From the Integrated Program in Neuroscience (IPN), McGill University, Montréal, Que., Canada (Morgunova); the Department of Psychiatry, Faculty of Medicine, McGill University, Montréal, Que., Canada (O'Donnell, Meaney, Silveira, Flores); the Department of Neurology and Neurosurgery, McGill University, Montréal, Que., Canada (Flores); the Douglas Research Centre, Montréal, Que., Canada (Morgunova, Flores, Silveira); the Ludmer Centre for Neuroinformatics and Mental Health, Douglas Research Centre, McGill University, Montréal, Que., Canada (Pokhvisneva, O'Donnell, Meaney, Silveira); the Child and Brain Development Program, Canadian Institute for Advanced Research (CIFAR), Toronto, Ont., Canada (O'Donnell, Meaney); the Singapore Institute for Clinical Sciences, Agency for Science, Technology and Research (A*STAR; Meaney); the Department of Medical Psychology Charité Universitätsmedizin, Berlin, Germany (Nolvi, Buss); the FinnBrain Birth Cohort Study, Department of Clinical Medicine, University of Turku, Turku, Finland (Nolvi); the Development, Health and Disease Research Program, School of Medicine, University of California, Irvine, Irvine, CA, USA (Entringer, Wadhwa); the Department of Pediatrics, School of Medicine, University of California, Irvine, Irvine, CA, USA (Entringer, Wadhwa); the Institute of Medical Psychology, Charité-Universitätsmedizin Berlin, Berlin, Germany (Entringer); the Department of Psychiatry and Human Behavior, School of Medicine, University of California, Irvine, CA, USA (Wadhwa); the Department of Obstetrics and Gynecology, School of Medicine, University of California, Irvine, CA, USA (Wadhwa); the Department of Epidemiology, School of Medicine, University of California, Irvine, CA, USA (Wadhwa); the Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA (Gilmore, Styner); the Department of Computer Science, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA (Styner); the Mood Disorders Program, Department of Psychiatry and Behavioural Neurosciences, McMaster University, Hamilton, Ont., Canada (Sassi); and the Department of Psychology, Neuroscience and Behaviour, McMaster University, Hamilton, Ont., Canada (Hall).
J Psychiatry Neurosci. 2020 Nov 18;46(1):E154-E163. doi: 10.1503/jpn.200081.
Genetic variation in the guidance cue gene is linked to psychopathologies involving dysfunction in the prefrontal cortex. We created an expression-based polygenic risk score (ePRS) based on the coexpression gene network in the prefrontal cortex, hypothesizing that it would be associated with individual differences in total brain volume.
We filtered single nucleotide polymorphisms (SNPs) from genes coexpressed with in the prefrontal cortex obtained from an adult postmortem donors database (BrainEAC) for genes enriched in children 1.5 to 11 years old (BrainSpan). The SNPs were weighted by their effect size in predicting gene expression in the prefrontal cortex, multiplied by their allele number based on an individual's genotype data, and then summarized into an ePRS. We evaluated associations between the ePRS and total brain volume in children in 2 community-based cohorts: the Maternal Adversity, Vulnerability and Neurodevelopment (MAVAN) and University of California, Irvine (UCI) projects. For comparison, we calculated a conventional PRS based on a genome-wide association study of total brain volume.
Higher ePRS was associated with higher total brain volume in children 8 to 10 years old (β = 0.212, = 0.043; = 88). The conventional PRS at several different thresholds did not predict total brain volume in this cohort. A replication analysis in an independent cohort of newborns from the UCI study showed an association between the ePRS and newborn total brain volume (β = 0.101, = 0.048; = 80). The genes included in the ePRS demonstrated high levels of coexpression throughout the lifespan and are primarily involved in regulating cellular function.
The relatively small sample size and age differences between the main and replication cohorts were limitations.
Our findings suggest that the coexpression network in the prefrontal cortex is critically involved in whole brain development during the first decade of life. Genes comprising the ePRS are involved in gene translation control and cell adhesion, and their expression in the prefrontal cortex at different stages of life provides a snapshot of their dynamic recruitment.
导向因子基因的遗传变异与前额叶皮层功能障碍相关的精神病理学有关。我们基于前额叶皮层的共表达基因网络创建了一个基于表达的多基因风险评分（ePRS），假设它与大脑总容量的个体差异有关。
我们从成人死后捐献者数据库（BrainEAC）中与前额叶皮层共表达的基因中筛选出单核苷酸多态性（SNP），用于富集儿童 1.5 至 11 岁（BrainSpan）的基因。SNP 按照其在预测前额叶皮层基因表达中的效应大小进行加权，乘以个体基因型数据中的等位基因数量，然后汇总为 ePRS。我们在两个基于社区的队列中评估了儿童 ePRS 与大脑总容量之间的关联：母婴逆境、脆弱性和神经发育（MAVAN）和加利福尼亚大学欧文分校（UCI）项目。为了比较，我们基于全基因组关联研究计算了大脑总容量的传统 PRS。
较高的 ePRS 与 8 至 10 岁儿童的大脑总容量较高相关（β=0.212，=0.043；=88）。在该队列中，几个不同阈值的传统 PRS 不能预测大脑总容量。在来自 UCI 研究的新生儿独立队列的复制分析中，ePRS 与新生儿大脑总容量之间存在关联（β=0.101，=0.048；=80）。ePRS 中包含的基因在整个生命周期中表现出高度的共表达，主要参与调节细胞功能。
主要和复制队列之间的样本量较小和年龄差异是限制因素。
我们的研究结果表明，前额叶皮层的共表达网络在生命的第一个十年中对整个大脑的发育至关重要。构成 ePRS 的基因参与基因翻译控制和细胞黏附，它们在生命不同阶段在前额叶皮层的表达提供了其动态募集的快照。
