Journal Article

Fine-mapping analysis including over 254,000 East Asian and European descendants identifies 136 putative colorectal cancer susceptibility genes

Loic Le Marchand, Wanqing Wen, Aung Ko Win, Vicente Martín-Sánchez, Jane C. Figueiredo, Jeremy P. Cheadle, Iva Kirac, Amit D. Joshi, Zomoroda Abu-Ful, Xingyi Guo, Peter G. Vaughan-Shaw, Li Hsu, James Studd, Wei-Hua Jia, Daniel D. Buchanan, Graham Casey, Chao Li, Kostas K. Tsilidis, David Shibata, Stephen B. Gruber, Yi Lin, Sun-Seog Kweon, Jenny Chang-Claude, W. James Gauderman, Matthias B. Schulze, Mireia Obón-Santacana, Rachel Pearlman, Keum Ji Jung, Harri Rissanen, Steven Gallinger, Juan Fernandez-Tajes, Yuhan Xie, Kala Visvanathan, Andrew T. Chan, Barbara Pardini, Jeongseon Kim, Li Yin Ooi, Eero Pukkala, Malcolm G. Dunlop, Peter C. Scacheri, Ross Prentice, Susan M. Farrington, Charles Kooperberg, Sushma S. Thomas, Franzel van Duijnhoven, Jan Böhm, Melissa C. Southey, Kevin Donnelly, Fredrick R. Schumacher, D. Timothy Bishop, Sarah E. Harris, Alicja Wolk, Ran Tao, Edith J. M. Feskens, Robert E. Schoen, Christopher K. Edlund, Stefanie Brezina, Ferran Moratalla-Navarro, Lauri A. Aaltonen, Marilena Melas, Heinz-Josef Lenz, Katerina Shulman, Jae Hwan Oh, Polly A. Newcomb, Paul Knekt, Sergi Castellví-Bel, Jirong Long, E

2024

Overview

Genome-wide association studies (GWAS) have identified more than 200 common genetic variants independently associated with colorectal cancer (CRC) risk, but the causal variants and target genes are mostly unknown. We sought to fine-map all known CRC risk loci using GWAS data from 100,204 cases and 154,587 controls of East Asian and European ancestry. Our stepwise conditional analyses revealed 238 independent association signals of CRC risk, each with a set of credible causal variants (CCVs), of which 28 signals had a single CCV. Our cis-eQTL/mQTL and colocalization analyses using colorectal tissue-specific transcriptome and methylome data separately from 1299 and 321 individuals, along with functional genomic investigation, uncovered 136 putative CRC susceptibility genes, including 56 genes not previously reported. Analyses of single-cell RNA-seq data from colorectal tissues revealed 17 putative CRC susceptibility genes with distinct expression patterns in specific cell types. Analyses of whole exome sequencing data provided additional support for several target genes identified in this study as CRC susceptibility genes. Enrichment analyses of the 136 genes uncover pathways not previously linked to CRC risk. Our study substantially expanded association signals for CRC and provided additional insight into the biological mechanisms underlying CRC development. Here, the authors perform large trans-ancestry fine-mapping analyses identifying large numbers of association signals and putative target genes for colorectal cancer risk, advancing our understanding of the genetic and biological basis of this cancer.

• Publisher: Springer Science and Business Media LLC,Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 45 / 692/308/174 / 692/699/67/2324 / Asian People / Asian People/genetics / Cancer / Cancers / Case-Control Studies / Chromosome Mapping / Colorectal cancer / Colorectal carcinoma / Colorectal Neoplasms / Colorectal Neoplasms - genetics / East Asian People / East Asian People - genetics / Exome Sequencing / Female / Gene expression / Gene mapping / Genes / Genetic diversity / Genetic Predisposition to Disease / Genetic variance / Genome-wide association studies / Genome-Wide Association Study / Health risks / Humanities and Social Sciences / Humans / Life Science / Male / Mapping / Medical Genetics / Medicinsk genetik / multidisciplinary / Polymorphism / Polymorphism, Single Nucleotide / Q / Quantitative Trait Loci / Risk / Science / Science (multidisciplinary) / Single Nucleotide / Susceptibility / Transcriptome / Transcriptomes / White People / White People - genetics