Genome-Wide Association Study of African and European Americans Implicates Multiple Shared and Ethnic Specific Loci in Sarcoidosis Susceptibility

<div><p>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, <em>NOTCH4</em>, that reached genome-wide significance in the combined AA samples (rs715299, <em>P</em>_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 <em>HLA-DRA, HLA-DRB5, HLA-DRB1</em>, <em>BTNL2,</em> and <em>ANXA11</em> in both our AA and EA datasets. We also confirmed significant associations to the previously reported <em>HLA-C</em> and <em>HLA-B</em> regions in the EA but not AA samples. We further identified suggestive associations with several other genes previously reported in lung or inflammatory diseases.</p> </div

Sample summary before and after quality control (QC).

a<p>Taken from the Illumina YRI-ASW iControlDB;</p>b<p>175 Caucasian healthy controls from the Illumina iControlDB, 1047 controls from the dbGaP GENEVA Melanoma study, and 1986 controls from the dbGAP CIDR: NGRC Parkinson’s Disease Study.</p

Frequencies of homozygous risk allele genotypes in Korean SLE patients compared to controls.

<p>OR, odds ratio; CI, confidence interval.</p>*<p>A total of 628 independent female SLE patients and 736 healthy unrelated female controls were genotyped</p

Meta-analysis for risk alleles in SLE-associated <i>MECP2</i> SNPs in Korean and European-derived cohorts

<p>OR, odds ratio; CI, confidence interval</p

Allelic association results and linkage disequilibrium (LD) plot of the chromosome Xq28 region around the <i>MECP2</i> gene.

<p>The allelic association p values of the SNPs analyzed are shown in the Korean cohort included in this study.</p

<i>MECP2</i> haplotype frequencies in the European-derived female SLE patients and controls.

<p>OR, odds ratio; CI, confidence interval.</p

Allelic association results and linkage disequilibrium (LD) plot of the chromosome Xq28 region around the <i>MECP2</i> gene.

<p>The allelic association p values of the SNPs analyzed are shown in the European-derived cohort included in this study.</p

<i>MECP2</i> haplotype frequencies in the Korean SLE patients and controls.

<p>OR, odds ratio; CI, confidence interval.</p

SNPs genotyped in the <i>MECP2</i> region in SLE patients and controls

<p>SNPs genotyped in the <i>MECP2</i> region in SLE patients and controls</p

Replication of previously reported SNPs associated with sarcoidosis [9], [11], [25], [27].

1<p>Major/minor allele of AAs as the reference;</p>2<p>Minor allele frequency;</p>3<p>The odds ratio (OR) was calculated with respect to the minor allele of AAs.</p