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Published Online: 31 October 2014

COMT Haplotypes Modulate Associations of Antenatal Maternal Anxiety and Neonatal Cortical Morphology

Anqi Qiu, Ph.D., Ta Anh Tuan, M.S., Mei Lyn Ong, Ph.D., Yue Li, B.S., Helen Chen, M.D., Anne Rifkin-Graboi, Ph.D., Birit F.P. Broekman, M.D., … Show All … , Kenneth Kwek, M.D., Seang-Mei Saw, Ph.D., Yap-Seng Chong, M.D., Peter D. Gluckman, Ph.D., Marielle V. Fortier, M.D., Joanna Dawn Holbrook, Ph.D., and Michael J. Meaney, Ph.D.Authors Info & Affiliations
Publication: American Journal of Psychiatry
Volume 172, Number 2
https://doi.org/10.1176/appi.ajp.2014.14030313
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Abstract

Objective:

Exposure to antenatal maternal anxiety and complex genetic variations may shape fetal brain development. In particular, the catechol-O-methyltransferase (COMT) gene, located on chromosome 22q11.2, regulates catecholamine signaling in the prefrontal cortex and is implicated in anxiety, pain, and stress responsivity. This study examined whether individual single-nucleotide polymorphisms (SNPs) of the COMT gene and their haplotypes moderate the association between antenatal maternal anxiety and in utero cortical development.

Method:

A total of 146 neonates were genotyped and underwent MRI shortly after birth. Neonatal cortical morphology was characterized using cortical thickness. Antenatal maternal anxiety was assessed using the State-Trait Anxiety Inventory at week 26 of pregnancy.

Results:

Individual COMT SNPs (val158met, rs737865, and rs165599) modulated the association between antenatal maternal anxiety and the prefrontal and parietal cortical thickness in neonates. Based on haplotype trend regression analysis, findings also showed that among rs737865-val158met-rs165599 haplotypes, the A-val-G (AGG) haplotype probabilities modulated positive associations of antenatal maternal anxiety with cortical thickness in the right ventrolateral prefrontal cortex and the right superior parietal cortex and precuneus. In contrast, the G-met-A (GAA) haplotype probabilities modulated negative associations of antenatal maternal anxiety with cortical thickness in bilateral precentral gyrus and the dorsolateral prefrontal cortex.

Conclusions:

These results suggest that the association between maternal anxiety and in utero neurodevelopment is modified through complex genetic variation in COMT. Such genetic moderation may explain, in part, the variation in phenotypic outcomes in offspring associated with maternal emotional well-being.

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Information & Authors

Information

Published In

Go to American Journal of Psychiatry
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American Journal of Psychiatry
Volume 172 • Number 2 • February 01, 2015
Pages: 163 - 172
PubMed: 25320962

History

Received: 10 March 2014
Revision received: 21 May 2014
Revision received: 8 July 2014
Accepted: 18 July 2014
Published ahead of print: 31 October 2014
Published online: 1 February 2015
Published in print: February 01, 2015

