NHLBI TOPMed: African American Sarcoidosis Genetics Resource

This study aims to comprehensively interrogate the genomes of African American sarcoidosis families. 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. 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.]]>
TOPMed Whole Genome Sequencing Methods: Freeze 9TOPMed Whole Genome Sequencing Methods: Freeze 10Our AA sample collection was taken from an extensive cohort of AA sarcoidosis patients and family members from the sarcoidosis genetic analysis (SAGA) sample ascertained through affected sib pairs and a nuclear family-based sample ascertained through single sarcoidosis-affected offspring from the Henry Ford Health System in Detroit, Michigan. Subjects were considered as sarcoidosis cases if they met criteria for either definite or highly probable cases of sarcoidosis. Definite cases had noncaseating granulomas (histologically confirmed) and clinical manifestations in either the thorax or at least two other organs. Highly probable cases showed bilateral hilar adenopathy in their chest radiographs and either had a history of erythema nodosum or no other disease was diagnosed at least for 2 years observation to explain radiographic abnormalities. Cases with active tuberculosis were excluded. Unaffected family members were included in the study to serve as a control group.]]>