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: 8037073
• 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/8037073
• 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）：该项目的目标是利用高密度全基因组关联（GWA）分析识别影响大脑结构和功能变异的基因。这项研究的最终前景是发现易导致大脑紊乱和精神疾病的基因。我们的重点是在随机抽样的扩展谱系中对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相关的特定基因的重要线索。2006年，我们开始收集墨西哥裔美国人相关个体的脑相关内表型，进行基于连锁的分析（MH078111和MH078143）。然而，考虑到最近使用GWA的成功数量，我们相信改变我们的设计，利用高密度snp的可用性，将大大减少我们基于连锁的研究中提名的感兴趣的基因组区域，从而大大加快基因发现。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固有的多次测试导致功率问题，有必要扩大原始样本以获得足够的功率进行基因鉴定。通过增加500个来自相同大谱系的新个体，并在原始样本中完成高密度基因分型（n= 1000），我们将有80%的能力检测到相对较小的遗传对脑相关内表型的影响。我们对这个独立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30个先前研究的大家庭的成员；2)进行GWA分析，优先考虑与大脑结构/功能相关的潜在基因，对所有1500个人使用100万个snp基因分型；3)通过对另外500个样本进行相同的分析来增加我们的全基因组转录谱数据，以确定总样本中淋巴细胞衍生表达水平与大脑结构/功能测量相关的基因；4)通过对192个创始人进行重测序，确定5个最佳经验提名候选基因中最可能的功能变异；5)在独立数据集中确认最强关联。将这些新样本与目前正在收集的样本结合起来，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。这项单一申请的联合主要研究人员包括圣安东尼奥德克萨斯大学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人类遗传学计划，使它们能够提供给更广泛的科学界的合格研究人员。公共卫生相关性：脑相关精神疾病是一个主要的公共卫生负担，其生物学在很大程度上仍然未知。通过识别参与大脑功能和结构的基因，我们将为这些疾病的决定因素提供新的生物学候选物，从而提高干预的潜力。全基因组关联方法的使用将显著加快基因发现的速度。