Variation at 2q35 (PNKD and TMBIM1) influences colorectal cancer risk and identifies a pleiotropic effect with inflammatory bowel disease

Giulia Orlando; Philip J. Law; Kimmo Palin; Sari Tuupanen; Alexandra Gylfe; Ulrika A. Hänninen; Tatiana Cajuso; Tomas Tanskanen; Johanna Kondelin; Eevi Kaasinen; Antti Pekka Sarin; Jaakko Kaprio; Johan G. Eriksson; Harri Rissanen; Paul Knekt; Eero Pukkala; Pekka Jousilahti; Veikko Salomaa; Samuli Ripatti; Aarno Palotie; Heikki Järvinen; Laura Renkonen-Sinisalo; Anna Lepistö; Jan Böhm; Jukka Pekka Mecklin; Nada A. Al-Tassan; Claire Palles; Lynn Martin; Ella Barclay; Albert Tenesa; Susan Farrington; Maria N. Timofeeva; Brian F. Meyer; Salma M. Wakil; Harry Campbell; Christopher G. Smith; Shelley Idziaszczyk; Timothy S. Maughan; Richard Kaplan; Rachel Kerr; David Kerr; Daniel D. Buchanan; Aung Ko Win; John Hopper; Mark Jenkins; Noralane M. Lindor; Polly A. Newcomb; Steve Gallinger; David Conti; Fred Schumacher; Graham Casey; Jussi Taipale; Jeremy P. Cheadle; Malcolm G. Dunlop; Ian P. Tomlinson; Lauri A. Aaltonen; Richard S. Houlston

doi:10.1093/hmg/ddw087

Variation at 2q35 (PNKD and TMBIM1) influences colorectal cancer risk and identifies a pleiotropic effect with inflammatory bowel disease

Giulia Orlando, Philip J. Law, Kimmo Palin, Sari Tuupanen, Alexandra Gylfe, Ulrika A. Hänninen, Tatiana Cajuso, Tomas Tanskanen, Johanna Kondelin, Eevi Kaasinen, Antti Pekka Sarin, Jaakko Kaprio, Johan G. Eriksson, Harri Rissanen, Paul Knekt, Eero Pukkala, Pekka Jousilahti, Veikko Salomaa, Samuli Ripatti, Aarno PalotieHeikki Järvinen, Laura Renkonen-Sinisalo, Anna Lepistö, Jan Böhm, Jukka Pekka Mecklin, Nada A. Al-Tassan, Claire Palles, Lynn Martin, Ella Barclay, Albert Tenesa, Susan Farrington, Maria N. Timofeeva, Brian F. Meyer, Salma M. Wakil, Harry Campbell, Christopher G. Smith, Shelley Idziaszczyk, Timothy S. Maughan, Richard Kaplan, Rachel Kerr, David Kerr, Daniel D. Buchanan, Aung Ko Win, John Hopper, Mark Jenkins, Noralane M. Lindor, Polly A. Newcomb, Steve Gallinger, David Conti, Fred Schumacher, Graham Casey, Jussi Taipale, Jeremy P. Cheadle, Malcolm G. Dunlop, Ian P. Tomlinson, Lauri A. Aaltonen, Richard S. Houlston

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Abstract

To identify new risk loci for colorectal cancer (CRC), we conducted a meta-analysis of seven genome-wide association studies (GWAS) with independent replication, totalling 13 656 CRC cases and 21 667 controls of European ancestry. The combined analysis identified a new risk association for CRC at 2q35 marked by rs992157 (P=3.15x10^-8, odds ratio=1.10, 95% confidence interval=1.06^-1.13), which is intronic to PNKD (paroxysmal non-kinesigenic dyskinesia) and TMBIM1 (transmembrane BAX inhibitor motif containing 1). Intriguingly this susceptibility single-nucleotide polymorphism (SNP) is in strong linkage disequilibrium (r²=0.90, D' =0.96) with the previously discovered GWAS SNP rs2382817 for inflammatory bowel disease (IBD). Following on from this observation we examined for pleiotropy, or shared genetic susceptibility, between CRC and the 200 established IBD risk loci, identifying an additional 11 significant associations (false discovery rate [FDR])<0.05). Our findings provide further insight into the biological basis of inherited genetic susceptibility to CRC, and identify risk factors that may influence the development of both CRC and IBD.

