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 & 41 others 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

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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 languageEnglish
    Article number16286
    Number of pages10
    JournalScientific Reports
    Volume5
    DOIs
    Publication statusPublished - 10 Nov 2015

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    Colorectal Neoplasms
    Genes
    Exome
    DNA Mismatch Repair
    Nucleic Acid Regulatory Sequences
    Neoplasm Genes
    Genome-Wide Association Study
    Multigene Family
    Alleles
    Population

    Cite this

    Timofeeva, M. N., Kinnersley, B., Farrington, S. M., Whiffin, N., Palles, C., Svinti, V., ... 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
    Timofeeva, Maria N. ; Kinnersley, Ben ; Farrington, Susan M. ; Whiffin, Nicola ; Palles, Claire ; Svinti, Victoria ; Lloyd, Amy ; Gorman, Maggie ; Ooi, Li Yin ; Hosking, Fay ; Barclay, Ella ; Zgaga, Lina ; Dobbins, Sara ; Martin, Lynn ; Theodoratou, Evropi ; Broderick, Peter ; Tenesa, Albert ; Smillie, Claire ; Grimes, Graeme ; Hayward, Caroline ; Campbell, Archie ; Porteous, David ; Deary, Ian J. ; Harris, Sarah E. ; Northwood, Emma L. ; Barrett, Jennifer H. ; Smith, Gillian ; Wolf, Roland ; Forman, David ; Morreau, Hans ; Ruano, Dina ; Tops, Carli ; Wijnen, Juul ; Schrumpf, Melanie ; Boot, Arnoud ; Vasen, Hans F A ; Hes, Frederik J. ; Van Wezel, Tom ; Franke, Andre ; Lieb, Wolgang ; Schafmayer, Clemens ; Hampe, Jochen ; Buch, Stephan ; Propping, Peter ; Hemminki, Kari ; Försti, Asta ; Westers, Helga ; Hofstra, Robert ; Pinheiro, Manuela ; Pinto, Carla ; Teixeira, Manuel ; Ruiz-Ponte, Clara ; Fernández-Rozadilla, Ceres ; Carracedo, Angel ; Castells, Antoni ; Castellví-Bel, Sergi ; Campbell, Harry ; Bishop, D. Timothy ; Tomlinson, Ian P M ; Dunlop, Malcolm G. ; Houlston, Richard S. / Recurrent Coding Sequence Variation Explains only A Small Fraction of the Genetic Architecture of Colorectal Cancer. In: Scientific Reports. 2015 ; Vol. 5.
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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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    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

    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; Hosking, Fay; Barclay, Ella; Zgaga, Lina; Dobbins, Sara; Martin, Lynn; Theodoratou, Evropi; Broderick, Peter; Tenesa, Albert; Smillie, Claire; Grimes, Graeme; Hayward, Caroline; Campbell, Archie; Porteous, David; Deary, Ian J.; Harris, Sarah E.; Northwood, Emma L.; Barrett, Jennifer H.; Smith, Gillian; Wolf, Roland; Forman, David; Morreau, Hans; Ruano, Dina; Tops, Carli; Wijnen, Juul; Schrumpf, Melanie; Boot, Arnoud; Vasen, Hans F A; Hes, Frederik J.; Van Wezel, Tom; Franke, Andre; Lieb, Wolgang; Schafmayer, Clemens; Hampe, Jochen; Buch, Stephan; Propping, Peter; Hemminki, Kari; Försti, Asta; Westers, Helga; Hofstra, Robert; Pinheiro, Manuela; Pinto, Carla; Teixeira, Manuel; Ruiz-Ponte, Clara; Fernández-Rozadilla, Ceres; Carracedo, Angel; Castells, Antoni; Castellví-Bel, Sergi; Campbell, Harry; Bishop, D. Timothy; Tomlinson, Ian P M; Dunlop, Malcolm G.; Houlston, Richard S.

    In: Scientific Reports, Vol. 5, 16286, 10.11.2015.

    Research output: Contribution to journalArticle

    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.

    UR - http://www.scopus.com/inward/record.url?scp=84946593635&partnerID=8YFLogxK

    U2 - 10.1038/srep16286

    DO - 10.1038/srep16286

    M3 - Article

    VL - 5

    JO - Scientific Reports

    JF - Scientific Reports

    SN - 2045-2322

    M1 - 16286

    ER -