GWAS identifies genetic loci, lifestyle factors and circulating biomarkers that are risk factors for sarcoidosis

Abstract

Sarcoidosis is a complex inflammatory disease with a strong genetic component. Here, we perform a genome-wide association study in 9755 sarcoidosis cases to identify risk loci and map associated genes. We then use transcriptome-wide association studies and enrichment analyses to explore pathways involved in sarcoidosis and use Mendelian randomization to examine associations with modifiable factors and circulating biomarkers. We identify 28 genomic loci associated with sarcoidosis, with the C1orf141-IL23R locus showing the largest effect size. We observe gene expression patterns related to sarcoidosis in the spleen, whole blood, and lung, and highlight 75 tissue-specific genes through transcriptome-wide association studies. Furthermore, we use enrichment analysis to establish key roles for T cell activation, leukocyte adhesion, and cytokine production in sarcoidosis. Additionally, we find associations between sarcoidosis and genetically predicted body mass index, interleukin-23 receptor, and eight circulating proteins.

Fig. 1. Transcriptome-wide association study (TWAS) of sarcoidosis and pathway enrichment.

a TWAS in spleen. b TWAS in whole blood. c TWAS in lung. In a–c, statistical analyses were conducted using a two-sided test, with Bonferroni correction applied for multiple comparisons, and the top 20 signals were labeled. d genes identified by TWAS associated with pathways. e GO pathway enrichment based on TWAS signals survived after Bonferroni correction. GO enrichment analysis was performed using a two-sided test, with false discovery rate (FDR) correction applied to account for multiple comparisons. Source data are provided as a Source Data file.

Fig. 2. Associations between genetically predicted lifestyle factors and risk of sarcoidosis in Mendelian randomization (MR) analysis.

Statistical analyses were conducted using a two-sided test. Data are presented as odds ratio +/− 95% confidence interval. The analysis was based on European GWAS data including 7554 cases 1,367,006 and controls. The number of genetic instruments for these traits is presented in Supplementary Data 7. Source data are provided as a Source Data file. CI, confidence interval; IVW, inverse variance weighted with multiplicative random effects; OR, odds ratio.

Fig. 3. Associations between genetically predicted levels of 65 inflammatory markers and the risk of sarcoidosis in Mendelian randomization (MR) analysis.

Statistical analyses were conducted using a two-sided test. The analysis was based on European GWAS data including 7554 cases 1,367,006 and controls. The number of genetic instruments for inflammatory markers is presented in Supplementary Data 4. a Volcano plot of MR associations between 65 inflammatory markers and sarcoidosis. b Forest plot of 10 associations with P-value < 0.05. Data are presented as odds ratio +/− 95% confidence interval. c Reginal locus plot for interleukin 23 receptor (IL23R) and sarcoidosis. The associations in a and b were scaled to one standard deviation increase in genetically predicted markers. Source data are provided as a Source Data file. OR, odds ratio.

Fig. 4. Protein-wide Mendelian randomization analysis of sarcoidosis and corresponding colocalization analysis.

a Volcano plot of genetically predicted levels of proteins in relation to sarcoidosis. The associations with false discovery rate (FDR) < 0.05 were labeled. b Forest plot of the associations survived after multiple testing correction. Data are presented as odds ratio +/− 95% confidence interval. The analysis was based on European GWAS data including 7554 cases 1,367,006 and controls. The levels of proteins were genetically instrumented by one lead cis genetic variant. c Colocalization analysis of identified protein-AF association. Posterior probabilities (PP) H0 stands for no association between the genetic variants and either trait. PPH1 stands for an association between the genetic variants and only the protein, with no association with sarcoidosis. PPH2 stands for an association between the genetic variants and only sarcoidosis, with no association with the protein. PPH3 stands for an association between the genetic variants and both traits, but with independent signals. PPH4 stands for colocalization, where a shared genetic signal is associated with both traits. PPH4 > 0.7 was deemed strong colocalization evidence. Source data are provided as a Source Data file.