Recurrent Coding Sequence Variation Explains Only A Small Fraction of the Genetic Architecture of Colorectal Cancer.

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
Year of publication:
2015
Volume:
5
Issue:
-
Issn:
2045-2322
Journal title abbreviated:
SCI REP-UK
Journal title long:
Scientific Reports
Impact factor:
4.259
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.