Immune-cell-expressed candidate genes for esophageal carcinoma prioritised by whole-blood eQTL colocalisation, Mendelian randomisation, and single-cell eGene annotation

Background Esophageal carcinoma (EC) is the seventh leading cause of cancer-related mortality worldwide, yet its immune-regulatory circuitry remains poorly defined. We aimed to prioritise immune-cell-expressed candidate genes for EC by integrating whole-blood expression quantitative trait loci (eQTL) summary statistics with Bayesian colocalisation, two-sample Mendelian randomisation (MR), and single-cell eGene annotation from OneK1K. Methods Summary-data-based Mendelian randomisation (SMR) used eQTLGen whole-blood cis-eQTL and EC GWAS summary statistics (GCST90018841; 998 European-ancestry and 1,388 East-Asian cases; 475,308 European-ancestry and 159,201 East-Asian controls), with 14 OneK1K immune-cell-subset eGene lists (26,597 entries) defining testing scopes. Benjamini-Hochberg correction covered all tests. Colocalisation used coloc v5.2.3, all regional SNPs and twelve prior settings; two-sample MR was repeated after standard LD clumping (r 2 < 0.001, 10,000 kb; 1000 Genomes EUR). Because the outcome GWAS is shared, MR is an internal consistency and directionality check, not independent replication. Candidates were tiered under pre-specified criteria and annotated by STRING, DGIdb, TRRUST, GeneMANIA, CTD and UniProt. Differential expression was assessed in GSE20347 (Affymetrix microarray; 17 paired ESCC/normal; patient-matched limma) and TCGA-ESCA (RNA-seq; DESeq2). Results Across 5,331 unique genes (14,491 gene-by-subset tests), 571 gene-by-subset associations (238 unique genes) were nominally significant, and none survived global FDR correction (smallest q = 0.08); the study is therefore framed as exploratory. Of the 22 candidates carried forward from the previous sentinel-SNP screen, multi-SNP colocalisation supported seven at PPH4 > 0.5 under default priors; PPH4 ranged from 0.06 to 0.99 across prior settings and no gene maintained PPH4 > 0.8 in all settings. Six candidates with significant MR after standard clumping formed the primary panel: NFAM1 (OR = 2.32) and SRI (1.68) were risk-increasing, whereas ZC3H7A (0.63), UBE2Q2 (0.72), TSPAN32 (0.85) and ASCL2 (0.86) were protective. Transcriptomic support was partial and gene-specific (ASCL2 and SRI up-regulated in TCGA-ESCA; TSPAN32 down-regulated in both cohorts; ZC3H7A elevated in GSE20347 but decreased in TCGA-ESCA). One medium-confidence STRING interaction (TSPAN32–ASCL2, score 0.65) and four approved drugs targeting SRI were identified. Conclusion This exploratory, sensitivity-tested analysis nominates six immune-cell-expressed candidate genes for EC and provides the complete, auditable evidence trail; experimental validation is required to establish any functional or clinical role.