Please use this identifier to cite or link to this item: https://doi.org/10.1038/srep16286
Title: Recurrent Coding Sequence Variation Explains only A Small Fraction of the Genetic Architecture of Colorectal Cancer
Authors: Timofeeva, M.N
Kinnersley, B
Farrington, S.M
Keywords: activating transcription factor 1
ATF1 protein, human
cadherin
LNK protein, human
protein
allele
case control study
Caucasian
colorectal tumor
gene frequency
gene linkage disequilibrium
genetic variation
genetics
genome-wide association study
genotype
human
odds ratio
pathology
single nucleotide polymorphism
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
Issue Date: 2015
Publisher: Nature Publishing Group
Citation: Timofeeva, M.N, Kinnersley, B, Farrington, S.M (2015). Recurrent Coding Sequence Variation Explains only A Small Fraction of the Genetic Architecture of Colorectal Cancer. Scientific Reports 5 : 16286. ScholarBank@NUS Repository. https://doi.org/10.1038/srep16286
Rights: Attribution 4.0 International
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.
Source Title: Scientific Reports
URI: https://scholarbank.nus.edu.sg/handle/10635/180418
ISSN: 2045-2322
DOI: 10.1038/srep16286
Rights: Attribution 4.0 International
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