Cognitive Genomics as a Window on Neurodevelopment and Psychopathology

认知基因组学作为神经发育和精神病理学的窗口

• 批准号: 10360609
• 负责人: TODD LENCZ
• 金额: $ 54.43万
• 依托单位: FEINSTEIN INSTITUTE FOR MEDICAL RESEARCH
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-06-08 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10360609
• 关键词: Adult; Alleles; Attention; Attention deficit hyperactivity disorder; Bayesian Method; Brain; Candidate Disease Gene; Cognition; Cognitive; Cognitive deficits; Collaborations; Data; Data Set; Dissociation; Drug Targeting; Etiology; Family Study; Functional Magnetic Resonance Imaging; Generations; Genetic; Genomics; Human; Image; Individual; Intervention; Investigation; Mediating; Memory; Mental Health; Mental disorders; Meta-Analysis; Molecular; Molecular Genetics; Mood Disorders; Neurocognitive Deficit; Nootropic Agents; Pathway Analysis; Pathway interactions; Pharmaceutical Preparations; Pharmacology; Phenotype; Philadelphia; Process; Psychopathology; Publications; Publishing; Research Domain Criteria; Risk; Sample Size; Sampling; Schizophrenia; Severities; Short-Term Memory; Symptoms; age related; autism spectrum disorder; base; biobank; brain volume; cognitive ability; cognitive enhancement; cognitive performance; cognitive system; cohort; connectome; deprivation; design; druggable target; endophenotype; genome wide association study; genome-wide; genomic locus; insight; neural circuit; neurodevelopment; neuroimaging; neuropsychiatric disorder; neuropsychiatry; new therapeutic target; novel; novel strategies; processing speed; severe mental illness; side effect

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).

项目总结 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性反映在RDoC矩阵中，在RDoC矩阵中 系统“是调查的五个基本领域之一。然而，RDoC的基因栏目 矩阵目前是空的，因为已经认识到较早一代的候选基因接近 缺乏足够的能量和可复制性。 认知基因组学联盟(COGINT)由该应用程序的PI领导，于今年早些时候成立 十年，对认知表型进行大规模全基因组关联研究。多数 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，得出了两项研究 每组100,000名受试者，最终确定了数十个基因组范围内的有意义的基因座 认知能力(GCA)。我们还证明了基因组水平上的显著遗传重叠-- 广泛的多基因得分，介于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基因重叠可以提供有用的 病因学洞察和帮助确定新的可用药靶点。在拟议的研究中，我们的目标是扩大我们的 认知领域(例如，言语记忆、工作记忆、注意力和 处理速度)，每个样本大小为数万。然后我们将利用我们的将军和 识别关键分子机制和途径的特定认知Gwas结果可以识别 促性药靶点(目标1)。然后我们将研究我们认知能力和认知能力之间的分子遗传重叠。 Gwas结果和精神疾病，利用新的分析方法梳理分离的 机制(目标2)。最后，我们将利用公开可用的神经成像数据集以及伴随而来的GWA 研究认知相关等位基因的基于回路的神经发育表现和 多基因评分(目标3)。