Original language	English (US)
Pages (from-to)	2349-2359
Number of pages	11
Journal	Human molecular genetics
Volume	25
Issue number	11
DOIs	https://doi.org/10.1093/hmg/ddw087
State	Published - Jun 1 2016

ASJC Scopus subject areas

Molecular Biology
Genetics
Genetics(clinical)

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10.1093/hmg/ddw087

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Orlando, G., Law, P. J., Palin, K., Tuupanen, S., Gylfe, A., Hänninen, U. A., Cajuso, T., Tanskanen, T., Kondelin, J., Kaasinen, E., Sarin, A. P., Kaprio, J., Eriksson, J. G., Rissanen, H., Knekt, P., Pukkala, E., Jousilahti, P., Salomaa, V., Ripatti, S., ... Houlston, R. S. (2016). Variation at 2q35 (PNKD and TMBIM1) influences colorectal cancer risk and identifies a pleiotropic effect with inflammatory bowel disease. Human molecular genetics, 25(11), 2349-2359. https://doi.org/10.1093/hmg/ddw087

Orlando, G, Law, PJ, Palin, K, Tuupanen, S, Gylfe, A, Hänninen, UA, Cajuso, T, Tanskanen, T, Kondelin, J, Kaasinen, E, Sarin, AP, Kaprio, J, Eriksson, JG, Rissanen, H, Knekt, P, Pukkala, E, Jousilahti, P, Salomaa, V, Ripatti, S, Palotie, A, Järvinen, H, Renkonen-Sinisalo, L, Lepistö, A, Böhm, J, Mecklin, JP, Al-Tassan, NA, Palles, C, Martin, L, Barclay, E, Tenesa, A, Farrington, S, Timofeeva, MN, Meyer, BF, Wakil, SM, Campbell, H, Smith, CG, Idziaszczyk, S, Maughan, TS, Kaplan, R, Kerr, R, Kerr, D, Buchanan, DD, Win, AK, Hopper, J, Jenkins, M, Lindor, NM, Newcomb, PA, Gallinger, S, Conti, D, Schumacher, F, Casey, G, Taipale, J, Cheadle, JP, Dunlop, MG, Tomlinson, IP, Aaltonen, LA & Houlston, RS 2016, 'Variation at 2q35 (PNKD and TMBIM1) influences colorectal cancer risk and identifies a pleiotropic effect with inflammatory bowel disease', Human molecular genetics, vol. 25, no. 11, pp. 2349-2359. https://doi.org/10.1093/hmg/ddw087

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title = "Variation at 2q35 (PNKD and TMBIM1) influences colorectal cancer risk and identifies a pleiotropic effect with inflammatory bowel disease",

abstract = "To identify new risk loci for colorectal cancer (CRC), we conducted a meta-analysis of seven genome-wide association studies (GWAS) with independent replication, totalling 13 656 CRC cases and 21 667 controls of European ancestry. The combined analysis identified a new risk association for CRC at 2q35 marked by rs992157 (P=3.15x10-8, odds ratio=1.10, 95% confidence interval=1.06-1.13), which is intronic to PNKD (paroxysmal non-kinesigenic dyskinesia) and TMBIM1 (transmembrane BAX inhibitor motif containing 1). Intriguingly this susceptibility single-nucleotide polymorphism (SNP) is in strong linkage disequilibrium (r2=0.90, D' =0.96) with the previously discovered GWAS SNP rs2382817 for inflammatory bowel disease (IBD). Following on from this observation we examined for pleiotropy, or shared genetic susceptibility, between CRC and the 200 established IBD risk loci, identifying an additional 11 significant associations (false discovery rate [FDR])<0.05). Our findings provide further insight into the biological basis of inherited genetic susceptibility to CRC, and identify risk factors that may influence the development of both CRC and IBD.",

author = "Giulia Orlando and Law, {Philip J.} and Kimmo Palin and Sari Tuupanen and Alexandra Gylfe and H{\"a}nninen, {Ulrika A.} and Tatiana Cajuso and Tomas Tanskanen and Johanna Kondelin and Eevi Kaasinen and Sarin, {Antti Pekka} and Jaakko Kaprio and Eriksson, {Johan G.} and Harri Rissanen and Paul Knekt and Eero Pukkala and Pekka Jousilahti and Veikko Salomaa and Samuli Ripatti and Aarno Palotie and Heikki J{\"a}rvinen and Laura Renkonen-Sinisalo and Anna Lepist{\"o} and Jan B{\"o}hm and Mecklin, {Jukka Pekka} and Al-Tassan, {Nada A.} and Claire Palles and Lynn Martin and Ella Barclay and Albert Tenesa and Susan Farrington and Timofeeva, {Maria N.} and Meyer, {Brian F.} and Wakil, {Salma M.} and Harry Campbell and Smith, {Christopher G.} and Shelley Idziaszczyk and Maughan, {Timothy S.} and Richard Kaplan and Rachel Kerr and David Kerr and Buchanan, {Daniel D.} and Win, {Aung Ko} and John Hopper and Mark Jenkins and Lindor, {Noralane M.} and Newcomb, {Polly A.} and Steve Gallinger and David Conti and Fred Schumacher and Graham Casey and Jussi Taipale and Cheadle, {Jeremy P.} and Dunlop, {Malcolm G.} and Tomlinson, {Ian P.} and Aaltonen, {Lauri A.} and Houlston, {Richard S.}",

note = "Publisher Copyright: {\textcopyright} The Author 2016.",

year = "2016",

month = jun,

day = "1",

doi = "10.1093/hmg/ddw087",

language = "English (US)",

volume = "25",

pages = "2349--2359",

journal = "Human molecular genetics",

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number = "11",

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TY - JOUR

T1 - Variation at 2q35 (PNKD and TMBIM1) influences colorectal cancer risk and identifies a pleiotropic effect with inflammatory bowel disease

AU - Orlando, Giulia

AU - Law, Philip J.