Authors

Details

Anqi Qiu, Ph.D.
From the Department of Biomedical Engineering and Clinical Imaging Research Center, National University of Singapore, Singapore; the Singapore Institute for Clinical Sciences, Singapore; the Department of Diagnostic and Interventional Imaging, KK Women’s and Children’s Hospital, Singapore; the Department of Obstetrics and Gynecology, Yong Loo Lin School of Medicine, National University of Singapore, National University Health System, Singapore; the Ludmer Centre for Neuroinformatics and Mental Health, Douglas Mental Health University Institute, McGill University, Montreal; the Sackler Program for Epigenetics and Psychobiology at McGill University, Montreal; the Department of Psychological Medicine, Yong Loo Lin School of Medicine, National University of Singapore, National University Health System, Singapore; the KK Women’s and Children’s Hospital, Singapore; and the Saw Swee Hock School of Public Health, National University of Singapore, Singapore.
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Ta Anh Tuan, M.S.
From the Department of Biomedical Engineering and Clinical Imaging Research Center, National University of Singapore, Singapore; the Singapore Institute for Clinical Sciences, Singapore; the Department of Diagnostic and Interventional Imaging, KK Women’s and Children’s Hospital, Singapore; the Department of Obstetrics and Gynecology, Yong Loo Lin School of Medicine, National University of Singapore, National University Health System, Singapore; the Ludmer Centre for Neuroinformatics and Mental Health, Douglas Mental Health University Institute, McGill University, Montreal; the Sackler Program for Epigenetics and Psychobiology at McGill University, Montreal; the Department of Psychological Medicine, Yong Loo Lin School of Medicine, National University of Singapore, National University Health System, Singapore; the KK Women’s and Children’s Hospital, Singapore; and the Saw Swee Hock School of Public Health, National University of Singapore, Singapore.
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Mei Lyn Ong, Ph.D.
From the Department of Biomedical Engineering and Clinical Imaging Research Center, National University of Singapore, Singapore; the Singapore Institute for Clinical Sciences, Singapore; the Department of Diagnostic and Interventional Imaging, KK Women’s and Children’s Hospital, Singapore; the Department of Obstetrics and Gynecology, Yong Loo Lin School of Medicine, National University of Singapore, National University Health System, Singapore; the Ludmer Centre for Neuroinformatics and Mental Health, Douglas Mental Health University Institute, McGill University, Montreal; the Sackler Program for Epigenetics and Psychobiology at McGill University, Montreal; the Department of Psychological Medicine, Yong Loo Lin School of Medicine, National University of Singapore, National University Health System, Singapore; the KK Women’s and Children’s Hospital, Singapore; and the Saw Swee Hock School of Public Health, National University of Singapore, Singapore.
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Yue Li, B.S.
From the Department of Biomedical Engineering and Clinical Imaging Research Center, National University of Singapore, Singapore; the Singapore Institute for Clinical Sciences, Singapore; the Department of Diagnostic and Interventional Imaging, KK Women’s and Children’s Hospital, Singapore; the Department of Obstetrics and Gynecology, Yong Loo Lin School of Medicine, National University of Singapore, National University Health System, Singapore; the Ludmer Centre for Neuroinformatics and Mental Health, Douglas Mental Health University Institute, McGill University, Montreal; the Sackler Program for Epigenetics and Psychobiology at McGill University, Montreal; the Department of Psychological Medicine, Yong Loo Lin School of Medicine, National University of Singapore, National University Health System, Singapore; the KK Women’s and Children’s Hospital, Singapore; and the Saw Swee Hock School of Public Health, National University of Singapore, Singapore.
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Helen Chen, M.D.
From the Department of Biomedical Engineering and Clinical Imaging Research Center, National University of Singapore, Singapore; the Singapore Institute for Clinical Sciences, Singapore; the Department of Diagnostic and Interventional Imaging, KK Women’s and Children’s Hospital, Singapore; the Department of Obstetrics and Gynecology, Yong Loo Lin School of Medicine, National University of Singapore, National University Health System, Singapore; the Ludmer Centre for Neuroinformatics and Mental Health, Douglas Mental Health University Institute, McGill University, Montreal; the Sackler Program for Epigenetics and Psychobiology at McGill University, Montreal; the Department of Psychological Medicine, Yong Loo Lin School of Medicine, National University of Singapore, National University Health System, Singapore; the KK Women’s and Children’s Hospital, Singapore; and the Saw Swee Hock School of Public Health, National University of Singapore, Singapore.
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Anne Rifkin-Graboi, Ph.D.
