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

Maria N. Timofeeva; Ben Kinnersley; Susan M. Farrington; Nicola Whiffin; Claire Palles; 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 F??rsti; Helga Westers; Robert Hofstra; Manuela Pinheiro; Carla Pinto; Manuel Teixeira; Clara Ruiz-ponte; Ceres Fern??ndez-rozadilla; Angel Carracedo; Antoni Castells; Sergi Castellv??-bel; Harry Campbell; D. Timothy Bishop; Ian P M Tomlinson; Malcolm G. Dunlop; Richard S. Houlston

doi:10.1038/srep16286

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

Maria N. Timofeeva, Ben Kinnersley, Susan M. Farrington, Nicola Whiffin, Claire Palles, 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 HaywardArchie 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 F??rsti, Helga Westers, Robert Hofstra, Manuela Pinheiro, Carla Pinto, Manuel Teixeira, Clara Ruiz-ponte, Ceres Fern??ndez-rozadilla, Angel Carracedo, Antoni Castells, Sergi Castellv??-bel, Harry Campbell, D. Timothy Bishop, Ian P M Tomlinson, Malcolm G. Dunlop, Richard S. Houlston

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Pages (from-to)	16286
Journal	Scientific Reports
Volume	5
DOIs	https://doi.org/10.1038/srep16286
Publication status	Published - 10 Nov 2015

Keywords / Materials (for Non-textual outputs)

Activating Transcription Factor 1/genetics
Alleles
Cadherins/genetics
Case-Control Studies
Colorectal Neoplasms/genetics
European Continental Ancestry Group/genetics
Gene Frequency
Genetic Variation
Genome-Wide Association Study
Genotype
Humans
Linkage Disequilibrium
Odds Ratio
Polymorphism, Single Nucleotide
Proteins/genetics

Access to Document

10.1038/srep16286

srep16286
This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
Final published version, 278 KB

http://www.nature.com/articles/srep16286

RA2661 Centre for Cognitive Ageing and Cognitive Epidemiology Phase 2. Main Budget.
Deary, I. (Principal Investigator), Gale, C. (Co-investigator), Holmes, M. (Co-investigator), Logie, P. (Co-investigator), Maclullich, A. (Co-investigator), Porteous, D. (Co-investigator), Seckl, J. (Co-investigator), Starr, J. (Co-investigator), Wardlaw, J. (Co-investigator) & Okely, J. (Researcher)
1/09/13 → 31/08/19
Project: Research
Dissecting the Genetics of Colorectal Cancer: New Quinque
Dunlop, M. (Principal Investigator)
UK-based charities
1/01/11 → 31/12/15
Project: Research
MRC Centre for Cognitive Ageing and Cognitive Epidemiology
Deary, I. (Principal Investigator), Holmes, M. (Co-investigator), Logie, P. (Co-investigator), McCulloch, J. (Co-investigator), Porteous, D. (Co-investigator), Roberts, N. (Co-investigator), Seckl, J. (Co-investigator), Starr, J. (Co-investigator) & Wardlaw, J. (Co-investigator)
MRC
1/09/08 → 31/08/13
Project: Research

Susan Farrington
- Edinburgh Cancer Research Centre
- School of Genetics and Cancer - Personal Chair of Colorectal Cancer Genetics
Person: Academic: Research Active

Cite this

Timofeeva, M. N., Kinnersley, B., Farrington, S. M., Whiffin, N., Palles, C., Svinti, V., Lloyd, A., Gorman, M., Ooi, L., Hosking, F., Barclay, E., Zgaga, L., Dobbins, S., Martin, L., Theodoratou, E., Broderick, P., Tenesa, A., Smillie, C., Grimes, G., ... Houlston, R. S. (2015). Recurrent Coding Sequence Variation Explains Only A Small Fraction of the Genetic Architecture of Colorectal Cancer. Scientific Reports, 5, 16286. https://doi.org/10.1038/srep16286

@article{f102749b78a74864b32fecadb7f9dd22,

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. ",

keywords = "Activating Transcription Factor 1/genetics, Alleles, Cadherins/genetics, Case-Control Studies, Colorectal Neoplasms/genetics, European Continental Ancestry Group/genetics, Gene Frequency, Genetic Variation, Genome-Wide Association Study, Genotype, Humans, Linkage Disequilibrium, Odds Ratio, Polymorphism, Single Nucleotide, Proteins/genetics",

author = "Timofeeva, {Maria N.} and Ben Kinnersley and Farrington, {Susan M.} and Nicola Whiffin and Claire Palles and Victoria Svinti and Amy Lloyd and Maggie Gorman and Li-yin Ooi and Fay Hosking and Ella Barclay and Lina Zgaga and Sara Dobbins and Lynn Martin and Evropi Theodoratou and Peter Broderick and Albert Tenesa and Claire Smillie and Graeme Grimes and Caroline Hayward and Archie Campbell and David Porteous and Deary, {Ian J.} and Harris, {Sarah E.} and Northwood, {Emma L.} and Barrett, {Jennifer H.} and Gillian Smith and Roland Wolf and David Forman and Hans Morreau and Dina Ruano and Carli Tops and Juul Wijnen and Melanie Schrumpf and Arnoud Boot and Vasen, {Hans F A} and Hes, {Frederik J.} and {Van Wezel}, Tom and Andre Franke and Wolgang Lieb and Clemens Schafmayer and Jochen Hampe and Stephan Buch and Peter Propping and Kari Hemminki and Asta F??rsti and Helga Westers and Robert Hofstra and Manuela Pinheiro and Carla Pinto and Manuel Teixeira and Clara Ruiz-ponte and Ceres Fern??ndez-rozadilla and Angel Carracedo and Antoni Castells and Sergi Castellv??-bel and Harry Campbell and Bishop, {D. Timothy} and Tomlinson, {Ian P M} and Dunlop, {Malcolm G.} and Houlston, {Richard S.}",

