全基因组关联研究（GWAS）对于阐明神经母细胞瘤（NB）的遗传易感性具有决定性作用。 GWAS 中发现的大多数遗传变异都存在于非编码区域，这表明它们可能是基因表达致病性失调的原因。尽管如此，查明相关基因座中潜在的致病基因仍然是一个重大挑战。在这项研究中，我们整合了来自肾上腺的 NB GWAS 和表达数量性状位点 (eQTL) 数据，以确定影响 NB 易感性的候选基因。我们发现 ZMYM1、CBL、GSKIP 和 WDR81 的表达因 NB 易感变异而失调。我们通过对 NB、神经嵴和肾上腺组织的单细胞和全组织样本的 RNA 测序 (RNA-seq) 数据进行计算分析，以及通过体外分化测定，进一步研究了已识别基因的功能作用。在 NB 细胞培养中。我们的结果表明，ZMYM1、CBL、GSKIP、WDR81 的失调可能通过影响神经元分化正常程序的早期和晚期而导致恶性转化。我们的研究结果通过强调特定基因对神经元分化的影响并强调遗传风险变异对参与关键生物过程的基因调控的影响，增强了对特定基因如何促进 NB 发病机制的理解。© 2024。作者。

Genome-Wide Association Studies (GWAS) have been decisive in elucidating the genetic predisposition of neuroblastoma (NB). The majority of genetic variants identified in GWAS are found in non-coding regions, suggesting that they can be causative of pathogenic dysregulations of gene expression. Nonetheless, pinpointing the potential causal genes within implicated genetic loci remains a major challenge. In this study, we integrated NB GWAS and expression Quantitative Trait Loci (eQTL) data from adrenal gland to identify candidate genes impacting NB susceptibility. We found that ZMYM1, CBL, GSKIP and WDR81 expression was dysregulated by NB predisposing variants. We further investigated the functional role of the identified genes through computational analysis of RNA sequencing (RNA-seq) data from single-cell and whole-tissue samples of NB, neural crest, and adrenal gland tissues, as well as through in vitro differentiation assays in NB cell cultures. Our results indicate that dysregulation of ZMYM1, CBL, GSKIP, WDR81 may lead to malignant transformation by affecting early and late stages of normal program of neuronal differentiation. Our findings enhance the understanding of how specific genes contribute to NB pathogenesis by highlighting their influence on neuronal differentiation and emphasizing the impact of genetic risk variants on the regulation of genes involved in critical biological processes.© 2024. The Author(s).