Prioritization of nasal polyp-associated genes by integrating GWAS and eQTL summary data

Area of Science:

• Genetics
• Immunology
• Otolaryngology

Background:

• Nasal polyps (NP) are inflammatory growths causing significant quality of life impairment, with challenging relapse rates post-surgery.
• Current understanding of NP's underlying genetic mechanisms is limited, hindering effective curative therapies.
• Genome-wide association studies (GWASs) have identified loci, but causal genes remain elusive.

Purpose of the Study:

• To prioritize genes causally associated with nasal polyps for future functional studies.
• To integrate GWAS data with expression quantitative trait locus (eQTL) data to identify potential causal genes for NP.
• To elucidate the genetic underpinnings of nasal polyps to inform therapeutic strategies.

Main Methods:

• Utilized summary-level data from a large GWAS of NP (5,554 cases, 258,553 controls) and eQTL data (31,684 participants).
• Employed summary data-based Mendelian Randomization (SMR) and Bayesian colocalization (COLOC) methods to identify and validate gene-trait associations.
• Performed enrichment analysis using Metascape to explore the biological functions of prioritized genes.

Main Results:

• Identified TNFRSF18, CTSK, and IRF1 as genes associated with NP through pleiotropy or causality, not just linkage.
• COLOC analysis confirmed shared causal variants between these genes and NP, indicating colocalization.
• Enrichment analysis suggested these genes are involved in cellular response to cytokine stimulus.

Conclusions:

• Prioritized TNFRSF18, CTSK, and IRF1 as key candidate genes for nasal polyps.
• These findings provide a foundation for future functional studies to unravel NP pathogenesis.
• The study offers insights into potential therapeutic targets for nasal polyps.