Neurodevelopment: Genes, Environment, and their Interactions

 描述(申请人提供)：这项研究的目标是定位和表征影响神经认知、神经解剖学和神经生理学指标中正常成熟相关变化的基因。大量与大脑相关的性状表现出年龄与基因的交互作用，这表明随着年龄的增长，神经认知、神经解剖学和神经生理学的变化是可遗传的基础，并突出了基因在大脑差异成熟中的潜在作用。我们将利用新的分析方法，从发育的角度研究遗传和环境对大脑、认知和行为变异的影响，在费城神经发育队列(PNC)中，模拟遗传和环境领域的复杂影响，以及它们之间的潜在交互作用，同时允许这些影响在整个发育过程中的变化。PNC包括大约9500名年龄在8-21岁之间的人，他们具有大脑、行为和遗传变量的特征。所有参与者都接受了神经精神病学评估，并完成了计算机化神经认知成套测验(CNB)。访谈包括评估人口统计学、生活事件和压力源、学校表现、病史、精神病理学筛查以及相关症状的存在和持续时间。CNB包括对智商的估计以及14项旨在评估五种神经行为功能的测试。约1450名参与者接受了神经成像，包括结构和功能磁共振成像和扩散张量成像。大约8700名PNC参与者已经在不同的基因分型平台上获得了全基因组500K-950K SNPs的基因分型。这一庞大的数据集，再加上在各种表型领域的丰富和详细的评估，为研究神经发育中基因与年龄和基因与环境的相互作用及其对精神疾病风险的潜在贡献提供了一个无与伦比的机会。这项拟议研究的具体目的是：1)定位影响神经发育变异的基因；2)评估这些遗传效应是否随年龄变化，并确定更多显示基因与年龄交互作用的基因座；3)评估复杂的环境对神经发育的影响，并测试它们是否与遗传效应交互作用，以及是否与中度或中度遗传效应交互作用。德克萨斯州生物医学研究所的Laura Almasy是此应用程序的联系人PI，共同PI是耶鲁大学的David Glahn和宾夕法尼亚大学的Raquel Gur将领导分包合同。阿尔马西博士在复杂表型的遗传分析方面提供专业知识，包括基因与年龄和基因与环境的相互作用。Glahn博士和Gur博士提供认知神经心理学、神经成像和精神病学方面的专业知识。

 DESCRIPTION (provided by applicant): The goal of this study is to localize and characterize genes that influence normal maturation-related changes in neurocognitive, neuroanatomic and neurophysiological indices. A substantial number of brain-related traits exhibit gene by age interactions, suggesting a heritable basis for neurocognitive, neuroanatomic and neurophysiological changes with age and highlighting the potential role of genes in differential brain maturation. We will utilize novel analytical approaches to investigate genetic and environmental influences on variation in brain, cognition, and behavior from a developmental perspective, modeling complex effects in both the genetic and environmental realms, and potential interactions between them, while allowing for changes in these effects across development, in the Philadelphia Neurodevelopmental Cohort (PNC). The PNC includes ~9500 individuals between the ages of 8 - 21 years who have been characterized for brain, behavior, and genetic variables. All participants were assessed neuropsychiatrically and completed a Computerized Neurocognitive Battery (CNB). Interviews included assessment of demographics, life events and stressors, school performance, medical history, and screening for psychopathology and presence and duration of associated symptoms. The CNB included an estimate of IQ as well as 14 tests designed to assess five neurobehavioral functions. A subset of ~1450 participants underwent neuroimaging, including structural and functional MRI and diffusion tensor imaging. Approximately 8700 PNC participants have been genotyped for 500K - 950K genome-wide SNPs, obtained on a diverse variety of genotyping platforms. The large size of this data set, combined with the rich and detailed assessments in a variety of phenotypic domains, provides an unparalleled opportunity to study gene-by-age and gene-by-environment interactions in neurodevelopment and their potential contribution to risk of mental illness. The specific aims of the proposed study are to: 1) Localize genes influencing variation in neurodevelopment in the PNC; 2) Assess whether these genetic effects change with age and identify additional loci exhibiting gene- by-age interactions; and 3) Assess complex environmental effects on neurodevelopment and test whether they interact with, and moderate or mediate, genetic effects. Laura Almasy, Texas Biomedical Research Institute, is contact PI of this application and co-PIs David Glahn, Yale University, and Raquel Gur, University of Pennsylvania, will lead subcontracts. Dr. Almasy provides expertise in genetic analysis of complex phenotypes, including gene-by-age and gene-by-environment interactions. Drs. Glahn and Gur provide expertise in cognitive neuropsychology, neuroimaging, and psychiatry.