ArticleScientific reports2015
Recurrent Coding Sequence Variation Explains Only A Small Fraction of the Genetic Architecture of Colorectal Cancer.
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Article in Scientific reports, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers, 2 of them syntheses that pooled it.
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17citing papers in PubMed, 2 pooled it
2.7field-weighted citation impact, top 11% of its field
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Who cites it
17 citing papers in PubMed, 2 syntheses or guidelines pooled it, 25 citations in OpenAlex.
- MicroRNA-binding site polymorphisms and risk of colorectal cancer: A systematic review and meta-analysis.Cancer medicine · 2019Pooled it
- Validation of Recently Proposed Colorectal Cancer Susceptibility Gene Variants in an Analysis of Families and Patients-a Systematic Review.Gastroenterology · 2017Pooled it
- Exploring causality in the association between circulating 25-hydroxyvitamin D and colorectal cancer risk: a large Mendelian randomisation study.BMC medicine · 2018Trial
- The additive interaction of healthy lifestyles and genetic susceptibility on colorectal cancer risk in prediabetes: a large population-based prospective cohort study.BMC gastroenterology · 2024Article
- Review
- Rare Variants in the DNA Repair Pathway and the Risk of Colorectal Cancer.Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology · 2021Article
- A Systematic Analysis of Interactions between Environmental Risk Factors and Genetic Variation in Susceptibility to Colorectal Cancer.Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology · 2020Article
- Head-to-Head Comparison of Family History of Colorectal Cancer and a Genetic Risk Score for Colorectal Cancer Risk Stratification.Clinical and translational gastroenterology · 2019Observational
- Effects of common genetic variants associated with colorectal cancer risk on survival outcomes after diagnosis: A large population-based cohort study.International journal of cancer · 2019Article
- Screening of molecular targets and construction of a ceRNA network for oxaliplatin resistance in colorectal cancer.RSC advances · 2019Article
- Novel significant stage-specific differentially expressed genes in hepatocellular carcinoma.BMC cancer · 2019Article
- Genome-wide scan of the effect of common nsSNPs on colorectal cancer survival outcome.British journal of cancer · 2018Article
- Recurrent, low-frequency coding variants contributing to colorectal cancer in the Swedish population.PloS one · 2018Article
- Coding variants in NOD-like receptors: An association study on risk and survival of colorectal cancer.PloS one · 2018Article
- Evidence for genetic association between chromosome 1q loci and predisposition to colorectal neoplasia.British journal of cancer · 2017Article
- Rare disruptive mutations and their contribution to the heritable risk of colorectal cancer.Nature communications · 2016Article
- Correspondence: SEMA4A variation and risk of colorectal cancer.Nature communications · 2016Article
Corrections and comments
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Authors and funding
61 authors at 20 institutions in 7 countries.
Maria N TimofeevaColon 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.
Ben KinnersleyDivision of Genetics and Epidemiology, The Institute of Cancer Research, Sutton, Surrey SM2 5NG, United Kingdom.
Susan M FarringtonColon 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.
Nicola WhiffinDivision of Genetics and Epidemiology, The Institute of Cancer Research, Sutton, Surrey SM2 5NG, United Kingdom.
Claire PallesWellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, United Kingdom.
Victoria SvintiColon 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.
Amy LloydDivision of Genetics and Epidemiology, The Institute of Cancer Research, Sutton, Surrey SM2 5NG, United Kingdom.
Maggie GormanWellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, United Kingdom.
Li-Yin OoiColon 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.
Fay HoskingDivision of Genetics and Epidemiology, The Institute of Cancer Research, Sutton, Surrey SM2 5NG, United Kingdom.
Ella BarclayWellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, United Kingdom.
Lina ZgagaColon 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.
Sara DobbinsDivision of Genetics and Epidemiology, The Institute of Cancer Research, Sutton, Surrey SM2 5NG, United Kingdom.
Lynn MartinWellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, United Kingdom.
Evropi TheodoratouColon 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.
Peter BroderickDivision of Genetics and Epidemiology, The Institute of Cancer Research, Sutton, Surrey SM2 5NG, United Kingdom.
Albert TenesaRoslin Institute, University of Edinburgh, Easter Bush, Roslin EH25 9RG, United Kingdom.
Claire SmillieColon 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.
Graeme GrimesInstitute of Genetics and Molecular Medicine, University of Edinburgh and MRC Human Genetics Unit, Western General Hospital Edinburgh, Crewe Road, Edinburgh, EH4 2XU, United Kingdom.
Caroline HaywardInstitute of Genetics and Molecular Medicine, University of Edinburgh and MRC Human Genetics Unit, Western General Hospital Edinburgh, Crewe Road, Edinburgh, EH4 2XU, United Kingdom.
Archie CampbellInstitute of Genetics and Molecular Medicine, University of Edinburgh and MRC Human Genetics Unit, Western General Hospital Edinburgh, Crewe Road, Edinburgh, EH4 2XU, United Kingdom.
David PorteousInstitute of Genetics and Molecular Medicine, University of Edinburgh and MRC Human Genetics Unit, Western General Hospital Edinburgh, Crewe Road, Edinburgh, EH4 2XU, United Kingdom.
Ian J DearyUniversity of Edinburgh Centre for Cognitive Ageing and Cognitive Epidemiology, Department of Psychology, University of Edinburgh, Edinburgh EH8 9JZ, United Kingdom.
Sarah E HarrisInstitute of Genetics and Molecular Medicine, University of Edinburgh and MRC Human Genetics Unit, Western General Hospital Edinburgh, Crewe Road, Edinburgh, EH4 2XU, United Kingdom.
