Fine-mapping analysis including over 254,000 East Asian and European descendants identifies 136 putative colorectal cancer susceptibility genes.
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Date
2024-04-26
Open Access Location
Journal Title
Journal ISSN
Volume Title
Publisher
Springer Nature
Rights
(c) 2024 The Author/s
CC BY 4.0
CC BY 4.0
Abstract
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.
Description
Keywords
Humans, Colorectal Neoplasms, Genetic Predisposition to Disease, Genome-Wide Association Study, Asian People, White People, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Exome Sequencing, Case-Control Studies, Transcriptome, Chromosome Mapping, Male, Female, East Asian People
Citation
Chen Z, Guo X, Tao R, Huyghe JR, Law PJ, Fernandez-Rozadilla C, Ping J, Jia G, Long J, Li C, Shen Q, Xie Y, Timofeeva MN, Thomas M, Schmit SL, Díez-Obrero V, Devall M, Moratalla-Navarro F, Fernandez-Tajes J, Palles C, Sherwood K, Briggs SEW, Svinti V, Donnelly K, Farrington SM, Blackmur J, Vaughan-Shaw PG, Shu X-O, Lu Y, Broderick P, Studd J, Harrison TA, Conti DV, Schumacher FR, Melas M, Rennert G, Obón-Santacana M, Martín-Sánchez V, Oh JH, Kim J, Jee SH, Jung KJ, Kweon S-S, Shin M-H, Shin A, Ahn Y-O, Kim D-H, Oze I, Wen W, Matsuo K, Matsuda K, Tanikawa C, Ren Z, Gao Y-T, Jia W-H, Hopper JL, Jenkins MA, Win AK, Pai RK, Figueiredo JC, Haile RW, Gallinger S, Woods MO, Newcomb PA, Duggan D, Cheadle JP, Kaplan R, Kerr R, Kerr D, Kirac I, Böhm J, Mecklin J-P, Jousilahti P, Knekt P, Aaltonen LA, Rissanen H, Pukkala E, Eriksson JG, Cajuso T, Hänninen U, Kondelin J, Palin K, Tanskanen T, Renkonen-Sinisalo L, Männistö S, Albanes D, Weinstein SJ, Ruiz-Narvaez E, Palmer JR, Buchanan DD, Platz EA, Visvanathan K, Ulrich CM, Siegel E, Brezina S, Gsur A, Campbell PT, Chang-Claude J, Hoffmeister M, Brenner H, Slattery ML, Potter JD, Tsilidis KK, Schulze MB, Gunter MJ, Murphy N, Castells A, Castellví-Bel S, Moreira L, Arndt V, Shcherbina A, Bishop DT, Giles GG, Southey MC, Idos GE, McDonnell KJ, Abu-Ful Z, Greenson JK, Shulman K, Lejbkowicz F, Offit K, Su Y-R, Steinfelder R, Keku TO, van Guelpen B, Hudson TJ, Hampel H, Pearlman R, Berndt SI, Hayes RB, Martinez ME, Thomas SS, Pharoah PDP, Larsson SC, Yen Y, Lenz H-J, White E, Li L, Doheny KF, Pugh E, Shelford T, Chan AT, Cruz-Correa M, Lindblom A, Hunter DJ, Joshi AD, Schafmayer C, Scacheri PC, Kundaje A, Schoen RE, Hampe J, Stadler ZK, Vodicka P, Vodickova L, Vymetalkova V, Edlund CK, Gauderman WJ, Shibata D, Toland A, Markowitz S, Kim A, Chanock SJ, van Duijnhoven F, Feskens EJM, Sakoda LC, Gago-Dominguez M, Wolk A, Pardini B, FitzGerald LM, Lee SC, Ogino S, Bien SA, Kooperberg C, Li CI, Lin Y, Prentice R, Qu C, Bézieau S, Yamaji T, Sawada N, Iwasaki M, Le Marchand L, Wu AH, Qu C, McNeil CE, Coetzee G, Hayward C, Deary IJ, Harris SE, Theodoratou E, Reid S, Walker M, Ooi LY, Lau KS, Zhao H, Hsu L, Cai Q, Dunlop MG, Gruber SB, Houlston RS, Moreno V, Casey G, Peters U, Tomlinson I, Zheng W. (2024). Fine-mapping analysis including over 254,000 East Asian and European descendants identifies 136 putative colorectal cancer susceptibility genes.. Nat Commun. 15. 1. (pp. 3557-).