Recurrent Coding Sequence Variation Explains Only A Small Fraction of the Genetic Architecture of Colorectal Cancer.
Timofeeva MN., Kinnersley B., Farrington SM., Whiffin N., Palles C., Svinti V., Lloyd A., Gorman M., Ooi L-Y., Hosking F., Barclay E., Zgaga L., Dobbins S., Martin L., Theodoratou E., Broderick P., Tenesa A., Smillie C., Grimes G., Hayward C., Campbell A., Porteous D., Deary IJ., Harris SE., Northwood EL., Barrett JH., Smith G., Wolf R., Forman D., Morreau H., Ruano D., Tops C., Wijnen J., Schrumpf M., Boot A., Vasen HFA., Hes FJ., van Wezel T., Franke A., Lieb W., Schafmayer C., Hampe J., Buch S., Propping P., Hemminki K., Försti A., Westers H., Hofstra R., Pinheiro M., Pinto C., Teixeira M., Ruiz-Ponte C., Fernández-Rozadilla C., Carracedo A., Castells A., Castellví-Bel S., Campbell H., Bishop DT., Tomlinson IPM., Dunlop MG., Houlston RS.
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