Emma L NorthwoodSection of Epidemiology &Biostatistics, Leeds Institute of Cancer and Pathology, University of Leeds, St James's University Hospital, Leeds, UK.
Jennifer H BarrettSection of Epidemiology &Biostatistics, Leeds Institute of Cancer and Pathology, University of Leeds, St James's University Hospital, Leeds, UK.
Gillian SmithMedical Research Institute, University of Dundee, Dundee, UK.
Roland WolfMedical Research Institute, University of Dundee, Dundee, UK.
David FormanIARC, Cancer Surveillance Unit, Lyon, France.
Hans MorreauDepartment of Pathology, Leiden University Medical Center, The Netherlands.
Dina RuanoDepartment of Pathology, Leiden University Medical Center, The Netherlands.
Carli TopsDepartment of Clinical Genetics, Leiden University Medical Center, The Netherlands.
Juul WijnenDepartment of Human Genetics, Leiden University Medical Center, The Netherlands.
Melanie SchrumpfDepartment of Pathology, Leiden University Medical Center, The Netherlands.
Arnoud BootDepartment of Pathology, Leiden University Medical Center, The Netherlands.
Hans F A VasenDepartment of Gastroenterology, Leiden University Medical Center, The Netherlands.
Frederik J HesDepartment of Clinical Genetics, Leiden University Medical Center, The Netherlands.
Tom van WezelDepartment of Pathology, Leiden University Medical Center, The Netherlands.
Andre FrankeInstitute of Clinical Molecular Biology, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany.
Wolgang LiebInstitute of Epidemiology, Christian-Albrechts-University Kiel, Kiel.
Clemens SchafmayerDepartment of General and Thoracic Surgery, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany.
Jochen HampeMedical Department 1, University Hospital Dresden, TU Dresden, Dresden, Germany.
Stephan BuchMedical Department 1, University Hospital Dresden, TU Dresden, Dresden, Germany.
Peter ProppingInstitute of Human Genetics, University Hospital Bonn, Bonn, Germany.
Kari HemminkiDivision of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 580, D-69120 Heidelberg, Germany.
Asta FörstiDivision of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 580, D-69120 Heidelberg, Germany.
Helga WestersUniversity of Groningen, University Medical Centre Groningen, Department of Genetics, PO Box 30001, 9700 RB Groningen, the Netherlands.
Robert HofstraUniversity of Groningen, University Medical Centre Groningen, Department of Genetics, PO Box 30001, 9700 RB Groningen, the Netherlands.
Manuela PinheiroDepartment of Genetics, Portuguese Oncology Institute and Biomedical Sciences Institute (ICBAS), University of Porto, Porto, Portugal.
Carla PintoDepartment of Genetics, Portuguese Oncology Institute and Biomedical Sciences Institute (ICBAS), University of Porto, Porto, Portugal.
Manuel TeixeiraDepartment of Genetics, Portuguese Oncology Institute and Biomedical Sciences Institute (ICBAS), University of Porto, Porto, Portugal.
Clara Ruiz-PonteFundación 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.
Ceres Fernández-RozadillaFundación 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.
Angel CarracedoFundación 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.
Antoni CastellsServei 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.
Sergi Castellví-BelServei 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.
Harry CampbellColon 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.
D Timothy BishopSection of Epidemiology &Biostatistics, Leeds Institute of Cancer and Pathology, University of Leeds, St James's University Hospital, Leeds, UK.
Ian P M TomlinsonWellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, United Kingdom.
Malcolm G DunlopColon 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.
Richard S HoulstonDivision of Genetics and Epidemiology, The Institute of Cancer Research, Sutton, Surrey SM2 5NG, United Kingdom.
Leiden University Medical Center · NLWestern General Hospital · GBInstitute of Cancer Research · GBUniversity of Edinburgh · GBCentre for Human Genetics · GBSt James's University Hospital · GBTU Dresden · DEUniversidade do Porto · PTUniversity Hospital Schleswig-Holstein · DEUniversity Medical Center Groningen · NLUniversity of Dundee · GBUniversity of Oxford · GBCentre for Biomedical Network Research on Rare Diseases · ESCentre International de Recherche sur le Cancer · FRCentro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas · ESFundación Pública Galega de Medicina Xenómica · ESGerman Cancer Research Center · DEInstituto Português de Oncologia Francisco Gentil · PTKiel University · DELund University · SE
Funding
Biotechnology and Biological Sciences Research Council BB/F019394/1Cancer Research UK 10589Cancer Research UK 12076Cancer Research UK 13154Cancer Research UK 15116Cancer Research UK 16459Cancer Research UK 19167Cancer Research UK C1298/A8362Cancer Research UK C348/A12076Cancer Research UK C588/A19167Chief Scientist Office CZD/16/6/4Medical Research Council G0700704Medical Research Council MC_PC_U127527198Medical Research Council MC_PC_U127561128Medical Research Council MC_U127527198Medical Research Council MR/K018647/1Medical Research Council MR/K026992/1Medical Research Council MR/KO18647/1Medical Research Council MR/L01629X/1Wellcome TrustWellcome Trust 090532/Z/09/ZWorld Health Organization 001Worldwide Cancer Research 12-1087
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.
Indexed as
Genetic VariationActivating Transcription Factor 1Adaptor Proteins, Signal TransducingAllelesCadherinsCase-Control StudiesColorectal NeoplasmsGene FrequencyGenome-Wide Association StudyGenotypeHumansIntracellular Signaling Peptides and ProteinsLinkage DisequilibriumOdds RatioPolymorphism, Single NucleotideProteinsActivating Transcription Factor 1Adaptor Proteins, Signal TransducingATF1 protein, humanCadherinsIntracellular Signaling Peptides and ProteinsProteinsSH2B3 protein, human
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