A genome-wide association study in Chinese children identifies and functionally validates 5q31.1 as a neuroblastoma susceptibility locus

Abstract

BackgroundNeuroblastoma, the most common extracranial solid tumor in children, exhibits considerable clinical heterogeneity influenced by genetic predisposition. While genome-wide association studies (GWAS) in European populations have identified eight susceptibility loci, the genetic basis of neuroblastoma in East Asian populations remains poorly understood. MethodsWe conducted the first GWAS in a Chinese cohort comprising 235 neuroblastoma patients and 3,100 controls, followed by multi-omics analyses of gene expression. The novel risk loci were further validated in an independent East Asian cohort (76 cases/269 controls). Functional characterization of a novel locus was carried out in neuroblastoma cell lines using CRISPR/Cas9-mediated deletion and overexpression assays to evaluate its regulatory effects on candidate genes. FindingsWe replicated six of eight known loci including genome-wide significant associations at CASC15 (6p22.3; P = 1.55 x 10-) and BARD1 (2q35; P = 3.44 x 10-), and identified 11 novel risk loci. These novel associations implicate genes involved in DNA repair (MUTYH at 1p34.1), neurodevelopment (BASP1 at 4q13.2 and SLC22A4/SLC22A5 at 5q31.1), and immune regulation (HLA at 6p21 and IDO1/IDO2 at 5q31.1). Multi-omics integration revealed that lead variants modulate gene expression (cis-eQTLs) and DNA methylation (mQTLs) in neural crest-derived tissues and immune cells. Two loci (rs2631372 at 5q31.1: P= 0.045; rs2956095 at 11p13: P= 0.027) showed consistent associations in the replication cohort. Functional studies demonstrated that deletion of the 5q31.1 risk interval reduced expression of SLC22A4, SLC22A5, and LOC553103, while their overexpression promoted neuroblastoma cell proliferation. InterpretationThese findings highlight both shared and population-specific genetic contributions to neuroblastoma susceptibility, underscoring the importance of diversifying GWAS efforts to advance ancestry-informed risk assessment and therapeutic strategies.