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: 9478546
• 负责人: Soumya Raychaudhuri
• 金额: $ 37.61万
• 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 2021-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9478546
• 关键词: 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 Screening; Drug Targeting; Ethnic group; European; Exons; Family; Finding by Cause; Gene Expression Profile; General Population; Genes; Genetic; Genetic study; Goals; Heritability; Human; Human Genetics; Individual; Japanese Population; Korea; Manuscripts; Maps; Methods; Molecular; Mutation; Pathogenesis; Pathway interactions; Patient Care; 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; ethnic diversity; experience; experimental study; gain of function; genome wide association study; high throughput screening; improved; innovation; insight; loss of function; new therapeutic target; novel; protein protein interaction; public health relevance; rare variant; risk variant; small molecule; targeted sequencing; theories; tool; transcription activator-like effector nucleases

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) 和相关方法已确定超过 60 个类风湿性关节炎 (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。我们发布的数据表明，最常见的 RA 风险等位基因在不同种族群体中是共有的。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 - 我们将对约 20,000 个 RA 病例和 60,000 个匹配对照（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（待出版的手稿）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。结合其他疾病的数据，这导致了这样的假设：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（其中大多数在普通人群中很少见）。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 GWAS 在 1,300 个 RA 病例和 1,300 个欧洲血统的非 RA 对照中发现了这一点。我们还将对约 2,000 个亚洲血统的 RA 病例对照样本进行测序，以便比较和对比两个种族群体的遗传发现。我们将进行遗传负担测试，以确定与对照组相比，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（即影响疾病风险的多个等位基因）的基因是极好的药物靶标，尤其是携带可预防疾病的功能丧失（LOF）等位基因的基因。我们拥有关于一个 RA 风险位点的未发表数据，这些数据表明我们有能力从 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 TALEN、RNA​​i）了解新的 RA 风险等位基因的功能后果，并使用此信息进行 HTS。这三个目标共同将（1）利用 GWAS 在欧洲人和亚洲人中发现新的 RA 风险位点，（2）从 GWAS 位点（也在欧洲人和亚洲人中）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：我们将在过去的成就的基础上，对 RA 进行迄今为止最全面的遗传学研究（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。