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 Försti; Helga Westers; Robert Hofstra; Manuela Pinheiro; Carla Pinto; Manuel Teixeira; Clara Ruiz-Ponte; Ceres Fernández-Rozadilla; Angel Carracedo; Antoni Castells; Sergi Castellví-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 Försti, Helga Westers, Robert Hofstra, Manuela Pinheiro, Carla Pinto, Manuel Teixeira, Clara Ruiz-Ponte, Ceres Fernández-Rozadilla, Angel Carracedo, Antoni Castells, Sergi Castellví-Bel, Harry Campbell, D. Timothy Bishop, Ian P M Tomlinson, Malcolm G. Dunlop, Richard S. Houlston

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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
Article number	16286
Number of pages	10
Journal	Scientific Reports
Volume	5
DOIs	https://doi.org/10.1038/srep16286
Publication status	Published - 10 Nov 2015

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Timofeeva, M. N., Kinnersley, B., Farrington, S. M., Whiffin, N., Palles, C., Svinti, V., Lloyd, A., Gorman, M., Ooi, L. Y., 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, Article 16286. https://doi.org/10.1038/srep16286

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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.",

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 Ooi, {Li Yin} 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{\"o}rsti and Helga Westers and Robert Hofstra and Manuela Pinheiro and Carla Pinto and Manuel Teixeira and Clara Ruiz-Ponte and Ceres Fern{\'a}ndez-Rozadilla and Angel Carracedo and Antoni Castells and Sergi Castellv{\'i}-Bel and Harry Campbell and Bishop, {D. Timothy} and Tomlinson, {Ian P M} and Dunlop, {Malcolm G.} and Houlston, {Richard S.}",

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day = "10",

doi = "10.1038/srep16286",

language = "English",

volume = "5",

journal = "Scientific Reports",

issn = "2045-2322",

publisher = "Nature Research",

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Timofeeva, MN, Kinnersley, B, Farrington, SM, Whiffin, N, Palles, C, Svinti, V, Lloyd, A, Gorman, M, Ooi, LY, 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, Försti, A, Westers, H, Hofstra, R, Pinheiro, M, Pinto, C, Teixeira, M, Ruiz-Ponte, C, Fernández-Rozadilla, C, Carracedo, A, Castells, A, Castellví-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, 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 - Försti, Asta

AU - Westers, Helga

AU - Hofstra, Robert

AU - Pinheiro, Manuela

AU - Pinto, Carla

AU - Teixeira, Manuel

AU - Ruiz-Ponte, Clara

AU - Fernández-Rozadilla, Ceres

AU - Carracedo, Angel

AU - Castells, Antoni

AU - Castellví-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.

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U2 - 10.1038/srep16286

DO - 10.1038/srep16286

M3 - Article

C2 - 26553438

AN - SCOPUS:84946593635

SN - 2045-2322

VL - 5

JO - Scientific Reports

JF - Scientific Reports

M1 - 16286

ER -

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

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