AU - Palin, Kimmo

AU - Tuupanen, Sari

AU - Gylfe, Alexandra

AU - Hänninen, Ulrika A.

AU - Cajuso, Tatiana

AU - Tanskanen, Tomas

AU - Kondelin, Johanna

AU - Kaasinen, Eevi

AU - Sarin, Antti Pekka

AU - Kaprio, Jaakko

AU - Eriksson, Johan G.

AU - Rissanen, Harri

AU - Knekt, Paul

AU - Pukkala, Eero

AU - Jousilahti, Pekka

AU - Salomaa, Veikko

AU - Ripatti, Samuli

AU - Palotie, Aarno

AU - Järvinen, Heikki

AU - Renkonen-Sinisalo, Laura

AU - Lepistö, Anna

AU - Böhm, Jan

AU - Mecklin, Jukka Pekka

AU - Al-Tassan, Nada A.

AU - Palles, Claire

AU - Martin, Lynn

AU - Barclay, Ella

AU - Tenesa, Albert

AU - Farrington, Susan

AU - Timofeeva, Maria N.

AU - Meyer, Brian F.

AU - Wakil, Salma M.

AU - Campbell, Harry

AU - Smith, Christopher G.

AU - Idziaszczyk, Shelley

AU - Maughan, Timothy S.

AU - Kaplan, Richard

AU - Kerr, Rachel

AU - Kerr, David

AU - Buchanan, Daniel D.

AU - Win, Aung Ko

AU - Hopper, John

AU - Jenkins, Mark

AU - Lindor, Noralane M.

AU - Newcomb, Polly A.

AU - Gallinger, Steve

AU - Conti, David

AU - Schumacher, Fred

AU - Casey, Graham

AU - Taipale, Jussi

AU - Cheadle, Jeremy P.

AU - Dunlop, Malcolm G.

AU - Tomlinson, Ian P.

AU - Aaltonen, Lauri A.

AU - Houlston, Richard S.

PY - 2016/6/1

Y1 - 2016/6/1

N2 - To identify new risk loci for colorectal cancer (CRC), we conducted a meta-analysis of seven genome-wide association studies (GWAS) with independent replication, totalling 13 656 CRC cases and 21 667 controls of European ancestry. The combined analysis identified a new risk association for CRC at 2q35 marked by rs992157 (P=3.15x10-8, odds ratio=1.10, 95% confidence interval=1.06-1.13), which is intronic to PNKD (paroxysmal non-kinesigenic dyskinesia) and TMBIM1 (transmembrane BAX inhibitor motif containing 1). Intriguingly this susceptibility single-nucleotide polymorphism (SNP) is in strong linkage disequilibrium (r2=0.90, D' =0.96) with the previously discovered GWAS SNP rs2382817 for inflammatory bowel disease (IBD). Following on from this observation we examined for pleiotropy, or shared genetic susceptibility, between CRC and the 200 established IBD risk loci, identifying an additional 11 significant associations (false discovery rate [FDR])<0.05). Our findings provide further insight into the biological basis of inherited genetic susceptibility to CRC, and identify risk factors that may influence the development of both CRC and IBD.

AB - To identify new risk loci for colorectal cancer (CRC), we conducted a meta-analysis of seven genome-wide association studies (GWAS) with independent replication, totalling 13 656 CRC cases and 21 667 controls of European ancestry. The combined analysis identified a new risk association for CRC at 2q35 marked by rs992157 (P=3.15x10-8, odds ratio=1.10, 95% confidence interval=1.06-1.13), which is intronic to PNKD (paroxysmal non-kinesigenic dyskinesia) and TMBIM1 (transmembrane BAX inhibitor motif containing 1). Intriguingly this susceptibility single-nucleotide polymorphism (SNP) is in strong linkage disequilibrium (r2=0.90, D' =0.96) with the previously discovered GWAS SNP rs2382817 for inflammatory bowel disease (IBD). Following on from this observation we examined for pleiotropy, or shared genetic susceptibility, between CRC and the 200 established IBD risk loci, identifying an additional 11 significant associations (false discovery rate [FDR])<0.05). Our findings provide further insight into the biological basis of inherited genetic susceptibility to CRC, and identify risk factors that may influence the development of both CRC and IBD.

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DO - 10.1093/hmg/ddw087

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JF - Human molecular genetics

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ER -

Variation at 2q35 (PNKD and TMBIM1) influences colorectal cancer risk and identifies a pleiotropic effect with inflammatory bowel disease

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