Pathway analysis of genome-wide association study data highlights pancreatic development genes as susceptibility factors for pancreatic cancer

Donghui Li, Eric J. Duell, Kai Yu, Harvey A. Risch, Sara H. Olson, Charles Kooperberg, Brian M. Wolpin, Li Jiao, Xiaoqun Dong, Bill Wheeler, Alan A. Arslan, H. Bas Bueno-de-Mesquita, Charles S. Fuchs, Steven Gallinger, Myron Gross, Patricia Hartge, Robert N. Hoover, Elizabeth A. Holly, Eric J. Jacobs, Alison P. KleinAndrea LaCroix, Margaret T. Mandelson, Gloria Petersen, Wei Zheng, Ilir Agalliu, Demetrius Albanes, Marie Christine Boutron-Ruault, Paige M. Bracci, Julie E. Buring, Federico Canzian, Kenneth Chang, Stephen J. Chanock, Michelle Cotterchio, J. Michael Gaziano, Edward L. Giovannucci, Michael Goggins, Göran Hallmans, Susan E. Hankinson, Judith A. Hoffman Bolton, David J. Hunter, Amy Hutchinson, Kevin B. Jacobs, Mazda Jenab, Kay Tee Khaw, Peter Kraft, Vittorio Krogh, Robert C. Kurtz, R. McWilliams Robert, Julie B. Mendelsohn, Alpa V. Patel, Kari G. Rabe, Elio Riboli, Xiao Ou Shu, A. Tjønneland, Geoffrey S. Tobias, Dimitrios Trichopoulos, Jarmo Virtamo, Kala Visvanathan, Joanne Watters, Herbert Yu, Anne Zeleniuch-Jacquotte, Laufey Amundadottir, Rachael Z. Stolzenberg-Solomon

Research output: Contribution to journalArticle

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Abstract

Four loci have been associated with pancreatic cancer through genome-wide association studies (GWAS). Pathway-based analysis of GWAS data is a complementary approach to identify groups of genes or biological pathways enriched with disease-associated single-nucleotide polymorphisms (SNPs) whose individual effect sizes may be too small to be detected by standard single-locus methods. We used the adaptive rank truncated product method in a pathway-based analysis of GWAS data from 3851 pancreatic cancer cases and 3934 control participants pooled from 12 cohort studies and 8 case-control studies (PanScan). We compiled 23 biological pathways hypothesized to be relevant to pancreatic cancer and observed a nominal association between pancreatic cancer and five pathways (P < 0.05), i.e. pancreatic development, Helicobacter pylori lacto/neolacto, hedgehog, Th1/Th2 immune response and apoptosis (P = 2.0 × 10 -6, 1.6 × 10 -5, 0.0019, 0.019 and 0.023, respectively). After excluding previously identified genes from the original GWAS in three pathways (NR5A2, ABO and SHH), the pancreatic development pathway remained significant (P = 8.3 × 10 -5), whereas the others did not. The most significant genes (P < 0.01) in the five pathways were NR5A2, HNF1A, HNF4G and PDX1 for pancreatic development; ABO for H.pylori lacto/neolacto; SHH for hedgehog; TGFBR2 and CCL18 for Th1/Th2 immune response and MAPK8 and BCL2L11 for apoptosis. Our results provide a link between inherited variation in genes important for pancreatic development and cancer and show that pathway-based approaches to analysis of GWAS data can yield important insights into the collective role of genetic risk variants in cancer.

Original languageEnglish (US)
Pages (from-to)1384-1390
Number of pages7
JournalCarcinogenesis
Volume33
Issue number7
DOIs
StatePublished - Jul 2012

Fingerprint

Genome-Wide Association Study
Pancreatic Neoplasms
Genes
Apoptosis
Pylorus
Helicobacter pylori
Single Nucleotide Polymorphism
Case-Control Studies
Cohort Studies
Neoplasms

ASJC Scopus subject areas

  • Cancer Research

Cite this

Li, D., Duell, E. J., Yu, K., Risch, H. A., Olson, S. H., Kooperberg, C., ... Stolzenberg-Solomon, R. Z. (2012). Pathway analysis of genome-wide association study data highlights pancreatic development genes as susceptibility factors for pancreatic cancer. Carcinogenesis, 33(7), 1384-1390. https://doi.org/10.1093/carcin/bgs151

