
bioRxiv 487181; doi: https://doi.org/10.1101/487181

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