■肝细胞癌(HCC)是全球最常见的癌症之一,在东亚很普遍。虽然肝癌的全基因组关联研究(GWAS)已经确定了23个风险区域,这些关联背后的易感基因在很大程度上仍不清楚.确定肝癌的新候选基因,我们在两个东亚人群中进行了肝脏单组织和跨组织全转录组关联研究(TWASs).
■使用来自中国启东队列的2,514名受试者(1,161例HCC病例和1,353例对照)和来自BioBank日本项目的161,323名受试者(2,122例HCC病例和159,201例对照)的GWAS汇总统计数据进行TWAS分析。单组织和跨组织TWAS方法均用于检测易感基因与HCC风险之间的关联。TWAS鉴定的基因通过Metascape进一步注释,UALCAN,GEPIA2和DepMap。
■我们在Bonferroni校正后,在16个独立位点鉴定出22个新基因与HCC风险显著相关。其中,13个基因位于新区域。此外,我们发现中国和日本队列中有83个基因重叠,P<0.05,通过单组织和跨组织TWAS方法可识别三个基因(NUAK2,HLA-DQA1和ATP6V1G2).在通过TWAS鉴定的基因中,其中很大一部分在肝癌生物学中表现出可信的作用,例如FAM96B,HSPA5、POLRMT、MPHOSPH10和RABL2A。HLA-DQA1,NUAK2和HSPA5与先前报道的HCC癌变过程相关。
■我们的发现强调了利用基因表达数据来识别超出GWAS关联的新候选基因的价值,并可以进一步为HCC的生物学提供遗传见解。
UNASSIGNED: Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide and is prevalent in East Asia. Although genome-wide association studies (GWASs) of HCC have identified 23 risk regions, the susceptibility genes underlying these associations largely remain unclear. To identify novel candidate genes for HCC, we conducted liver single-tissue and cross-tissue transcriptome-wide association studies (TWASs) in two populations of East Asia.
UNASSIGNED: GWAS summary statistics of 2,514 subjects (1,161 HCC cases and 1,353 controls) from the Chinese Qidong cohort and 161,323 subjects (2,122 HCC cases and 159,201 controls) from the BioBank Japan project were used to conduct TWAS analysis. The single-tissue and cross-tissue TWAS approaches were both used to detect the association between susceptible genes and the risk of HCC. TWAS identified genes were further annotated by Metascape, UALCAN, GEPIA2, and DepMap.
UNASSIGNED: We identified 22 novel genes at 16 independent loci significantly associated with HCC risk after Bonferroni correction. Of these, 13 genes were located in novel regions. Besides, we found 83 genes overlapped in the Chinese and Japanese cohorts with P < 0.05, of which, three genes (NUAK2, HLA-DQA1, and ATP6V1G2) were discerned by both single-tissue and cross-tissue TWAS approaches. Among the genes identified through TWAS, a significant proportion of them exhibit a credible role in HCC biology, such as FAM96B, HSPA5, POLRMT, MPHOSPH10, and RABL2A. HLA-DQA1, NUAK2, and HSPA5 associated with the process of carcinogenesis in HCC as previously reported.
UNASSIGNED: Our findings highlight the value of leveraging the gene expression data to identify new candidate genes beyond the GWAS associations and could further provide a genetic insight for the biology of HCC.