Cognitive Genomics as a Window on Neurodevelopment and Psychopathology

项目摘要 神经认知缺陷是几种主要神经精神障碍的核心组成部分，包括 精神分裂症、情感障碍、自闭症谱系障碍和注意力缺陷/多动障碍 （ADHD），认知对心理健康的中心地位反映在RDoC矩阵中，其中“认知 “系统”是研究的五个基本领域之一。然而，RDoC的基因栏 矩阵目前是空的，因为已经认识到，早期的候选基因方法 缺乏足够的力量和可复制性。 由本申请的PI领导的认知基因组学联盟（COGENT）于今年早些时候成立， 十年来，进行大规模的认知表型全基因组关联研究（GWAS）。最 最近，我们对我们的结果与其他大规模队列进行了荟萃分析，结果是两项研究， 每个研究对象超过10万人，最终确定了几十个基因组范围内的重要基因座， 认知能力（GCA）。我们还证明了在基因组水平上的显著遗传重叠- 广泛的多基因得分，在一般认知能力和大多数形式的精神疾病之间。 解构认知和神经精神疾病风险之间的遗传重叠可以提供有用的 病因学的见解，并帮助确定新的药物靶点。在拟议的研究中，我们的目标是扩大我们的 认知GWAS到特定的认知域（例如，语言记忆，工作记忆，注意力， 处理速度），每个样本量为数万。然后我们将利用我们的一般和 特定的认知GWAS结果，以确定关键的分子机制和途径， 促智药物靶点（Aim 1）。然后，我们将研究我们的认知能力与 GWAS结果和精神疾病，利用新的分析方法来梳理分离 机制（目标2）。最后，我们将利用公共可用的神经影像数据集与伴随的GWAS 数据来检查认知相关等位基因的基于电路的神经发育表现， 多基因评分（Aim 3）。

PROJECT SUMMARY Neurocognitive deficits represent a core component of several major neuropsychiatric disorders, including schizophrenia, affective disorders, autism spectrum disorders, and attention-deficit/hyperactivity disorder (ADHD), and the centrality of cognition to mental health is reflected in the RDoC matrix, in which “Cognitive Systems” is one of the five fundamental domains of investigation. However, the genetic column of the RDoC matrix is currently empty, as it has been recognized that the earlier generation of candidate gene approaches lacked sufficient power and replicability. The Cognitive Genomics Consortium (COGENT), led by the PI of this application, was formed earlier this decade to perform large scale genome-wide association studies (GWAS) of cognitive phenotypes. Most recently, we have meta-analyzed our results with other large-scale cohorts, resulting in two studies with >100,000 subjects in each, which have finally identified dozens of genome-wide significant loci for general cognitive ability (GCA). We have also demonstrated the significant genetic overlap, at the level of genome- wide polygene scores, between general cognitive ability and most forms of psychiatric illness. Deconstructing the genetic overlap between cognition and risk for neuropsychiatric illness can provide useful etiological insights and help identify novel druggable targets. In the proposed study, we aim to extend our cognitive GWAS to specific cognitive domains (e.g., verbal memory, working memory, attention, and processing speed) with sample sizes in the tens of thousands for each. We will then utilize our general and specific cognitive GWAS results to identify key molecular mechanisms and pathways that can identify nootropic drug targets (Aim 1). We will then examine the molecular genetic overlap between our cognitive GWAS results and psychiatric illness, utilizing novel analytic approaches to tease apart dissociable mechanisms (Aim 2). Finally, we will utilize publicly available neuroimaging datasets with concomitant GWAS data to examine the circuit-based, neurodevelopmental manifestations of cognition-relevant alleles and polygene scores (Aim 3).