Discovery and Functional Impact of Common and Rare Variants in RA

RA 常见和罕见变异的发现及其功能影响

• 批准号: 8712363
• 负责人: Soumya Raychaudhuri
• 金额: $ 37.59万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-02 至 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8712363
• 关键词: Accounting; Alleles; Asians; Base Sequence; Bioinformatics; Biological Assay; Biological Process; Biology; Cell Line; Cells; Code; DNA; Data; Data Set; Development; Diagnosis; Dideoxy Chain Termination DNA Sequencing; Disease; Disease Pathway; Drug Targeting; Ethnic group; European; Exons; Family; Gene Expression Profile; General Population; Genes; Genetic; Goals; Heritability; Human; Human Genetics; Individual; Japanese Population; Korea; Manuscripts; Maps; Methods; Molecular; Mutation; Pathogenesis; Pathway interactions; Patient Care; Preclinical Drug Evaluation; Proteins; Publishing; RNA Interference; Resources; Rheumatoid Arthritis; Risk; Role; Sampling; Series; Symptoms; TNFRSF5 gene; Techniques; Technology; Testing; Translating; Variant; analytical method; base; bone; case control; cellular engineering; deep sequencing; disorder risk; drug development; drug discovery; experience; gain of function; genetic variant; genome wide association study; high throughput screening; improved; innovation; insight; loss of function; novel; protein protein interaction; public health relevance; rare variant; research study; risk variant; small molecule; theories; tool

DESCRIPTION (provided by applicant): Genome-wide association studies (GWAS) and related approaches have identified >60 rheumatoid arthritis (RA) risk loci. Despite this, many alleles remain to be discovered to account for heritability estimates observed in families. We have published data that most common RA risk alleles are shared across diverse ethnic groups. In Aim 1, we will exploit this observation to discover new RA risk alleles - we will conduct a multi- ethnic GWAS of ~20,000 RA cases and 60,000 matched controls (Asian and European ancestry). We will also compare and contrast genetic findings across two ethnic groups, and develop new analytical methods. We have data (manuscript in press) that RA risk genes identified from GWAS harbor rare alleles that contribute to risk of RA. Together with data from other diseases, this leads to the hypothesis that causal genes at RA risk loci discovered by GWAS will contain independent, protein-coding mutations (most of which will be rare in the general population). In Aim 2, we will test this hypothesis by sequencing all genes (~650 in total) identified by GWAS in 1,300 RA case and 1,300 non-RA controls of European ancestry. We will also sequence ~2,000 RA case-control samples of Asian ancestry in order to compare and contrast genetic findings across two ethnic groups. We will perform genetic burden tests to determine which genes harbor more rare risk alleles in cases compared to controls than would be expected by chance. However, finding causal variants and genes is only the first step in translating genetic discoveries to improved patient care, and drug discovery in particular. We hypothesize that genes with an allelic series (i.e., multiple alleles that influence disease risk) re excellent drug targets, especially genes that carry loss-of-function (LOF) alleles that protect from disease. We have unpublished data on one RA risk locus that demonstrates our ability to progress from a GWAS to a high-throughput screen (HTS) of ~2,000 small molecules. In Aim 3 we will extend this approach to new RA risk genes: for at least one gene, we will understand the functional consequences of new RA risk alleles using cutting-edge molecular techniques (e.g., TALENs, RNAi), and use this information to conduct an HTS. Together, these three Aims will (1) discover new RA risk loci using GWAS in Europeans and Asians, (2) discover rare RA risk alleles at causal genes from GWAS loci (also in Europeans and Asians), and (3) translate genetic discoveries into new biology and an HTS of small molecule compounds. IMPACT: We will build upon our past accomplishments to perform the most comprehensive genetic study of RA to date (from common to rare alleles). We will develop innovative methods for integrating GWAS and sequence data, as well as innovative methods to use human genetics to guide drug discovery. Our team has all of the experience and resources to accomplish these Aims.

描述(由申请人提供)：全基因组关联研究(GWAS)和相关方法已经确定了60个类风湿性关节炎(RA)风险基因。尽管如此，许多等位基因仍有待发现，以解释在家庭中观察到的遗传力估计。我们已经公布的数据表明，最常见的RA风险等位基因在不同的种族群体中是相同的。在目标1中，我们将利用这一观察结果来发现新的RA风险等位基因--我们将对大约20,000例RA病例和60,000名匹配的对照(亚洲和欧洲血统)进行多种族GWA。我们还将比较和对比两个民族的基因研究结果，并开发新的分析方法。我们有数据(手稿在印)表明，从GWAS中鉴定出的RA风险基因含有导致RA风险的稀有等位基因。与来自其他疾病的数据一起，这导致了一种假设，即GWAS发现的RA风险基因座上的因果基因将包含独立的蛋白质编码突变(其中大多数在普通人群中将是罕见的)。在目标2中，我们将通过对所有基因(总共约650个)进行测序来检验这一假设 在1300例类风湿性关节炎病例和1300例欧洲血统的非类风湿性关节炎对照中，由Gwas确定。我们还将对大约2,000个亚洲血统的RA病例对照样本进行测序，以比较和对比两个种族的遗传学发现。我们将进行遗传负荷测试，以确定与对照相比，哪些基因在病例中含有比偶然预期更多的罕见风险等位基因。然而，寻找因果变异和基因只是将基因发现转化为改善患者护理，特别是药物发现的第一步。我们假设具有等位基因系列的基因(即影响疾病风险的多个等位基因)是很好的药物靶点，特别是携带保护疾病的功能丧失(LOF)等位基因的基因。我们有关于一个RA风险基因座的未公布数据，这些数据表明我们有能力从GWAS发展到由大约2,000个小分子组成的高通量筛查(HTS)。在目标3中，我们将把这种方法扩展到新的RA风险基因：对于至少一个基因，我们将使用尖端分子技术(例如，TALENS，RNAi)了解新的RA风险等位基因的功能后果，并使用这些信息进行HTS。总而言之，这三个目标将(1)在欧洲和亚洲人中使用GWAS发现新的RA风险基因座，(2)从GWAS基因座(也在欧洲和亚洲人中)的因果基因中发现罕见的RA风险等位基因，以及(3)将遗传发现转化为新的生物学和小分子化合物的HTS。影响：我们将在过去成就的基础上进行迄今为止最全面的类风湿性关节炎基因研究(从常见等位基因到罕见等位基因)。我们将开发整合GWAS和序列数据的创新方法，以及利用人类遗传学指导药物发现的创新方法。我们的团队拥有实现这些目标的所有经验和资源。