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: 8576206
• 负责人: Soumya Raychaudhuri
• 金额: $ 37.49万
• 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/8576206
• 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; Genetic Variation; 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; genome wide association study; high throughput screening; improved; innovation; insight; loss of function; novel; protein protein interaction; public health relevance; research study; 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个类风湿关节炎（RA）风险位点。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。我们已经发表的数据表明，最常见的RA风险等位基因在不同的种族群体中共享。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-我们将对约20，000例RA病例和60，000例匹配对照（亚洲和欧洲血统）进行多种族GWAS。我们还将比较和对比两个种族的遗传发现，并开发新的分析方法。我们有数据（出版中的手稿）表明，从GWAS中鉴定出的RA风险基因含有导致RA风险的罕见等位基因。与其他疾病的数据一起，这导致了GWAS发现的RA风险位点的致病基因将包含独立的蛋白质编码突变的假设（其中大多数在一般人群中是罕见的）。在目标2中，我们将通过对所有基因（总共约650个）进行测序来验证这一假设。 GWAS在1,300例RA病例和1,300例欧洲血统非RA对照中鉴定出。我们还将对约2,000例亚洲血统的RA病例对照样本进行测序，以比较和对比两个种族群体的遗传学发现。我们将进行遗传负荷测试，以确定哪些基因在病例中含有比随机预期更多的罕见风险等位基因。然而，找到致病变异和基因只是将遗传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）是极好的药物靶点，特别是携带功能丧失（LOF）等位基因的基因，这些等位基因可以防止疾病。我们有关于一个RA风险位点的未发表数据，证明我们有能力从GWAS进展到约2，000个小分子的高通量筛选（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），并使用此信息进行HTS。总之，这三个目标将（1）在欧洲人和亚洲人中使用GWAS发现新的RA风险基因座，（2）在GWAS基因座（也在欧洲人和亚洲人中）的致病基因中发现罕见的RA风险等位基因，（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：我们将在过去的成就基础上进行迄今为止最全面的RA遗传研究（从常见到罕见等位基因）。我们将开发整合GWAS和序列数据的创新方法，以及使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。