year = "2015",

month = nov,

day = "10",

doi = "10.1038/srep16286",

language = "English",

volume = "5",

pages = "16286",

journal = "Scientific Reports",

issn = "2045-2322",

publisher = "Nature Publishing Group",

}

Timofeeva, MN, Kinnersley, B, Farrington, SM, Whiffin, N, Palles, C, Svinti, V, Lloyd, A, Gorman, M, Ooi, L, Hosking, F, Barclay, E, Zgaga, L, Dobbins, S, Martin, L, Theodoratou, E, Broderick, P, Tenesa, A, Smillie, C, Grimes, G, Hayward, C , Campbell, A, Porteous, D, Deary, IJ , Harris, SE, Northwood, EL, Barrett, JH, Smith, G, Wolf, R, Forman, D, Morreau, H, Ruano, D, Tops, C, Wijnen, J, Schrumpf, M, Boot, A, Vasen, HFA, Hes, FJ, Van Wezel, T, Franke, A, Lieb, W, Schafmayer, C, Hampe, J, Buch, S, Propping, P, Hemminki, K, F??rsti, A, Westers, H, Hofstra, R, Pinheiro, M, Pinto, C, Teixeira, M, Ruiz-ponte, C, Fern??ndez-rozadilla, C, Carracedo, A, Castells, A, Castellv??-bel, S, Campbell, H, Bishop, DT, Tomlinson, IPM, Dunlop, MG & Houlston, RS 2015, 'Recurrent Coding Sequence Variation Explains Only A Small Fraction of the Genetic Architecture of Colorectal Cancer', Scientific Reports, vol. 5, pp. 16286. https://doi.org/10.1038/srep16286

TY - JOUR

T1 - Recurrent Coding Sequence Variation Explains Only A Small Fraction of the Genetic Architecture of Colorectal Cancer

AU - Timofeeva, Maria N.

AU - Kinnersley, Ben

AU - Farrington, Susan M.

AU - Whiffin, Nicola

AU - Palles, Claire

AU - Svinti, Victoria

AU - Lloyd, Amy

AU - Gorman, Maggie

AU - Ooi, Li-yin

AU - Hosking, Fay

AU - Barclay, Ella

AU - Zgaga, Lina

AU - Dobbins, Sara

AU - Martin, Lynn

AU - Theodoratou, Evropi

AU - Broderick, Peter

AU - Tenesa, Albert

AU - Smillie, Claire

AU - Grimes, Graeme

AU - Hayward, Caroline

AU - Campbell, Archie

AU - Porteous, David

AU - Deary, Ian J.

AU - Harris, Sarah E.

AU - Northwood, Emma L.

AU - Barrett, Jennifer H.

AU - Smith, Gillian

AU - Wolf, Roland

AU - Forman, David

AU - Morreau, Hans

AU - Ruano, Dina

AU - Tops, Carli

AU - Wijnen, Juul

AU - Schrumpf, Melanie

AU - Boot, Arnoud

AU - Vasen, Hans F A

AU - Hes, Frederik J.

AU - Van Wezel, Tom

AU - Franke, Andre

AU - Lieb, Wolgang

AU - Schafmayer, Clemens

AU - Hampe, Jochen

AU - Buch, Stephan

AU - Propping, Peter

AU - Hemminki, Kari

AU - F??rsti, Asta

AU - Westers, Helga

AU - Hofstra, Robert

AU - Pinheiro, Manuela

AU - Pinto, Carla

AU - Teixeira, Manuel

AU - Ruiz-ponte, Clara

AU - Fern??ndez-rozadilla, Ceres

AU - Carracedo, Angel

AU - Castells, Antoni

AU - Castellv??-bel, Sergi

AU - Campbell, Harry

AU - Bishop, D. Timothy

AU - Tomlinson, Ian P M

AU - Dunlop, Malcolm G.

AU - Houlston, Richard S.

PY - 2015/11/10

Y1 - 2015/11/10

N2 - 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.

AB - 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.

KW - Activating Transcription Factor 1/genetics

KW - Alleles

KW - Cadherins/genetics

KW - Case-Control Studies

KW - Colorectal Neoplasms/genetics

KW - European Continental Ancestry Group/genetics

KW - Gene Frequency

KW - Genetic Variation

KW - Genome-Wide Association Study

KW - Genotype

KW - Humans

KW - Linkage Disequilibrium

KW - Odds Ratio

KW - Polymorphism, Single Nucleotide

KW - Proteins/genetics

U2 - 10.1038/srep16286

DO - 10.1038/srep16286

M3 - Article

C2 - 26553438

SN - 2045-2322

VL - 5

SP - 16286

JO - Scientific Reports

JF - Scientific Reports

ER -

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

Abstract

Keywords / Materials (for Non-textual outputs)

Access to Document

Fingerprint

Projects

RA2661 Centre for Cognitive Ageing and Cognitive Epidemiology Phase 2. Main Budget.

Dissecting the Genetics of Colorectal Cancer: New Quinque

MRC Centre for Cognitive Ageing and Cognitive Epidemiology

Profiles

Susan Farrington

Cite this