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

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 HaywardArchie 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 F??rsti, Helga Westers, Robert Hofstra, Manuela Pinheiro, Carla Pinto, Manuel Teixeira, Clara Ruiz-ponte, Ceres Fern??ndez-rozadilla, Angel Carracedo, Antoni Castells, Sergi Castellv??-bel, Harry Campbell, D. Timothy Bishop, Ian P M Tomlinson, Malcolm G. Dunlop, Richard S. Houlston

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)16286
JournalScientific Reports
Volume5
DOIs
Publication statusPublished - 10 Nov 2015

Keywords

  • Activating Transcription Factor 1/genetics
  • Alleles
  • Cadherins/genetics
  • Case-Control Studies
  • Colorectal Neoplasms/genetics
  • European Continental Ancestry Group/genetics
  • Gene Frequency
  • Genetic Variation
  • Genome-Wide Association Study
  • Genotype
  • Humans
  • Linkage Disequilibrium
  • Odds Ratio
  • Polymorphism, Single Nucleotide
  • Proteins/genetics

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