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.
Am J Psychiatry. 2015 Feb 1;172(2):163-72. doi: 10.1176/appi.ajp.2014.14030313. Epub 2014 Oct 31.
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.
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.
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.
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.
产前母体焦虑和复杂的遗传变异可能会影响胎儿大脑发育。特别是位于 22q11.2 染色体上的儿茶酚-O-甲基转移酶（COMT）基因，调节前额叶皮质中的儿茶酚胺信号传递，与焦虑、疼痛和应激反应性有关。本研究探讨了 COMT 基因的个体单核苷酸多态性（SNP）及其单倍型是否调节产前母体焦虑与宫内皮质发育之间的关系。
共对 146 名新生儿进行基因分型，并在出生后不久进行 MRI 检查。使用皮质厚度来描述新生儿皮质形态。在妊娠 26 周时使用状态-特质焦虑量表评估产前母体焦虑。
COMT 的个体 SNP（val158met、rs737865 和 rs165599）调节了产前母体焦虑与新生儿前额叶和顶叶皮质厚度之间的关系。基于单倍型趋势回归分析，结果还表明，在 rs737865-val158met-rs165599 单倍型中，A-val-G（AGG）单倍型概率调节了产前母体焦虑与右侧腹外侧前额叶皮质和右侧顶叶上皮质和楔前叶皮质厚度之间的正相关关系。相反，G-met-A（GAA）单倍型概率调节了产前母体焦虑与双侧中央前回和背外侧前额叶皮质皮质厚度之间的负相关关系。
这些结果表明，COMT 中的复杂遗传变异调节了母体焦虑与宫内神经发育之间的关系。这种遗传调节可能部分解释了与母体情绪健康相关的后代表型结果的变异性。
