Unveiling novel susceptibility genes for sarcoidosis by a cross-tissue transcriptome-wide association study
1Zhongshan School of Medicine, Sun Yat-sen University.
Summary
This study identified four novel genes (RNF215, PLCL1, FAM117B, RFTN2) associated with sarcoidosis risk and protection. Findings offer new insights into sarcoidosis pathogenesis and potential therapeutic targets.
Area of Science:
- Genetics and Genomics
- Immunology
- Systems Biology
Background:
- Sarcoidosis is a systemic granulomatous disease with unknown causes.
- Previous genome-wide association studies (GWAS) identified some immune-related genes, but their functions are unclear.
- Integrative transcriptome-wide approaches are needed to find new susceptibility genes and understand disease mechanisms.
Purpose of the Study:
- To identify novel susceptibility genes for sarcoidosis using a cross-tissue transcriptome-wide association study (TWAS).
- To gain mechanistic insights into sarcoidosis pathogenesis.
- To explore functional roles of identified genes through various bioinformatics and association analyses.
Main Methods:
- Conducted a cross-tissue TWAS using the UTMOST framework and single-tissue TWAS via FUSION.
- Prioritized candidate genes using Multi-marker Analysis of Genomic Annotation (MAGMA), Mendelian randomization (MR), and Bayesian colocalization.
- Performed functional characterization using the Comparative Toxicogenomics Database (CTD) and UK Biobank phenome-wide association studies (PheWAS).
Main Results:
- Identified 48 genes through cross-tissue TWAS, prioritizing four novel susceptibility genes: RNF215, PLCL1, FAM117B, and RFTN2.
- MR and colocalization analyses supported causal roles for RNF215 (risk-increasing), FAM117B and RFTN2 (protective), and tissue-dependent effects for PLCL1.
- Discovered gene interactions with environmental chemicals (e.g., bisphenol A) and pleiotropic associations with immune, respiratory, hematological, and cardiovascular traits.
Conclusions:
- Identified four biologically plausible susceptibility genes for sarcoidosis, expanding the known genetic architecture of the disease.
- These findings suggest potential new targets for mechanistic research and therapeutic interventions in sarcoidosis.
- Highlights the utility of integrative transcriptome-wide approaches for uncovering complex disease genetics.
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