2/2 Genetics of Brain Structure and Function

描述(申请人提供)：我们续签申请的最终目标是发现易患精神疾病的基因。虽然一些全基因组范围的显著数量性状基因座(QTL)已经被定位为精神疾病，但这些发现尚未导致真正的基因识别。然而，在阐明主要精神障碍的病理生理学和随后的治疗干预方面的进展，是基于因果基因识别的。在我们的续订申请中，我们将利用获得的详尽的基因组信息 从全基因组测序(WGS)中识别影响精神分裂症、双相情感障碍和/或严重抑郁症的内表型的因果变异/基因。内表型是一种可遗传的特征，在基因上与疾病易感性相关， 与情感状态相比，定位疾病相关基因的能力更大。罕见的变异似乎在精神疾病中很重要。基于系谱的研究代表了一种识别稀有变异的隐含丰富策略，而家系特有的稀有功能变异足以验证给定的基因参与了表型变异。在我们研究的初始阶段，我们从随机选择的扩展家系中获得了1350名墨西哥裔美国人的精神疾病的神经解剖学、神经生理学和神经认知内表型。利用现有的高密度SNP数据，我们成功地定位了多个影响内表型变异的全基因组显著QTL。我们现在将超越QTL定位来识别影响这些内表型的基因。WGS提供了约2100名个体的数据，包括所有内表型受试者，大大促进了这一目标的实现。我们的具体目标是：(1)获得结构和功能脑图像，并对另外600名有WGS数据但没有脑相关内表型的墨西哥裔美国家庭成员进行神经心理学检查；(2)确定影响精神疾病相关内表型的现有QTL的因果变量；(3)仅使用功能性非同义编码变量或假定的调控变量进行基于不可知家系的全基因组关联，以确定其他影响脑内表型的基因/变量；以及(4)对来自NIMH精神疾病合作遗传研究中心的1000名精神分裂症患者、1000名双相抑郁患者、1000名严重抑郁障碍患者和1000名对照样本进行AIMS 2和3中确定的最有可能的变异的多效性效应测试。我们的合作项目包括来自德克萨斯生物医学研究所的John Blangero和耶鲁大学的David C Glahn的申请。还包括表型分包合同(UTHSCSA；RE Olvera)和图像分析分包合同(马里兰大学，P Kochunov)。这一更新应用旨在通过识别影响精神疾病内表型的特定基因来扩展我们最初的研究。

DESCRIPTION (provided by applicant): The ultimate goal of our renewal application is the discovery of genes that predispose to mental illnesses. While a number of genome-wide significant quantitative trait loci (QTL) have been localized for mental illnesses, these findings have yet to result in true gene identifications. Yet, progress in elucidating the pathophysiology o major mental disorders, and subsequent treatment interventions, is predicated on causal gene identification. In our renewal application, we will utilize exhaustive genomic information obtained from whole genome sequencing (WGS) to identify causal variants/genes influencing endophenotypes for schizophrenia, bipolar disorder and/or major depression. An endophenotype is a heritable trait that is genetically correlated with disease liability, providing greater power to localize disease-related genes than affection status alone. Rare variants appear to be important in mental illness. Pedigree-based studies represent an implicit enrichment strategy for identifying rare variants and a pedigree-specific rare functional variant can be sufficient to verify that a given gene is involved in phenotypic variation. In the initial phase of our study, we acquired neuroanatomic, neurophysiologic and neurocognitive endophenotypes for mental illness in 1350 Mexican Americans from randomly selected extended pedigrees. Using existing high density SNP data, we successfully localized multiple genome-wide significant QTLs influencing endophenotypic variation. We will now move beyond QTL localization to the identification of genes that influence these endophenotypes. Achieving this goal is greatly enhanced by the availability of WGS data on ~2100 individuals, including all endophenotyped subjects. Our specific aims are to: (1) acquire structural and functional brain images and conduct neuropsychological examinations on 600 additional Mexican American family members with WGS data but without brain-related endophenotypes; (2) identify causal variants underlying existing QTLs influencing mental illness-relevant endophenotypes; (3) perform agnostic pedigree-based genome-wide association using only functional non-synonymous coding variants or putative regulatory variants to identify additional genes/variants influencing brain endophenotypes; and (4) Test for pleiotropic effects of the most likely variants identified in Aims 2 & 3 in a sample of 1000 schizophrenia cases, 1000 bipolar depression cases, 1000 major depressive disorder cases and 1000 controls from the NIMH's Center for Collaborative Genetic Studies of Mental Disorders. Our collaborative project includes applications from John Blangero, Texas Biomedical Research Institute, and David C Glahn, Yale University. Subcontracts for phenotyping (UTHSCSA; RE Olvera) and image analysis (University of Maryland, P Kochunov) are also included. This renewal application is designed to extend our initial study by identifying the specific genes that influence mental illness endophenotypes.