From the Department of Biomedical Engineering and Clinical Imaging Research Center, National University of Singapore, Singapore; the Singapore Institute for Clinical Sciences, Singapore; the Department of Diagnostic and Interventional Imaging, KK Women’s and Children’s Hospital, Singapore; the Department of Obstetrics and Gynecology, Yong Loo Lin School of Medicine, National University of Singapore, National University Health System, Singapore; the Ludmer Centre for Neuroinformatics and Mental Health, Douglas Mental Health University Institute, McGill University, Montreal; the Sackler Program for Epigenetics and Psychobiology at McGill University, Montreal; the Department of Psychological Medicine, Yong Loo Lin School of Medicine, National University of Singapore, National University Health System, Singapore; the KK Women’s and Children’s Hospital, Singapore; and the Saw Swee Hock School of Public Health, National University of Singapore, Singapore.
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Birit F.P. Broekman, M.D.
From the Department of Biomedical Engineering and Clinical Imaging Research Center, National University of Singapore, Singapore; the Singapore Institute for Clinical Sciences, Singapore; the Department of Diagnostic and Interventional Imaging, KK Women’s and Children’s Hospital, Singapore; the Department of Obstetrics and Gynecology, Yong Loo Lin School of Medicine, National University of Singapore, National University Health System, Singapore; the Ludmer Centre for Neuroinformatics and Mental Health, Douglas Mental Health University Institute, McGill University, Montreal; the Sackler Program for Epigenetics and Psychobiology at McGill University, Montreal; the Department of Psychological Medicine, Yong Loo Lin School of Medicine, National University of Singapore, National University Health System, Singapore; the KK Women’s and Children’s Hospital, Singapore; and the Saw Swee Hock School of Public Health, National University of Singapore, Singapore.
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Kenneth Kwek, M.D.
From the Department of Biomedical Engineering and Clinical Imaging Research Center, National University of Singapore, Singapore; the Singapore Institute for Clinical Sciences, Singapore; the Department of Diagnostic and Interventional Imaging, KK Women’s and Children’s Hospital, Singapore; the Department of Obstetrics and Gynecology, Yong Loo Lin School of Medicine, National University of Singapore, National University Health System, Singapore; the Ludmer Centre for Neuroinformatics and Mental Health, Douglas Mental Health University Institute, McGill University, Montreal; the Sackler Program for Epigenetics and Psychobiology at McGill University, Montreal; the Department of Psychological Medicine, Yong Loo Lin School of Medicine, National University of Singapore, National University Health System, Singapore; the KK Women’s and Children’s Hospital, Singapore; and the Saw Swee Hock School of Public Health, National University of Singapore, Singapore.
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Seang-Mei Saw, Ph.D.
From the Department of Biomedical Engineering and Clinical Imaging Research Center, National University of Singapore, Singapore; the Singapore Institute for Clinical Sciences, Singapore; the Department of Diagnostic and Interventional Imaging, KK Women’s and Children’s Hospital, Singapore; the Department of Obstetrics and Gynecology, Yong Loo Lin School of Medicine, National University of Singapore, National University Health System, Singapore; the Ludmer Centre for Neuroinformatics and Mental Health, Douglas Mental Health University Institute, McGill University, Montreal; the Sackler Program for Epigenetics and Psychobiology at McGill University, Montreal; the Department of Psychological Medicine, Yong Loo Lin School of Medicine, National University of Singapore, National University Health System, Singapore; the KK Women’s and Children’s Hospital, Singapore; and the Saw Swee Hock School of Public Health, National University of Singapore, Singapore.
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Yap-Seng Chong, M.D.
From the Department of Biomedical Engineering and Clinical Imaging Research Center, National University of Singapore, Singapore; the Singapore Institute for Clinical Sciences, Singapore; the Department of Diagnostic and Interventional Imaging, KK Women’s and Children’s Hospital, Singapore; the Department of Obstetrics and Gynecology, Yong Loo Lin School of Medicine, National University of Singapore, National University Health System, Singapore; the Ludmer Centre for Neuroinformatics and Mental Health, Douglas Mental Health University Institute, McGill University, Montreal; the Sackler Program for Epigenetics and Psychobiology at McGill University, Montreal; the Department of Psychological Medicine, Yong Loo Lin School of Medicine, National University of Singapore, National University Health System, Singapore; the KK Women’s and Children’s Hospital, Singapore; and the Saw Swee Hock School of Public Health, National University of Singapore, Singapore.
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Peter D. Gluckman, Ph.D.
