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

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  • Ben Kinnersley
  • Nicola Whiffin
  • Claire Palles
  • Amy Lloyd
  • Maggie Gorman
  • Li-yin Ooi
  • Fay Hosking
  • Ella Barclay
  • Sara Dobbins
  • Lynn Martin
  • Peter Broderick
  • Claire Smillie
  • Graeme Grimes
  • 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
  • D. Timothy Bishop
  • Richard S. Houlston

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


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.

    Research areas

  • 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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