Fine-mapping analysis including over 254,000 East Asian and European descendants identifies 136 putative colorectal cancer susceptibility genes
Authors: Chen Zhishan , Guo Xingyi , Tao Ran , Huyghe Jeroen R. , Law Philip J. , Fernandez-Rozadilla Ceres , Ping Jie , Jia Guochong , Long Jirong , Li Chao , Shen Quanhu , Xie Yuhan , Timofeeva Maria N. , Thomas Minta , Schmit Stephanie L. , Díez-Obrero Virginia , Devall Matthew , Moratalla-Navarro Ferran , Fernandez-Tajes Juan , Palles Claire , Sherwood Kitty , Briggs Sarah E. W. , Svinti Victoria , Donnelly Kevin , Farrington Susan M. , Blackmur James , Vaughan-Shaw Peter G. , Shu Xiao-Ou , Lu Yingchang , Broderick Peter , Studd James , Harrison Tabitha A. , Conti David V. , Schumacher Fredrick R. , Melas Marilena , Rennert Gad , Obón-Santacana Mireia , Martín-Sánchez Vicente , Oh Jae Hwan , Kim Jeongseon , Jee Sun Ha , Jung Keum Ji , Kweon Sun-Seog , Shin Min-Ho , Shin Aesun , Ahn Yoon-Ok , Kim Dong-Hyun , Oze Isao , Wen Wanqing , Matsuo Keitaro , Matsuda Koichi , Tanikawa Chizu , Ren Zefang , Gao Yu-Tang , Jia Wei-Hua , Hopper John L. , Jenkins Mark A. , Win Aung Ko , Pai Rish K. , Figueiredo Jane C. , Haile Robert W. , Gallinger Steven , Woods Michael O. , Newcomb Polly A. , Duggan David , Cheadle Jeremy P. , Kaplan Richard , Kerr Rachel , Kerr David , Kirac Iva , Böhm Jan , Mecklin Jukka-Pekka , Jousilahti Pekka , Knekt Paul , Aaltonen Lauri A. , Rissanen Harri , Pukkala Eero , Eriksson Johan G. , Cajuso Tatiana , Hänninen Ulrika , Kondelin Johanna , Palin Kimmo , Tanskanen Tomas , Renkonen-Sinisalo Laura , Männistö Satu , Albanes Demetrius , Weinstein Stephanie J. , Ruiz-Narvaez Edward , Palmer Julie R. , Buchanan Daniel D. , Platz Elizabeth A. , Visvanathan Kala , Ulrich Cornelia M. , Siegel Erin , Brezina Stefanie , Gsur Andrea , Campbell Peter T. , Chang-Claude Jenny , Hoffmeister Michael , Brenner Hermann , Slattery Martha L. , Potter John D. , Tsilidis Kostas K. , Schulze Matthias B. , Gunter Marc J. , Murphy Neil , Castells Antoni , Castellví-Bel Sergi , Moreira Leticia , Arndt Volker , Shcherbina Anna , Bishop D. Timothy , Giles Graham G. , Southey Melissa C. , Idos Gregory E. , McDonnell Kevin J. , Abu-Ful Zomoroda , Greenson Joel K. , Shulman Katerina , Lejbkowicz Flavio , Offit Kenneth , Su Yu-Ru , Steinfelder Robert , Keku Temitope O. , van Guelpen Bethany , Hudson Thomas J. , Hampel Heather , Pearlman Rachel , Berndt Sonja I. , Hayes Richard B. , Martinez Marie Elena , Thomas Sushma S. , Pharoah Paul D. P. , Larsson Susanna C. , Yen Yun , Lenz Heinz-Josef , White Emily , Li Li , Doheny Kimberly F. , Pugh Elizabeth , Shelford Tameka , Chan Andrew T. , Cruz-Correa Marcia , Lindblom Annika , Hunter David J. , Joshi Amit D. , Schafmayer Clemens , Scacheri Peter C. , Kundaje Anshul , Schoen Robert E. , Hampe Jochen , Stadler Zsofia K. , Vodicka Pavel , Vodickova Ludmila , Vymetalkova Veronika , Edlund Christopher K. , Gauderman W. James , Shibata David , Toland Amanda , Markowitz Sanford , Kim Andre , Chanock Stephen J. , van Duijnhoven Franzel , Feskens Edith J. M. , Sakoda Lori C. , Gago-Dominguez Manuela , Wolk Alicja , Pardini Barbara , FitzGerald Liesel M. , Lee Soo Chin , Ogino Shuji , Bien Stephanie A. , Kooperberg Charles , Li Christopher I. , Lin Yi , Prentice Ross , Qu Conghui , Bézieau Stéphane , Yamaji Taiki , Sawada Norie , Iwasaki Motoki , Le Marchand Loic , Wu Anna H. , Qu Chenxu , McNeil Caroline E. , Coetzee Gerhard , Hayward Caroline , Deary Ian J. , Harris Sarah E. , Theodoratou Evropi , Reid Stuart , Walker Marion , Ooi Li Yin , Lau Ken S. , Zhao Hongyu , Hsu Li , Cai Qiuyin , Dunlop Malcolm G. , Gruber Stephen B. , Houlston Richard S. , Moreno Victor , Casey Graham , Peters Ulrike , Tomlinson Ian , Zheng Wei 
Published: April 2024

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.