Comprehensive Genome Interrogation of African American Sarcoidosis Families

非裔美国结节病家族的综合基因组调查

基本信息

批准号：
9041664
负责人：
Courtney Montgomery
金额：
$ 80.83万
依托单位：
OKLAHOMA MEDICAL RESEARCH FOUNDATION
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-04-01 至 2019-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9041664
关键词：
Accounting Admixture Affect African American Age Bioinformatics Biological Assay Biometry Candidate Disease Gene Code Collection Coupled Custom DNA DNA Resequencing DNA Sequence Data Development Disease Environment Environmental Exposure Etiology Family Family member Gene Frequency Genes Genetic Genetic Predisposition to Disease Genetic Risk Genetic study Genome Genomics Genotype Granuloma Heritability High Prevalence Human Incidence Inflammation Inflammatory Lead Libraries Methods Minor Molecular Organ Pathology Patients Persons Phase Phenotype Physiology Predisposition Proteins Pulmonology Resources Role Sampling Sarcoidosis Scanning Signal Transduction Statistical Methods Susceptibility Gene Targeted Resequencing Testing Time Variant Work base caucasian American data integration exome exome sequencing gene environment interaction genetic epidemiology genetic variant genome sequencing genome wide association study insight mortality next generation sequencing novel novel strategies rare variant response risk variant targeted sequencing

项目摘要

DESCRIPTION (provided by applicant): Sarcoidosis is characterized by a hyperimmune response resulting in granuloma formation in multiple organs. It affects African Americans (AAs) more frequently and more severely than whites. While previous linkage, admixture, candidate gene and genome-wide association (GWA) studies show statistically compelling effects, causal variants are still unknown and much of sarcoidosis heritability is yet to be explained. This "missing" heritability likely includes effects of both common (minor allele frequency (MAF)>5%) and rare variants (MAF<5%), since, in AAs, the former are inadequately represented and the latter are completely unexplored by commercial genotyping arrays. These facts, coupled with the availability of next-generation sequencing compel us to perform an exhaustive search for genetic variants that form the basis of sarcoidosis. For this proposal, we will integrate massivel parallel human exome and targeted sequencing data with previously collected genotype and phenotype data in AA sarcoidosis families to identify undiscovered genetic variants. Our extensive, one-of-a-kind sample will maximize power to detect RV association and help to establish phase, which is critical in understanding the molecular physiology of variants. We will 1) identify coding region variants by exome sequencing, 2) capture variants in the coding and noncoding sequence of 39 regions identified by previous studies via targeted resequencing, and 3) replicate, in an independent sample, true positive CV and RV effects. Our assembled team has led the search for sarcoidosis genes in AAs, and with expertise in pulmonology, genetics, epidemiology, genome sequencing, biostatistics and bioinformatics, we are the only group in the world perfectly poised to successfully complete the proposed projects. The data generated are certain to identify candidate causal variants, provide fundamental insight for functional studies and lead to important new hypotheses of inflammation resulting in new treatments in not only sarcoidosis but other inflammatory diseases as well.

描述（由申请人提供）：结节病的特征是超免疫反应，导致多个器官形成肉芽肿。它比白人更频繁，更严重地影响非裔美国人（AAS）。虽然以前的联系，混合，候选基因和全基因组关联（GWA）研究表明统计上令人信服的效果，但因果变异仍然未知，大部分结节病遗传力尚待解释。这种“缺失”的遗传力可能包括常见的（MAF频率（MAF）> 5％）和稀有变体（MAF <5％）的影响，因为在AAS中，前者的代表不足，而后者完全无法通过商业基因分型阵列来探索。这些事实，再加上下一代测序的可用性迫使我们对构成结节病的基础的遗传变异进行了详尽的搜索。对于此提案，我们将将平行的人类外显子组和靶向测序数据与AA结节病中的先前收集的基因型和表型数据整合在一起，以鉴定未发现的遗传变异。我们广泛的，独一无二的样本将最大程度地提高能力检测RV关联并有助于建立阶段，这对于理解变体的分子生理至关重要。我们将1）通过外显子组测序识别编码区域变体，2）捕获以前研究通过靶向重新取证鉴定的39个区域的编码和非编码序列中的变体，3）在独立的样本，真实的正面CV和RV效应中复制。我们的组装团队领导了在AAS中寻找结节病基因，并且具有肺功学，遗传学，流行病学，基因组测序，生物统计学和生物信息学方面的专业知识，我们是世界上唯一完美准备成功完成所提出的项目的群体。生成的数据肯定可以识别候选因果变异，为功能研究提供基本见解，并导致重要的炎症新假设，从而导致新治疗不仅在结节症中，而且还导致其他炎症性疾病。