Genetics of Brain Structure and Function: Genome-Wide Association

描述(申请人提供)：该项目的目标是使用高密度全基因组关联(GWA)分析来识别影响大脑结构和功能变异的基因。这项研究的最终希望是发现易患脑部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变异的遗传分析，以提供与正常和病理大脑功能相关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的脑相关内表型，用于基于连锁的分析(MH078111和MH078143)。然而，考虑到最近成功使用GWA的数量，我们相信改变我们的设计以利用高密度SNPs的可用性将大大加快基因发现的速度，因为它大大减少了我们基于连锁的研究中提名的感兴趣的基因组区域。使用替代资金，我们已经开始了这一高密度基因分型的进程。由于GWA固有的多重测试的能力问题，有必要扩大我们的原始样本以获得足够的能力来进行基因鉴定。通过增加来自相同大家系的500个新个体，并在原始样本(n=1000)中完成高密度基因分型，我们将有80%的能力检测相对较小的遗传效应对大脑相关内表型的影响。我们独立R01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，这些人是以前研究过的30个大家庭的成员；2)进行GWA分析，使用在所有1500个人上分型的100万个SNP，对涉及大脑结构/功能的潜在基因进行优先排序；3)通过对另外500个样本进行相同的分析，增加我们的全基因组转录图谱数据，以确定其淋巴细胞衍生表达水平与总样本中大脑结构/功能的测量相关的基因；4)通过对192名创始人重新测序，确定五个最佳经验提名候选基因中最有可能的功能变异。以及5)确认独立数据集中的最强关联性。将这些新样本与目前正在收集的样本相结合，是发现与大脑相关特征相关的基因的最具成本效益和最快速的方法。这一单一应用的联合主要研究人员包括德克萨斯大学圣安东尼奥分校HSC的David Glahn博士和西南生物医学研究基金会的John Blangero博士。如果得到资助，我们的数据和生物材料将被纳入NIMH人类遗传学倡议，使其可供更广泛科学界的合格研究人员使用。公共卫生相关性：与大脑相关的精神疾病是一种主要的公共卫生负担，其生物学特性在很大程度上仍不清楚。通过识别与大脑功能和结构有关的基因，我们将为此类疾病的决定因素提供新的生物学候选，从而提高干预的可能性。全基因组关联方法的使用应该会大大加快基因发现的速度。

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. PUBLIC HEALTH RELEVANCE: Brain-related mental diseases are a major public health burden whose biology is still largely unknown. By identifying genes involved in brain function and structure, we will provide novel biological candidates for the determinants of such diseases and thus improve potential for intervention. The use of genome-wide association methods should significantly speed gene discovery.