Fetal sex-specific epigenetic associations with prenatal maternal depressive symptoms
Michelle Z.L. Kee,
Ai Ling Teh,
Andrew Clappison,
Irina Pokhvisneva,
Julie L. MacIssac,
David T.S. Lin,
Katia E. Ramadori,
Birit F.P. Broekman,
Helen Chen,
Mary Lourdes Daniel,
Neerja Karnani,
Michael S. Kobor,
Peter D. Gluckman,
Yap Seng Chong,
Jonathan Y. Huang,
Michael J. Meaney
Affiliations
Michelle Z.L. Kee
Translation Neuroscience, Singapore Institute for Clinical Sciences, A∗STAR, Singapore 117609, Singapore; Corresponding author
Ai Ling Teh
Bioinformatics, Singapore Institute for Clinical Sciences, A∗STAR, Singapore 117609, Singapore
Andrew Clappison
Department of Psychiatry, Douglas Mental Health University Institute, McGill University, Montreal, QC H4H 1R3, Canada
Irina Pokhvisneva
Department of Psychiatry, Douglas Mental Health University Institute, McGill University, Montreal, QC H4H 1R3, Canada
Julie L. MacIssac
Centre for Molecular Medicine and Therapeutics, BC Children’s Hospital Research Institute, Department of Medical Genetics, University of British Columbia, Vancouver, BC V5Z 4H4, Canada
David T.S. Lin
Centre for Molecular Medicine and Therapeutics, BC Children’s Hospital Research Institute, Department of Medical Genetics, University of British Columbia, Vancouver, BC V5Z 4H4, Canada
Katia E. Ramadori
Centre for Molecular Medicine and Therapeutics, BC Children’s Hospital Research Institute, Department of Medical Genetics, University of British Columbia, Vancouver, BC V5Z 4H4, Canada
Birit F.P. Broekman
Translation Neuroscience, Singapore Institute for Clinical Sciences, A∗STAR, Singapore 117609, Singapore; Department of Psychiatry, Amsterdam UMC and OLVG, VU University, 1007 Amsterdam, the Netherlands
Helen Chen
Department of Psychological Medicine (Mental Wellness Service), KK Women’s and Children’s Hospital, Singapore 229899, Singapore
Mary Lourdes Daniel
Department of Child Development, KK Women’s and Children’s Hospital, Singapore 229899, Singapore
Neerja Karnani
Translation Neuroscience, Singapore Institute for Clinical Sciences, A∗STAR, Singapore 117609, Singapore
Michael S. Kobor
Centre for Molecular Medicine and Therapeutics, BC Children’s Hospital Research Institute, Department of Medical Genetics, University of British Columbia, Vancouver, BC V5Z 4H4, Canada
Peter D. Gluckman
Translation Neuroscience, Singapore Institute for Clinical Sciences, A∗STAR, Singapore 117609, Singapore; Centre for Human Evolution, Adaptation and Disease, Liggins Institute, University of Auckland, Auckland 1142, New Zealand
Yap Seng Chong
Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228, Singapore
Jonathan Y. Huang
Translation Neuroscience, Singapore Institute for Clinical Sciences, A∗STAR, Singapore 117609, Singapore; Centre for Quantitative Medicine, Health Services and System Research Signature Research Programme, Duke-NUS Medical School, Singapore 169857, Singapore
Michael J. Meaney
Translation Neuroscience, Singapore Institute for Clinical Sciences, A∗STAR, Singapore 117609, Singapore; Bioinformatics, Singapore Institute for Clinical Sciences, A∗STAR, Singapore 117609, Singapore; Department of Pediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228, Singapore
Summary: Prenatal maternal mental health is a global health challenge with poorly defined biological mechanisms. We used maternal blood samples collected during the second trimester from a Singaporean longitudinal birth cohort study to examine the association between inter-individual genome-wide DNA methylation and prenatal maternal depressive symptoms. We found that (1) the maternal methylome was significantly associated with prenatal maternal depressive symptoms only in mothers with a female fetus; and (2) this sex-dependent association was observed in a comparable, UK-based birth cohort study. Qualitative analyses showed fetal sex-specific differences in genomic features of depression-related CpGs and genes mapped from these CpGs in mothers with female fetuses implicated in a depression-associated WNT/β-catenin signaling pathway. These same genes also showed enriched expression in brain regions linked to major depressive disorder. We also found similar female-specific associations with fetal-facing placenta methylome. Our fetal sex-specific findings provide evidence for maternal-fetal interactions as a mechanism for intergenerational transmission.
