Recurrent Coding Sequence Variation Explains Only A Small Fraction of the Genetic Architecture of Colorectal Cancer
Year: 2015
Type: article
Study design: Observational Study
Abstract: Whilst common genetic variation in many non-coding genomic regulatory regions are known to impart risk of colorectal cancer (CRC), much of the heritability of CRC remains unexplained. To examine the role of recurrent coding sequence variation in CRC aetiology, we genotyped 12,638 CRCs cases and 29,045 controls from six European populations. Single-variant analysis identified a coding variant (rs3184504) in SH2B3 (12q24) associated with CRC risk (OR = 1.08, P = 3.9 × 10(-7)), and novel damaging coding variants in 3 genes previously tagged by GWAS efforts; rs16888728 (8q24) in UTP23 (OR = 1.15, P = 1.4 × 10(-7)); rs6580742 and rs12303082 (12q13) in FAM186A (OR = 1.11, P = 1.2 × 10(-7) and OR = 1.09, P = 7.4 × 10(-8)); rs1129406 (12q13) in ATF1 (OR = 1.11, P = 8.3 × 10(-9)), all reaching exome-wide significance levels. Gene based tests identified associations between CRC and PCDHGA genes (P < 2.90 × 10(-6)). We found an excess of rare, damaging variants in base-excision (P = 2.4 × 10(-4)) and DNA mismatch repair genes (P = 6.1 × 10(-4)) consistent with a recessive mode of inheritance. This study comprehensively explores the contribution of coding sequence variation to CRC risk, identifying associations with coding variation in 4 genes and PCDHG gene cluster and several candidate recessive alleles. However, these findings suggest that recurrent, low-frequency coding variants account for a minority of the unexplained heritability of CRC.
Source: Scientific Reports
DOI: 10.1038/srep16286
Authors: Maria N. Timofeeva, Ben Kinnersley, Susan M. Farrington, Nicola Whiffin, Claire Palles, Victoria Svinti, Amy Lloyd, Maggie Gorman, Li-Yin Ooi, Fay Hosking, Ella Barclay, Lina Zgaga, Sara Dobbins, Lynn Martin, Evropi Theodoratou, Peter Broderick, Albert Tenesa, Claire Smillie, Graeme Grimes, Caroline Hayward, Archie Campbell, David Porteous, Ian J. Deary, Sarah E. Harris, Emma L. Northwood, Jennifer H. Barrett, Gillian Smith, Roland Wolf, David Forman, Hans Morreau, Dina Ruano, Carli Tops, Juul Wijnen, Melanie Schrumpf, Arnoud Boot, Hans F A Vasen, Frederik J. Hes, Tom van Wezel, Andre Franke, Wolgang Lieb, Clemens Schafmayer, Jochen Hampe, Stephan Buch, Peter Propping, Kari Hemminki, Asta Försti, Helga Westers, Robert Hofstra, Manuela Pinheiro, Carla Pinto, Manuel Teixeira, Clara Ruiz-Ponte, Ceres Fernández-Rozadilla, Angel Carracedo, Antoni Castells, Sergi Castellví-Bel, Harry Campbell, D. Timothy Bishop, Ian P M Tomlinson, Malcolm G. Dunlop, Richard S. Houlston
Institutions: Western General Hospital, Institute of Genetics and Cancer, MRC Human Genetics Unit, University of Edinburgh, Institute of Cancer Research, Centre for Human Genetics, University of Oxford, Roslin Institute, University of Leeds, St James's University Hospital, University of Dundee, Centre international de recherche sur le cancer, Leiden University, Leiden University Medical Center, University Hospital Schleswig-Holstein, Christian-Albrechts-Universität zu Kiel, University Hospital Carl Gustav Carus, Technische Universität Dresden, University Hospital Bonn, German Cancer Research Center, Lund University, University Medical Center Groningen, University of Groningen, Erasmus MC, Universidade do Porto, Instituto de Ciências Biomédicas Albel Salazar, Universidade de Santiago de Compostela, Centre for Biomedical Network Research on Rare Diseases, Fundación Pública Galega de Medicina Xenómica, Hospital Clínic de Barcelona, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Consorci Institut D'Investigacions Biomediques August Pi I Sunyer, Universitat de Barcelona
Language: English
Subfield: Pathology and Forensic Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $2,690
Awards: G1342751976, G276470579, G3097030853, G4641403149, G5067462658, G5348928089, G5617545779, G6165909648, A genome-wide association study of non-pathological cognitive ageing, G7203563959, G7956840597, G7964317829, G8451937923, G8724570043, Understanding the genetic basis of common human diseases: core funding for the Wellcome Trust Centre for Human Genetics., G895849274
OpenAlex ID: W2158757937