Association analyses identify 31 new risk loci for colorectal cancer susceptibility

Law, Philip J. and Timofeeva, Maria and Fernandez-Rozadilla, Ceres and Broderick, Peter and Studd, James and Fernandez-Tajes, Juan and Farrington, Susan and Svinti, Victoria and Palles, Claire and Orlando, Giulia and Sud, Amit and Holroyd, Amy and Penegar, Steven and Theodoratou, Evropi and Vaughan-Shaw, Peter and Campbell, Harry and Zgaga, Lina and Hayward, Caroline and Campbell, Archie and Harris, Sarah and Deary, Ian J. and Starr, John and Gatcombe, Laura and Pinna, Maria and Briggs, Sarah and Martin, Lynn and Jaeger, Emma and Sharma-Oates, Archana and East, James and Leedham, Simon and Arnold, Roland and Johnstone, Elaine and Wang, Haitao and Kerr, David and Kerr, Rachel and Maughan, Tim and Kaplan, Richard and Al-Tassan, Nada and Palin, Kimmo and Hänninen, Ulrika A. and Cajuso, Tatiana and Tanskanen, Tomas and Kondelin, Johanna and Kaasinen, Eevi and Sarin, Antti-Pekka and Eriksson, Johan G. and Rissanen, Harri and Knekt, Paul and Pukkala, Eero and Jousilahti, Pekka and Salomaa, Veikko and Ripatti, Samuli and Palotie, Aarno and Renkonen-Sinisalo, Laura and Lepistö, Anna and Böhm, Jan and Mecklin, Jukka-Pekka and Buchanan, Daniel D. and Win, Aung-Ko and Hopper, John and Jenkins, Mark E. and Lindor, Noralane M. and Newcomb, Polly A. and Gallinger, Steven and Duggan, David and Casey, Graham and Hoffmann, Per and Nöthen, Markus M. and Jöckel, Karl-Heinz and Easton, Douglas F. and Pharoah, Paul D. P. and Peto, Julian and Canzian, Federico and Swerdlow, Anthony and Eeles, Rosalind A. and Kote-Jarai, Zsofia and Muir, Kenneth and Pashayan, Nora and Harkin, Andrea and Allan, Karen and McQueen, John and Paul, James and Iveson, Timothy and Saunders, Mark and Butterbach, Katja and Chang-Claude, Jenny and Hoffmeister, Michael and Brenner, Hermann and Kirac, Iva and Matošević, Petar and Hofer, Philipp and Brezina, Stefanie and Gsur, Andrea and Cheadle, Jeremy P. and Aaltonen, Lauri A. and Tomlinson, Ian and Houlston, Richard S. and Dunlop, Malcolm G. (2019) Association analyses identify 31 new risk loci for colorectal cancer susceptibility. Nature Communications, 10 (1). ISSN 2041-1723

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Abstract

Colorectal cancer (CRC) is a leading cause of cancer-related death worldwide, and has a strong heritable basis. We report a genome-wide association analysis of 34,627 CRC cases and 71,379 controls of European ancestry that identifies SNPs at 31 new CRC risk loci. We also identify eight independent risk SNPs at the new and previously reported European CRC loci, and a further nine CRC SNPs at loci previously only identified in Asian populations. We use in situ promoter capture Hi-C (CHi-C), gene expression, and in silico annotation methods to identify likely target genes of CRC SNPs. Whilst these new SNP associations implicate target genes that are enriched for known CRC pathways such as Wnt and BMP, they also highlight novel pathways with no prior links to colorectal tumourigenesis. These findings provide further insight into CRC susceptibility and enhance the prospects of applying genetic risk scores to personalised screening and prevention.

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