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Recurrent Coding Sequence Variation Explains Only A Small Fraction of the Genetic Architecture of Colorectal Cancer
| Content Provider | Paperity |
|---|---|
| Author | Wijnen, Juul Wezel, Tom Van Teixeira, Manuel Dobbins, Sara Hayward, Caroline Pinto, Carla Boot, Arnoud Grimes, Graeme Northwood, Emma L. Schafmayer, Clemens Buch, Stephan Tenesa, Albert Pinheiro, Manuela Smith, Gillian Morreau, Hans Theodoratou, Evropi Harris, Sarah E. Schrumpf, Melanie Ooi, Li-yin Gorman, Maggie Zgaga, Lina Timofeeva, Maria N. Carracedo, Angel Campbell, Archie Tops, Carli Palles, Claire Broderick, Peter Deary, Ian J. Hosking, Fay Lieb, Wolgang Hampe, Jochen Campbell, Harry Dunlop, Malcolm G. Ruano, Dina Barrett, Jennifer H. Hofstra, Robert Svinti, Victoria Bishop, D. Timothy Ian, P. M. Tomlinson Försti, Asta Castellví-bel, Sergi Wolf, Roland Forman, David Hans, F. A. Vasen Propping, Peter Fernández-rozadilla, Ceres Porteous, David Houlston, Richard S. Franke, Andre Westers, Helga Ruiz-ponte, Clara Whiffin, Nicola Barclay, Ella Farrington, Susan M. Hes, Frederik J. Smillie, Claire Lloyd, Amy Castells, Antoni Martin, Lynn Kinnersley, Ben Hemminki, Kari |
| 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. |
| File Format | HTM / HTML |
| DOI | 10.1038/srep16286 |
| Journal | Scientific Reports |
| Volume Number | 5 |
| Language | English |
| Publisher | Nature Publishing Group |
| Publisher Date | 2015-11-10 |
| Access Restriction | Open |
| Content Type | Text |
| Resource Type | Article |
