Integrative Transcriptome‐Wide Association Study With Expression Quantitative Trait Loci Colocalization Identifies a Causal VAMP8 Variant for Nasopharyngeal Carcinoma Susceptibility

Abstract Nasopharyngeal carcinoma (NPC) is an Asia‐prevalent malignancy, yet its genetic underpinnings remain incompletely understood. Here, a transcriptome‐wide association study (TWAS) is conducted on NPC, leveraging gene expression prediction models based on epithelial tissues and genome‐wide association study (GWAS) summary statistics from 1577 NPC cases and 6359 controls of southern Chinese descent. The TWAS identifies VAMP8 on chromosome 2p11.2 as a novel susceptibility gene for NPC. Further fine‐mapping analyses pinpoint rs1058588, located within VAMP8 , as a causal variant through eQTL colocalization, and GWAS analyses across multiple cohorts, achieving GWAS significance (OR = 1.18, P = 3.09 × 10 −10 ). Functional assays demonstrate that VAMP8 exerts a tumorigenic role in NPC, enhancing cell proliferation, migration, and tumor growth. Mechanically, it is uncovered that rs1058588 modulates VAMP8 expression by altering its binding affinity to miR‐185 . Furthermore, the results show that VAMP8 interacts with DHX9 to facilitate the nuclear recruitment of p65, activating the NF‐κB pathway. Collectively, the findings shed light on the genetic predisposition to NPC and underscore the critical role of the functional axis involving miR‐185, VAMP8, DHX9, and the NF‐κB pathway in NPC pathogenesis.