Genetics of Brain Structure and Function: Genome-Wide Association

描述（由申请人提供）：该项目的目标是使用高密度全基因组关联（GWA）分析来鉴定影响脑结构和功能变化的基因。这项研究的最终希望是发现易患大脑疾病和精神疾病的基因。我们的重点是对随机抽样的扩展家系中大脑结构和功能的变异进行遗传分析，以提供有关参与正常和病理性大脑功能的特定基因的重要线索。2006年，我们开始收集相关墨西哥裔美国人个体的脑相关内表型，用于基于关联的分析（MH 078111和MH 078143）。然而，考虑到最近使用GWA的成功数量，我们相信，将我们的设计转移到利用高密度SNP的可用性将大大加快基因发现，通过大幅减少我们基于链接的研究中提名的基因组感兴趣区域。利用替代资金，我们已经开始了高密度基因分型的过程。由于GWA中固有的多重检测导致的功效问题，因此有必要扩展我们的原始样本以获得足够的基因鉴定功效。通过从相同的大谱系中添加500个新个体并完成原始样本（n= 1，000）的高密度基因分型，我们将有80%的把握检测到对脑相关内表型的相对较小的遗传影响。我们对这一独立R 01的具体目标是：1）通过对另外500名墨西哥裔美国人进行高质量的脑磁共振成像和神经心理学检查来扩展我们现有的研究，这些墨西哥裔美国人是30个先前研究的大家庭的成员，2）进行GWA分析，以优先考虑涉及大脑结构/功能的潜在基因，对所有1,500名个体进行100万个SNP基因分型，3）通过对另外的500个样品进行相同的测定来增加我们的全基因组转录谱数据，以鉴定其淋巴细胞衍生的表达水平与总样品中脑结构/功能的测量相关的基因，4）通过对192个创始者个体进行重新测序来鉴定五个最佳经验提名的候选基因中最可能的功能变异，以及5）确定独立数据集中的最强关联。将这些新样本与目前正在收集的样本相结合，是发现与大脑相关性状相关的基因的最具成本效益和最快速的方法。这一单一应用的共同主要研究者包括圣安东尼奥德克萨斯大学HSC的大卫格拉恩博士和西南生物医学研究基金会的约翰布朗杰罗博士。如果获得资助，我们的数据和生物材料将被纳入NIMH人类遗传学计划，使其可供更广泛的科学界的合格研究人员使用。

DESCRIPTION (provided by applicant): The goal of this project is to identify genes that influence variation in brain structure and function using high- density genome-wide association (GWA) analysis. The ultimate promise of this research is the discovery of genes that predispose to brain disorders and mental illnesses. Our focus is on the genetic analysis of variation in brain structure and function in randomly sampled extended pedigrees to provide significant clues regarding the specific genes that are involved in both normal and pathological brain function. In 2006, we began collecting brain-related endophenotypes on related Mexican American individuals for linkage-based analyses (MH078111 & MH078143). However, given the number of recent successes using GWA, we believe that shifting our design to exploit the availability of high density SNPs will dramatically speed gene discovery by substantially reducing the genomic region of interest nominated in our linkage-based study. Using alternative funding, we have begun this process of high-density genotyping. Because of power issues due to multiple testing inherent in GWA, it is necessary to expand our original sample to obtain sufficient power for gene identification. By adding 500 new individuals from the same large pedigrees and completing the high-density genotyping in the original sample (n=1,000), we will have 80 percent power to detect relatively small genetic effects on brain-related endophenotypes. Our specific aims for this independent R01 are to: 1) extend our existing study by performing high quality brain magnetic resonance imaging and neuropsychological examinations on an additional 500 Mexican Americans who are members of 30 previously studied extended families, 2) perform GWA analysis to prioritize potential genes involved in brain structure/function, using 1 million SNPs genotyped on all 1,500 individuals, 3) increase our genome-wide transcriptional profile data by performing identical assays on the additional 500 samples to identify genes whose lymphocyte-derived expression levels correlate with measures of brain structure/function in the total sample, 4) identify the most likely functional variations within the five best empirically nominated candidate genes by resequencing 192 founder individuals, and 5) confirm the strongest association in an independent data set. Combining these new samples with those currently being collected represents the most cost effective and rapid approach for the discovery of genes associated with brain-related traits. The co-principal investigators on this single application include Dr. David Glahn, University of Texas HSC at San Antonio, and Dr. John Blangero, Southwest Foundation for Biomedical Research. If funded, our data and biomaterials will be incorporated into the NIMH Human Genetics Initiative, making them available to qualified researchers in the wider scientific community.