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Placenta DNA methylation at ZNF300 is associated with fetal sex and placental morphology

Christine Ladd-Acosta, Shan V. Andrews, Kelly M. Bakulski, Jason I. Feinberg, Rakel Tryggvadottir, Ruofan Yao, Lisa A. Croen, Irva Hertz-Picciotto, Craig J. Newschaffer, Carolyn M. Salafia, Andrew P. Feinberg, Kasper D. Hansen, M. Daniele Fallin
doi: https://doi.org/10.1101/2021.03.05.433992
Christine Ladd-Acosta
1Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, 615 N. Wolfe Street, Baltimore, MD 21205, USA
2Wendy Klag Center for Autism and Developmental Disabilities, Johns Hopkins Bloomberg School of Public Health, 615 N. Wolfe Street, Baltimore, MD 21205, USA
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  • For correspondence: claddac1@jh.edu
Shan V. Andrews
1Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, 615 N. Wolfe Street, Baltimore, MD 21205, USA
2Wendy Klag Center for Autism and Developmental Disabilities, Johns Hopkins Bloomberg School of Public Health, 615 N. Wolfe Street, Baltimore, MD 21205, USA
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Kelly M. Bakulski
3Department of Epidemiology, University of Michigan School of Public Health, 1415 Washington Heights, Ann Arbor, MI 48109, USA
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Jason I. Feinberg
2Wendy Klag Center for Autism and Developmental Disabilities, Johns Hopkins Bloomberg School of Public Health, 615 N. Wolfe Street, Baltimore, MD 21205, USA
4Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, 624 N. Broadway, Baltimore, MD, 21205, USA
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Rakel Tryggvadottir
5Center for Epigenetics, Institute for Basic Biomedical Sciences, Johns Hopkins School of Medicine, 733 N. Broadway, Baltimore, MD 21205, USA
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Ruofan Yao
6Department of Obstetrics and Gynecology, Loma Linda University School of Medicine, 11234 Anderson St, Loma Linda, CA 92354, USA
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Lisa A. Croen
7Division of Research, Kaiser Permanente Northern California, 2000 Broadway, Oakland, CA 94612, USA
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Irva Hertz-Picciotto
8Department of Public Health Sciences, School of Medicine, University of California Davis, 4610 X St, Sacramento, CA 95817, USA
9MIND Institute, University of California Davis, 2825 50th St, Sacramento, CA 95817, USA
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Craig J. Newschaffer
10AJ Drexel Autism Institute, Drexel University, 3020 Market St #560, Philadelphia, PA 19104, USA. Present address: The Pennsylvania State University, College of Health and Human Development, 325 Health and Human Development Building, University Park, PA, 16802, USA
11Department of Epidemiology and Biostatistics, Drexel University Dornsife School of Public Health, 3125 Market St, Philadelphia, PA 19104, USA
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Carolyn M. Salafia
12Placental Analytics LLC, 187 Overlook Circle, New Rochelle, NY 10984, USA
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Andrew P. Feinberg
4Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, 624 N. Broadway, Baltimore, MD, 21205, USA
5Center for Epigenetics, Institute for Basic Biomedical Sciences, Johns Hopkins School of Medicine, 733 N. Broadway, Baltimore, MD 21205, USA
13Department of Medicine, Johns Hopkins School of Medicine, 733 N. Broadway, Baltimore, MD 21205, USA
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Kasper D. Hansen
14Department of Genomic Medicine, Johns Hopkins School of Medicine, 733 N. Broadway, Baltimore, MD 21205, USA
15Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, 615 N. Wolfe Street, Baltimore, MD 21205, USA
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M. Daniele Fallin
2Wendy Klag Center for Autism and Developmental Disabilities, Johns Hopkins Bloomberg School of Public Health, 615 N. Wolfe Street, Baltimore, MD 21205, USA
4Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, 624 N. Broadway, Baltimore, MD, 21205, USA
5Center for Epigenetics, Institute for Basic Biomedical Sciences, Johns Hopkins School of Medicine, 733 N. Broadway, Baltimore, MD 21205, USA
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Abstract

Fetal sex-specific differences in placental morphology and physiology have been associated with sexually dimorphic health outcomes. However, the molecular mechanisms underlying these sex differences are not well understood. We performed whole genome bisulfite sequencing in 133 placenta samples and discovered a significant difference in DNA methylation (DNAm) at the ZNF300 gene locus between male and female offspring and replicated this result in 6 independent datasets. Additionally, the sex-specific pattern appears to be placenta-specific, is robust to a wide range of gestational ages and adverse health outcomes and is present in sorted placenta villous cytotrophoblast cells. Integration of DNAm, genetic, and placental morphology data from the same individuals revealed ZNF300 methylation is also associated with placenta area, perimeter, and max diameter, genetic variants on chromosomes 5 and X, and may mediate the effects of genetic variation on placental area.

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • ↵‡ These authors contributed equally

  • Revised abstract.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted March 08, 2021.
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Placenta DNA methylation at ZNF300 is associated with fetal sex and placental morphology
Christine Ladd-Acosta, Shan V. Andrews, Kelly M. Bakulski, Jason I. Feinberg, Rakel Tryggvadottir, Ruofan Yao, Lisa A. Croen, Irva Hertz-Picciotto, Craig J. Newschaffer, Carolyn M. Salafia, Andrew P. Feinberg, Kasper D. Hansen, M. Daniele Fallin
bioRxiv 2021.03.05.433992; doi: https://doi.org/10.1101/2021.03.05.433992
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Placenta DNA methylation at ZNF300 is associated with fetal sex and placental morphology
Christine Ladd-Acosta, Shan V. Andrews, Kelly M. Bakulski, Jason I. Feinberg, Rakel Tryggvadottir, Ruofan Yao, Lisa A. Croen, Irva Hertz-Picciotto, Craig J. Newschaffer, Carolyn M. Salafia, Andrew P. Feinberg, Kasper D. Hansen, M. Daniele Fallin
bioRxiv 2021.03.05.433992; doi: https://doi.org/10.1101/2021.03.05.433992

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