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Genome-wide association study of colorectal polyps identified highly overlapping polygenic architecture with colorectal cancer

Abstract

No genome-wide association studies (GWAS) were reported for colorectal polyps and the overlap in polygenic backgrounds conferring risk of colorectal cancer and polyps remains unclear. We performed GWAS on subjects with colorectal polyps using the BioBank Japan data with 4447 cases and 157,226 controls. We evaluated genetic correlations between colorectal polyps and cancer, and effects on colorectal polyps of single nucleotide polymorphisms (SNPs) known to be associated with colorectal cancer. We identified CUX2, a known genetic locus to colorectal cancer, as a susceptibility locus to colorectal polyps (p value = 1.1 × 10−15). Subsequent fine-mapping analysis indicated that rs11065828 in CUX2 is the causal variant for colorectal polyps. We found that known colorectal cancer-susceptible SNPs were also associated with colorectal polyps. The genetic correlation between colorectal cancer and polyps is very high (r = 0.98 and p value = 0.0006). We additionally identified 14 significant loci of colorectal polyps and three significant loci of colorectal cancer by applying the multi-trait analysis of GWAS of colorectal cancer and colorectal polyps. We showed very similar germline polygenic features, which gives us the additional insight into potential cancers at polygenic levels for patients with polyps who are followed up at outpatients’ clinic; thus, close observation and polypectomy is critical to prevent colorectal cancers.

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Data availability

Full GWAS results are available via the website of the Japanese ENcyclopedia of GEnetic associations by Riken (JENGER, http://jenger.riken.jp/en/).

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Acknowledgements

We appreciate all the patients who participated in this study. The sample and data used for this study were provided from the BBJ supported by the Japan Agency for Medical Research and Development (AMED) (Grant Number: JP19km0605001). We express our gratitude to the staff of BBJ for their assistance. We would like to thank Dr. Nicholas Parrish at the Genome Immunobiology RIKEN Hakubi Research Team in RIKEN Center for Integrative Medical Sciences and RIKEN Cluster for Pioneering Research, Yokohama, Japan, for English language editing.

Funding

Grant support: The Japan Agency for Medical Research and Development (AMED) (Grant Number: JP19km0605001).

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KH, MK and CT designed the study. KH, NO and KT analyzed the data. KH, NO and CT interpreted the data. KH wrote the manuscript. MK, KT, SI, KM, YM, BJP, TM and CT performed the critical revision.

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Correspondence to Chikashi Terao.

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Hikino, K., Koido, M., Otomo, N. et al. Genome-wide association study of colorectal polyps identified highly overlapping polygenic architecture with colorectal cancer. J Hum Genet 67, 149–156 (2022). https://doi.org/10.1038/s10038-021-00980-4

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