NHLBI TOPMed: African American Sarcoidosis Genetics Resource

This study is part of the NHLBI Trans-Omics for Precision Medicine (TOPMed) Whole Genome Sequencing Program. TOPMed is part of a broader Precision Medicine Initiative, which aims to provide disease treatments that are tailored to an individual's unique genes and environment. TOPMed will contribute to this initiative through the integration of whole-genome sequencing (WGS) and other -omics (e.g., metabolic profiles, protein and RNA expression patterns) data with molecular, behavioral, imaging, environmental, and clinical data. In doing so, this program aims to uncover factors that increase or decrease the risk of disease, to identify subtypes of disease, and to develop more targeted and personalized treatments. Two genotype call sets derived from WGS are now available, Freeze 8 (GRCh38) and Freeze 9b (GRCh38), with largely overlapping sample sets. Information about how to identify other TOPMed WGS accessions for cross-study analysis, as well as descriptions of TOPMed methods of data acquisition, data processing and quality control, are provided in the accompanying documents, "TOPMed Whole Genome Sequencing Project - Freeze 8, Phases 1-4" and "TOPMed Whole Genome Sequencing Project - Freeze 9b, Phases 1-4". Please check the study list at the top of each of these methods documents to determine whether it applies to this study accession.

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.

• Study Design:
  • Family/Twin/Trios
• Study Type:
  • Affected Sib Pairs
  • Family
• dbGaP estimated ancestry using GRAF-pop
• Subject Sample Telemetry Report (SSTR)

Our 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.

• Primary Phenotype: Sarcoidosis

• ANXA11
• HLA-DRA
• HLA-DRB1
• NOTCH4
• BTNL2

• BioProject
• Sequence Read Archive
• BioSample
• MeSH
• PMC

• Principal Investigator
  • Courtney Montgomery, PhD. Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA.
• Funding Source
  • R01 HL113326. National Institutes of Health, Bethesda, MD, USA.