Genome-wide association study of African and European Americans implicates multiple shared and ethnic specific loci in sarcoidosis susceptibility

Abstract

Sarcoidosis is a systemic inflammatory disease characterized by the formation of granulomas in affected organs. Genome-wide association studies (GWASs) of this disease have been conducted only in European population. We present the first sarcoidosis GWAS in African Americans (AAs, 818 cases and 1,088 related controls) followed by replication in independent sets of AAs (455 cases and 557 controls) and European Americans (EAs, 442 cases and 2,284 controls). We evaluated >6 million SNPs either genotyped using the Illumina Omni1-Quad array or imputed from the 1000 Genomes Project data. We identified a novel sarcoidosis-associated locus, NOTCH4, that reached genome-wide significance in the combined AA samples (rs715299, P(AA-meta) = 6.51 × 10(-10)) and demonstrated the independence of this locus from others in the MHC region in the same sample. We replicated previous European GWAS associations within HLA-DRA, HLA-DRB5, HLA-DRB1, BTNL2, and ANXA11 in both our AA and EA datasets. We also confirmed significant associations to the previously reported HLA-C and HLA-B regions in the EA but not AA samples. We further identified suggestive associations with several other genes previously reported in lung or inflammatory diseases.

Figure 1. A graphical overview of the GWAS datasets.

(A–B) Summary of the AA (A) and EA (B) datasets.

Figure 2. Manhattan plots of SNP-sarcoidosis association test results.

(A–D) Association results in the AA discovery set (A), a meta-analysis between the AA discovery and AA replication sets (B), the EA dataset (C), and a meta-analysis of the AA discovery, AA replication and EA datasets (D). The black horizontal line represents the threshold for genome-wide significance (P<5×10⁻⁸) and the gray line is the suggestive evidence of association threshold (P<1×10⁻⁴).

Figure 3. Regional association plots of SNP-sarcoidosis association test results within the MHC Class II region.

(A–D) Association results in the AA discovery set (A), AA replication set (B), a meta-analysis between the AA discovery and AA replication sets (C), the EA dataset (D), and a meta-analysis of the AA discovery, AA replication and EA datasets (E). Each SNP is colored according to its LD (r ²) with the top SNP, except for (E) since the meta-analysis was performed on two different populations. The recombination rate is denoted by the blue solid line. Plots were drawn using LocusZoom .