Unveiling novel susceptibility genes for sarcoidosis by a cross-tissue transcriptome-wide association study
Keywords:
Sarcoidosis, Transcriptome-wide association study, Gene expression, Susceptibility genesAbstract
Background: Sarcoidosis is a systemic granulomatous disease with heterogeneous clinical manifestations and unclear pathogenesis. Although genome-wide association studies (GWAS) have identified several immune-related loci, the functional interpretation of these signals remains limited. Integrative transcriptome-wide approaches may uncover novel susceptibility genes and provide mechanistic insights.
Objectives: The primary objective of this study was to identify novel susceptibility genes for sarcoidosis and provide mechanistic insights into its pathogenesis through a comprehensive, cross-tissue transcriptome-wide approach.
Methods: We conducted a cross-tissue transcriptome-wide association study (TWAS) using the UTMOST framework, followed by single-tissue TWAS via FUSION. Candidate genes identified in both analyses were further evaluated using Multi-marker Analysis of Genomic Annotation (MAGMA), Mendelian randomization (MR), and Bayesian colocalization. Functional characterization was explored through gene–chemical–disease associations from the Comparative Toxicogenomics Database (CTD) and phenome-wide association studies (PheWAS) in the UK Biobank.
Results: Cross-tissue TWAS identified 48 genes. Integrative analyses prioritized four novel susceptibility genes: RNF215, PLCL1, FAM117B, and RFTN2. MR and colocalization supported causal effects of RNF215 (risk-increasing), FAM117B and RFTN2 (protective), and tissue-dependent effects for PLCL1. CTD analyses revealed interactions of these genes with environmental chemicals including bisphenol A and tetrachlorodibenzodioxin, while PheWAS demonstrated pleiotropic associations with immune, respiratory, hematological, and cardiovascular traits.
Conclusions: This comprehensive integrative study identifies four biologically plausible susceptibility genes for sarcoidosis, expanding the genetic architecture of sarcoidosis and suggest potential targets for mechanistic and therapeutic investigation.
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