Cross-cancer pleiotropic analysis identifies three novel genetic risk variants for colorectal cancer

Jing Sun, Lijuan Wang, Xuan Zhou, Lidan Hu, Shuai Yuan, Zilong Bian, Jie Chen, Yingshuang Zhu, Susan M Farrington, Harry Campbell, Kefeng Ding, Dongfeng Zhang, Malcolm G Dunlop, Evropi Theodoratou, Xue Li

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

BACKGROUND: To understand the shared genetic basis between colorectal cancer (CRC) and other cancers and identify potential pleiotropic loci for compensating the missing genetic heritability of CRC.

METHODS: We conducted a systematic genome-wide pleiotropy scan to appraise associations between cancer-related genetic variants and CRC risk among European populations. Single nucleotide polymorphism (SNP)-set analysis was performed using data from the UK Biobank and the Study of Colorectal Cancer in Scotland (10 039 CRC cases and 30 277 controls) to evaluate the overlapped genetic regions for susceptibility of CRC and other cancers. The variant-level pleiotropic associations between CRC and other cancers were examined by CRC genome-wide association study meta-analysis and the pleiotropic analysis under composite null hypothesis (PLACO) pleiotropy test. Gene-based, co-expression and pathway enrichment analyses were performed to explore potential shared biological pathways. The interaction between novel genetic variants and common environmental factors was further examined for their effects on CRC.

RESULTS: Genome-wide pleiotropic analysis identified three novel SNPs (rs2230469, rs9277378 and rs143190905) and three mapped genes (PIP4K2A, HLA-DPB1 and RTEL1) to be associated with CRC. These genetic variants were significant expressions quantitative trait loci in colon tissue, influencing the expression of their mapped genes. Significant interactions of PIP4K2A and HLA-DPB1 with environmental factors, including smoking and alcohol drinking, were observed. All mapped genes and their co-expressed genes were significantly enriched in pathways involved in carcinogenesis.

CONCLUSION: Our findings provide an important insight into the shared genetic basis between CRC and other cancers. We revealed several novel CRC susceptibility loci to help understand the genetic architecture of CRC.

Original languageEnglish
Pages (from-to)2093-2102
JournalHuman Molecular Genetics
Issue number12
Early online date16 Mar 2023
Publication statusPublished - 15 Jun 2023

Keywords / Materials (for Non-textual outputs)

  • Alcohol Drinking
  • Colorectal Neoplasms/genetics
  • Genetic Loci
  • Genetic Predisposition to Disease
  • Genome-Wide Association Study
  • Humans
  • Phosphotransferases (Alcohol Group Acceptor)
  • Polymorphism, Single Nucleotide/genetics
  • Quantitative Trait Loci/genetics
  • Risk


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