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

Research output: Contribution to journalArticle

Authors

  • Maria N Timofeeva
  • Ben Kinnersley
  • Susan M Farrington
  • Nicola Whiffin
  • 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

Colleges, School and Institutes

External organisations

  • Colon Cancer Genetics Group, Institute of Genetics and Molecular Medicine, University of Edinburgh and MRC Human Genetics Unit, Western General Hospital Edinburgh, Crewe Road, Edinburgh, EH4 2XU, United Kingdom.
  • Division of Genetics and Epidemiology, The Institute of Cancer Research, Sutton, Surrey SM2 5NG, United Kingdom.
  • Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, United Kingdom.
  • Centre for Population Health Sciences, University of Edinburgh, Teviot Place, Edinburgh EH8 9AG, United Kingdom.
  • Institute of Genetics and Molecular Medicine, University of Edinburgh and MRC Human Genetics Unit, Western General Hospital Edinburgh, Crewe Road, Edinburgh, EH4 2XU, United Kingdom.
  • Generation Scotland, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital Edinburgh, Crewe Road, Edinburgh, EH4 2XU, United Kingdom.
  • University of Edinburgh Centre for Cognitive Ageing and Cognitive Epidemiology, Department of Psychology, University of Edinburgh, Edinburgh EH8 9JZ, United Kingdom.
  • University of Leeds
  • University of Dundee
  • IARC, Cancer Surveillance Unit, Lyon, France.
  • Leiden Department of Pathology, Leiden University Medical Center, Leiden, 2333 ZA, The Netherlands.
  • Department of Clinical Genetics, Leiden University Medical Center, The Netherlands.
  • Department of Human Genetics, Leiden University Medical Center, The Netherlands.
  • Department of Gastroenterology, Leiden University Medical Center, The Netherlands.
  • Institute of Clinical Molecular Biology, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany.
  • Institute of Epidemiology, Christian-Albrechts-University Kiel, Kiel.
  • Department of General and Thoracic Surgery, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany.
  • Medical Department 1, University Hospital Dresden, TU Dresden, Dresden, Germany.
  • Institute of Human Genetics, University Hospital Bonn, Bonn, Germany.
  • Center for Primary Health Care Research, Lund University, 205 02 Malmö, Sweden.
  • University of Groningen, University Medical Centre Groningen, Department of Genetics, PO Box 30001, 9700 RB Groningen, the Netherlands.
  • Department of Clinical Genetics, Erasmus Medical Center, Dr. Molewaterplein 50, 3015 GE Rotterdam, the Netherlands.
  • Department of Genetics and IPO-Porto Research Center (CI-IPOP), Portuguese Oncology Institute of Porto (IPO-Porto), Porto, Portugal, and Biomedical Sciences Institute (ICBAS), University of Porto, Porto, Portugal.
  • Fundación Pública Galega de Medicina Xenómica (FPGMX), Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Genomics Medicine Group, Hospital Clínico, 15706 Santiago de Compostela, University of Santiago de Compostela, Galicia, Spain.
  • Servei de Gastroenterologia, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), University of Barcelona, 08036 Barcelona, Catalonia, Spain.

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.

Details

Original languageEnglish
Article number16286
JournalScientific Reports
Volume5
Publication statusPublished - 10 Nov 2015

Keywords

  • Activating Transcription Factor 1, Alleles, Cadherins, Case-Control Studies, Colorectal Neoplasms, European Continental Ancestry Group, Gene Frequency, Genetic Variation, Genome-Wide Association Study, Genotype, Humans, Linkage Disequilibrium, Odds Ratio, Polymorphism, Single Nucleotide, Proteins, Journal Article, Research Support, Non-U.S. Gov't