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：
8645728
负责人：
Courtney Montgomery
金额：
$ 117.96万
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 2017-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8645728
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 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 Targeted Resequencing Testing Time Variant Work base caucasian American data integration exome exome sequencing genetic epidemiology genetic variant genome sequencing genome wide association study insight mortality next generation sequencing novel novel strategies rare variant response risk variant

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）：结节病的特征是过度免疫反应，导致多个器官形成肉芽肿。它对非裔美国人 (AA) 的影响比白人更频繁、更严重。虽然之前的连锁、混合、候选基因和全基因组关联 (GWA) 研究显示出统计学上令人信服的影响，但因果变异仍然未知，结节病的遗传性也有待解释。这种“缺失”的遗传力可能包括常见变异（次要等位基因频率 (MAF)>5%）和罕见变异（MAF<5%）的影响，因为在 AA 中，前者没有得到充分的体现，而后者则完全没有被商业化探索。基因分型阵列。这些事实，加上下一代测序的可用性，迫使我们对构成结节病基础的遗传变异进行详尽的搜索。对于这项提案，我们将把大规模平行人类外显子组和靶向测序数据与之前收集的 AA 结节病家族基因型和表型数据整合起来，以识别尚未发现的遗传变异。我们广泛的、独一无二的样本将最大限度地提高检测 RV 关联的能力并帮助建立阶段，这对于理解变异的分子生理学至关重要。我们将 1) 通过外显子组测序鉴定编码区变异，2) 通过靶向重测序捕获先前研究鉴定的 39 个区域的编码和非编码序列中的变异，3) 在独立样本中复制真正的阳性 CV 和 RV 效应。我们的团队领导了 AA 中结节病基因的研究，凭借肺病学、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全准备好成功完成拟议项目的团队。生成的数据肯定能识别候选因果变异，为功能研究提供基本见解，并得出重要的炎症新假设，从而不仅为结节病而且为其他炎症性疾病带来新的治疗方法。