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Background Our previous genome-wide association study (GWAS) identified that chromosome 1p36.22 locus contributes to the risk of hepatocellular carcinoma (HCC).Objective We aimed to identify the functional causative variant(s) and target gene(s) at this locus.Design Two independent HCC case–control populations, totally consisting of 1934 cases and 1446 controls, were used to validate the association between 1p36.22 locus and HCC risk. The expression quantitative trait locus (eQTL) and eQTL-GWAS co-localisation analyses were used to identify the target gene at 1p36.22. The effects of the target gene on tumourigenesis were assessed in HCC cells, nude mouse models and conditional knockout mouse models.Results We confirmed the association between 1p36.22 locus and HCC risk (p=4.99×10 −24), and revealed that this locus is an eQTL of the kinesin family member 1B isoform β (KIF1Bβ) gene. Further, we demonstrated that KIF1Bβ plays a tumour suppressive role in HCC in vitro and in vivo. Mechanistically, KIF1Bβ interacts with the cargo Fibulin-5 and mediates its intracellular anterograde transport and extracellular secretion, therefore, reducing the activation of the integrin pathway. We further identified the functional causative variant rs61784580 at 1p36.22, which is located in the promoter of KIF1Bβ and regulates its expression in an allele-specific manner. Finally, we observed that downregulation of KIF1Bβ sensitises HCC cells to integrin αv inhibitor cilengitide.Conclusions Our findings shed light on the genetic and molecular mechanisms of the HCC-associated susceptibility locus at 1p36.22 and provide potential new strategies for the treatment of HCC.