Genetics of Brain Structure and Function: Genome-Wide Association

大脑结构和功能的遗传学：全基因组关联

• 批准号: 8231511
• 负责人: John Blangero
• 金额: $ 64.39万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-01 至 2014-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8231511
• 关键词: Accounting; Affect; Anatomy; Anxiety Disorders; Attention deficit hyperactivity disorder; Autistic Disorder; Biocompatible Materials; Biological; Biological Assay; Biology; Biomedical Research; Brain; Brain Diseases; Brain imaging; Commit; Communities; Complex; DNA; DNA Resequencing; Data; Data Correlations; Data Set; Dementia; Development; Disease; Economic Burden; Epilepsy; Evaluation; Exhibits; Extended Family; Foundations; Funding; Future; Genes; Genetic; Genetic Determinism; Genetic Research; Genome Scan; Genomics; Genotype; Goals; Health; Human Genetics; Individual; Individual Differences; Inherited; Intervention; Lead; Lymphocyte; Magnetic Resonance Imaging; Measurable; Measurement; Measures; Mental disorders; Methodology; Methods; Mexican Americans; Molecular Analysis; Mood Disorders; Morbidity - disease rate; National Institute of Mental Health; Neurocognitive; Neurologic; Neurosciences; Noise; Nucleotides; Participant; Pathology; Phenotype; Principal Investigator; Process; Psyche structure; Public Health; Qualifying; Quantitative Trait Loci; Recruitment Activity; Relative (related person); Research; Research Design; Research Personnel; Resource Sharing; Resources; Risk; SNP genotyping; Sampling; Schizophrenia; Short Tandem Repeat Polymorphism; Signal Transduction; Speed; Structure; System; Testing; Texas; Time; Universities; Variant; addiction; affection; base; cost effective; data sharing; density; design; disorder risk; endophenotype; genetic analysis; genetic linkage; genetic pedigree; genome wide association study; genome-wide; improved; in vivo; indexing; interest; member; mortality; neuroimaging; neuropsychological; novel; novel diagnostics; novel therapeutics; research study; success; trait; transcriptomics

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.

描述（由申请人提供）：该项目的目的是确定使用高密度全基因组关联（GWA）分析影响大脑结构和功能变化的基因。这项研究的最终希望是发现易感脑疾病和精神疾病的基因。我们的重点是对随机采样的扩展血统的大脑结构和功能变异的遗传分析，以提供有关正常和病理脑功能涉及的特定基因的重要线索。 2006年，我们开始收集有关墨西哥裔美国人的大脑相关的内表型，以进行基于连锁的分析（MH078111＆MH078143）。但是，考虑到最近使用GWA取得的成功次数，我们认为将设计转移以利用高密度SNP的可用性将通过大大降低基于链接的研究中提名的兴趣的基因组区域，从而极大地加快基因发现。使用替代资金，我们已经开始了这一高密度基因分型的过程。由于GWA固有的多次测试引起的功率问题，有必要扩展我们的原始样本以获得足够的基因识别能力。通过添加来自同一大家谱的500个新个体并完成原始样品中的高密度基因分型（n = 1,000），我们将具有80％的功率来检测对脑相关的遗传型相对较小的遗传影响。我们对这一独立R01的具体目的是：1）通过对另外500名墨西哥裔美国人进行高质量的大脑磁共振成像和神经心理学检查来扩展我们的现有研究，这些墨西哥裔美国人是30位先前研究的大家庭的成员，2）执行GWA分析以使用100万个SNP基因验证涉及大脑结构的概述，以在所有100万个基因范围内提高1,500个差异，3）对另外500个样品进行的测定，以鉴定其淋巴细胞衍生的表达水平与总样本中的大脑结构/功能的度量相关，4）确定五个最佳经验提名的候选基因中最可能的功能变化，通过重塑192个创建者，5）在独立的数据集中确认最强的关联。将这些新样本与当前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快速的方法。该单一申请的联合首席调查员包括得克萨斯大学HSC圣安东尼奥大学的David Glahn博士和西南生物医学研究基金会的John Blangero博士。如果资助，我们的数据和生物材料将被纳入NIMH人类遗传学计划中，使其可用于更广泛的科学界的合格研究人员。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，其生物学仍然在很大程度上未知。通过鉴定涉及大脑功能和结构的基因，我们将为此类疾病的决定因素提供新颖的生物学候选物，从而提高干预潜力。全基因组关联方法的使用应显着加快基因发现。