From the Department of Biomedical Engineering and Clinical Imaging Research Center, National University of Singapore, Singapore; the Singapore Institute for Clinical Sciences, Singapore; the Department of Diagnostic and Interventional Imaging, KK Women’s and Children’s Hospital, Singapore; the Department of Obstetrics and Gynecology, Yong Loo Lin School of Medicine, National University of Singapore, National University Health System, Singapore; the Ludmer Centre for Neuroinformatics and Mental Health, Douglas Mental Health University Institute, McGill University, Montreal; the Sackler Program for Epigenetics and Psychobiology at McGill University, Montreal; the Department of Psychological Medicine, Yong Loo Lin School of Medicine, National University of Singapore, National University Health System, Singapore; the KK Women’s and Children’s Hospital, Singapore; and the Saw Swee Hock School of Public Health, National University of Singapore, Singapore.
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Marielle V. Fortier, M.D.
From the Department of Biomedical Engineering and Clinical Imaging Research Center, National University of Singapore, Singapore; the Singapore Institute for Clinical Sciences, Singapore; the Department of Diagnostic and Interventional Imaging, KK Women’s and Children’s Hospital, Singapore; the Department of Obstetrics and Gynecology, Yong Loo Lin School of Medicine, National University of Singapore, National University Health System, Singapore; the Ludmer Centre for Neuroinformatics and Mental Health, Douglas Mental Health University Institute, McGill University, Montreal; the Sackler Program for Epigenetics and Psychobiology at McGill University, Montreal; the Department of Psychological Medicine, Yong Loo Lin School of Medicine, National University of Singapore, National University Health System, Singapore; the KK Women’s and Children’s Hospital, Singapore; and the Saw Swee Hock School of Public Health, National University of Singapore, Singapore.
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Joanna Dawn Holbrook, Ph.D.
From the Department of Biomedical Engineering and Clinical Imaging Research Center, National University of Singapore, Singapore; the Singapore Institute for Clinical Sciences, Singapore; the Department of Diagnostic and Interventional Imaging, KK Women’s and Children’s Hospital, Singapore; the Department of Obstetrics and Gynecology, Yong Loo Lin School of Medicine, National University of Singapore, National University Health System, Singapore; the Ludmer Centre for Neuroinformatics and Mental Health, Douglas Mental Health University Institute, McGill University, Montreal; the Sackler Program for Epigenetics and Psychobiology at McGill University, Montreal; the Department of Psychological Medicine, Yong Loo Lin School of Medicine, National University of Singapore, National University Health System, Singapore; the KK Women’s and Children’s Hospital, Singapore; and the Saw Swee Hock School of Public Health, National University of Singapore, Singapore.
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Michael J. Meaney, Ph.D.
From the Department of Biomedical Engineering and Clinical Imaging Research Center, National University of Singapore, Singapore; the Singapore Institute for Clinical Sciences, Singapore; the Department of Diagnostic and Interventional Imaging, KK Women’s and Children’s Hospital, Singapore; the Department of Obstetrics and Gynecology, Yong Loo Lin School of Medicine, National University of Singapore, National University Health System, Singapore; the Ludmer Centre for Neuroinformatics and Mental Health, Douglas Mental Health University Institute, McGill University, Montreal; the Sackler Program for Epigenetics and Psychobiology at McGill University, Montreal; the Department of Psychological Medicine, Yong Loo Lin School of Medicine, National University of Singapore, National University Health System, Singapore; the KK Women’s and Children’s Hospital, Singapore; and the Saw Swee Hock School of Public Health, National University of Singapore, Singapore.
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Notes

Address correspondence to Dr. Qiu ([email protected]).

Funding Information

Dr. Chong has received speaker’s fees from companies selling nutritional products and that are part of an academic consortium that has received research funding from Abbott Nutrition, Danone Nutrition, and Nestle. Dr. Gluckman has received travel expenses to speak at meetings sponsored by Abbott Nutrition, Danone Nutrition, and Nestle and has served as part of an academic consortium that has received research support from these companies unrelated to this study. All other authors report no financial relationships with commercial interests.Supported by the National Medical Research Council (NMRC; NMRC/TCR/004-NUS/2008 and NMRC/CBRG/0039/2013), the Young Investigator Award at the National University of Singapore (NUSYIA FY10 P07), the National University of Singapore MOE AcRF Tier 1, and the Singapore Ministry of Education Academic Research Fund Tier 2 (MOE2012-T2-2-130).

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