title: Recurrent Coding Sequence Variation Explains Only A Small Fraction of the Genetic Architecture of Colorectal Cancer.
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.
authors.affiliation: 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.
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authors.initials: MN
authors.lastname: Timofeeva
authors.affiliation: Division of Genetics and Epidemiology, The Institute of Cancer Research, Sutton, Surrey SM2 5NG, United Kingdom.
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authors.lastname: Kinnersley
authors.affiliation: 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.
authors.forename: Susan M
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authors.lastname: Farrington
authors.affiliation: Division of Genetics and Epidemiology, The Institute of Cancer Research, Sutton, Surrey SM2 5NG, United Kingdom.
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authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, United Kingdom.
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authors.affiliation: 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.
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authors.affiliation: Division of Genetics and Epidemiology, The Institute of Cancer Research, Sutton, Surrey SM2 5NG, United Kingdom.
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authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, United Kingdom.
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authors.affiliation: 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.
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authors.affiliation: Division of Genetics and Epidemiology, The Institute of Cancer Research, Sutton, Surrey SM2 5NG, United Kingdom.
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authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, United Kingdom.
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authors.affiliation: 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.
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authors.affiliation: Division of Genetics and Epidemiology, The Institute of Cancer Research, Sutton, Surrey SM2 5NG, United Kingdom.
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authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, United Kingdom.
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authors.affiliation: 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.|Centre for Population Health Sciences, University of Edinburgh, Teviot Place, Edinburgh EH8 9AG, United Kingdom.
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authors.affiliation: Division of Genetics and Epidemiology, The Institute of Cancer Research, Sutton, Surrey SM2 5NG, United Kingdom.
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authors.affiliation: Roslin Institute, University of Edinburgh, Easter Bush, Roslin EH25 9RG, 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.
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authors.affiliation: 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.
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authors.affiliation: 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.
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authors.affiliation: 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.
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authors.affiliation: 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.|Centre for Population Health Sciences, University of Edinburgh, Teviot Place, Edinburgh EH8 9AG, United Kingdom.
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mesh_terms: D051697:Activating Transcription Factor 1 / Q000235:genetics; D048868:Adaptor Proteins, Signal Transducing; D000483:Alleles; D015820:Cadherins / Q000235:genetics; D016022:Case-Control Studies; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000473:pathology; D005787:Gene Frequency; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D015810:Linkage Disequilibrium; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide; D011506:Proteins / Q000235:genetics; D044465:White People / Q000235:genetics
chemical_list: C531110:ATF1 protein, human; D051697:Activating Transcription Factor 1; D048868:Adaptor Proteins, Signal Transducing; D015820:Cadherins; D047908:Intracellular Signaling Peptides and Proteins; D011506:Proteins; C490778:SH2B3 protein, human