Fine-mapping in African-American women confirms the importance of the 10p12 locus to sarcoidosis

Abstract

Sarcoidosis is a chronic granulomatous disease with a wide spectrum of symptoms. Genome-wide association studies in European populations have reported significant associations between sarcoidosis and single-nucleotide polymorphisms (SNPs) located in the intergenic region between the C10ORF67 and OTUD1 genes on chromosome 10p12, and the ANXA11 gene (chromosome 10q22). We carried out fine-mapping at 10p12 and 10q22 to assess associations of genetic variants in these regions with sarcoidosis risk in African-American women, based on 486 sarcoidosis cases and 943 age- and geography-matched controls in a nested case-control study within the Black Women's Health Study. There were no significant associations with variants of the ANXA11 gene (P=0.17). Haplotypic analyses of the C10ORF67-OTUD1 intergenic region revealed a strong inverse association of the variants rs1398024 and rs11013452 with sarcoidosis (odds ratio=0.52; P=0.01). Both SNPs are located inside an ∼300 kb low recombination region of chromosome 10p12, suggesting that both SNPs are tagging the same causal variant. Our top SNP (rs11013452) is located inside a smaller linkage disequilibrium block in HapMap YRI, further narrowing the position of the causal SNP to a region of ~8 kb on chromosome 10p12. The present findings confirm the potential importance of the 10p12 locus in the etiology of sarcoidosis.

Figure 1

Scatterplot and LD map of the genotyped tagging SNPs along the 33 kb LD block in the C10ORF67/OTUD1 intergenic region. The upper panel shows the association in the logarithmic scale. The dotted line indicates the threshold of nominal significance α = 0.05. Position of the index SNP (rs1398024) is indicated as well as the newly identified SNP (rs11013452). The lower panels show the D′ pair-wise values in both CEU and YRI HapMap samples. The newly identified SNP is located in a smaller 8 kb LD block in YRI HapMap sample.