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

Timofeeva, Maria N; Kinnersley, Ben; Farrington, Susan M; Whiffin, Nicola; Palles, Claire; Svinti, Victoria; Lloyd, Amy; Gorman, Maggie; Ooi, Li-Yin and Hosking, Fay, et al. (2015) In Scientific Reports 5.
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... (More)
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. (Less)
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Scientific Reports
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Nature Publishing Group
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  • pmid:26553438
  • wos:000364448500001
  • scopus:84946593635
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2045-2322
DOI
10.1038/srep16286
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English
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@article{ec776600-f545-498e-8ad3-edbc8cae7f15,
  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 &lt; 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.},
  articleno    = {16286},
  author       = {Timofeeva, Maria N and Kinnersley, Ben and Farrington, Susan M and Whiffin, Nicola and Palles, Claire and Svinti, Victoria and Lloyd, Amy and Gorman, Maggie and Ooi, Li-Yin and Hosking, Fay and Barclay, Ella and Zgaga, Lina and Dobbins, Sara and Martin, Lynn and Theodoratou, Evropi and Broderick, Peter and Tenesa, Albert and Smillie, Claire and Grimes, Graeme and Hayward, Caroline and Campbell, Archie and Porteous, David and Deary, Ian J and Harris, Sarah E and Northwood, Emma L and Barrett, Jennifer H and Smith, Gillian and Wolf, Roland and Forman, David and Morreau, Hans and Ruano, Dina and Tops, Carli and Wijnen, Juul and Schrumpf, Melanie and Boot, Arnoud and Vasen, Hans F A and Hes, Frederik J and van Wezel, Tom and Franke, Andre and Lieb, Wolgang and Schafmayer, Clemens and Hampe, Jochen and Buch, Stephan and Propping, Peter and Hemminki, Kari and Försti, Asta and Westers, Helga and Hofstra, Robert and Pinheiro, Manuela and Pinto, Carla and Teixeira, Manuel and Ruiz-Ponte, Clara and Fernández-Rozadilla, Ceres and Carracedo, Angel and Castells, Antoni and Castellví-Bel, Sergi and Campbell, Harry and Bishop, D Timothy and Tomlinson, Ian P M and Dunlop, Malcolm G and Houlston, Richard S},
  issn         = {2045-2322},
  language     = {eng},
  publisher    = {Nature Publishing Group},
  series       = {Scientific Reports},
  title        = {Recurrent Coding Sequence Variation Explains Only A Small Fraction of the Genetic Architecture of Colorectal Cancer.},
  url          = {http://dx.doi.org/10.1038/srep16286},
  volume       = {5},
  year         = {2015},
}