2/2 Genetics of Brain Structure and Function

描述（由申请人提供）：我们更新申请的最终目标是发现易患精神疾病的基因。虽然一些全基因组显著的数量性状位点（QTL）已被定位为精神疾病，这些发现尚未导致真正的基因鉴定。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致病基因的鉴定。在我们的更新申请中，我们将利用获得的详尽的基因组信息 从全基因组测序（WGS）中鉴定影响精神分裂症、双相情感障碍和/或重性抑郁症的内表型的因果变体/基因。内表型是与疾病易感性遗传相关的可遗传性状， 更大的力量来定位疾病相关的基因比单独的情感状态。罕见的变异似乎在精神疾病中很重要。基于谱系的研究代表了用于鉴定罕见变体的隐含富集策略，并且谱系特异性罕见功能变体可以足以验证给定基因参与表型变异。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，以确定影响这些内表型的基因。通过获得约2100名个体（包括所有内表型受试者）的WGS数据，极大地促进了这一目标的实现。我们的具体目标是：（1）获取结构性和功能性大脑图像，并对另外600名具有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）识别影响精神疾病相关内表型的现有QTL的因果变异;（3）仅使用功能性非功能性基因组进行基于不可知谱系的全基因组关联，同义编码变体或推定的调节变体，以识别影响脑内表型的其他基因/变体;和（4）在1000例精神分裂症病例，1000例双相抑郁症病例，来自NIMH精神疾病协作遗传研究中心的1000例重度抑郁症病例和1000例对照。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和耶鲁大学的大卫C Glahn的应用。还包括表型分型（UTHSCSA; RE Olvera）和图像分析（马里兰州大学，P Kochunov）的分包合同。这项更新申请旨在通过确定影响精神疾病内在表型的特定基因来扩展我们的初步研究。

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.