Pathway analysis of genome-wide association study data highlights pancreatic development genes as susceptibility factors for pancreatic cancer. / Li, Donghui; Duell, Eric J.; Yu, Kai; Risch, Harvey A.; Olson, Sara H.; Kooperberg, Charles; Wolpin, Brian M.; Jiao, Li; Dong, Xiaoqun; Wheeler, Bill; Arslan, Alan A.; Bueno-de-Mesquita, H. Bas; Fuchs, Charles S.; Gallinger, Steven; Gross, Myron; Hartge, Patricia; Hoover, Robert N.; Holly, Elizabeth A.; Jacobs, Eric J.; Klein, Alison P.; LaCroix, Andrea; Mandelson, Margaret T.; Petersen, Gloria; Zheng, Wei; Agalliu, Ilir; Albanes, Demetrius; Boutron-Ruault, Marie Christine; Bracci, Paige M.; Buring, Julie E.; Canzian, Federico; Chang, Kenneth; Chanock, Stephen J.; Cotterchio, Michelle; Gaziano, J. Michael; Giovannucci, Edward L.; Goggins, Michael; Hallmans, Göran; Hankinson, Susan E.; Hoffman Bolton, Judith A.; Hunter, David J.; Hutchinson, Amy; Jacobs, Kevin B.; Jenab, Mazda; Khaw, Kay Tee; Kraft, Peter; Krogh, Vittorio; Kurtz, Robert C.; Robert, R. McWilliams; Mendelsohn, Julie B.; Patel, Alpa V.; Rabe, Kari G.; Riboli, Elio; Shu, Xiao Ou; Tjønneland, A.; Tobias, Geoffrey S.; Trichopoulos, Dimitrios; Virtamo, Jarmo; Visvanathan, Kala; Watters, Joanne; Yu, Herbert; Zeleniuch-Jacquotte, Anne; Amundadottir, Laufey; Stolzenberg-Solomon, Rachael Z.

In: Carcinogenesis, Vol. 33, No. 7, 07.2012, p. 1384-1390.

Research output: Contribution to journalArticle

Li, D, Duell, EJ, Yu, K, Risch, HA, Olson, SH, Kooperberg, C, Wolpin, BM, Jiao, L, Dong, X, Wheeler, B, Arslan, AA, Bueno-de-Mesquita, HB, Fuchs, CS, Gallinger, S, Gross, M, Hartge, P, Hoover, RN, Holly, EA, Jacobs, EJ, Klein, AP, LaCroix, A, Mandelson, MT, Petersen, G, Zheng, W, Agalliu, I, Albanes, D, Boutron-Ruault, MC, Bracci, PM, Buring, JE, Canzian, F, Chang, K, Chanock, SJ, Cotterchio, M, Gaziano, JM, Giovannucci, EL, Goggins, M, Hallmans, G, Hankinson, SE, Hoffman Bolton, JA, Hunter, DJ, Hutchinson, A, Jacobs, KB, Jenab, M, Khaw, KT, Kraft, P, Krogh, V, Kurtz, RC, Robert, RM, Mendelsohn, JB, Patel, AV, Rabe, KG, Riboli, E, Shu, XO, Tjønneland, A, Tobias, GS, Trichopoulos, D, Virtamo, J, Visvanathan, K, Watters, J, Yu, H, Zeleniuch-Jacquotte, A, Amundadottir, L & Stolzenberg-Solomon, RZ 2012, 'Pathway analysis of genome-wide association study data highlights pancreatic development genes as susceptibility factors for pancreatic cancer', Carcinogenesis, vol. 33, no. 7, pp. 1384-1390. https://doi.org/10.1093/carcin/bgs151
Li, Donghui ; Duell, Eric J. ; Yu, Kai ; Risch, Harvey A. ; Olson, Sara H. ; Kooperberg, Charles ; Wolpin, Brian M. ; Jiao, Li ; Dong, Xiaoqun ; Wheeler, Bill ; Arslan, Alan A. ; Bueno-de-Mesquita, H. Bas ; Fuchs, Charles S. ; Gallinger, Steven ; Gross, Myron ; Hartge, Patricia ; Hoover, Robert N. ; Holly, Elizabeth A. ; Jacobs, Eric J. ; Klein, Alison P. ; LaCroix, Andrea ; Mandelson, Margaret T. ; Petersen, Gloria ; Zheng, Wei ; Agalliu, Ilir ; Albanes, Demetrius ; Boutron-Ruault, Marie Christine ; Bracci, Paige M. ; Buring, Julie E. ; Canzian, Federico ; Chang, Kenneth ; Chanock, Stephen J. ; Cotterchio, Michelle ; Gaziano, J. Michael ; Giovannucci, Edward L. ; Goggins, Michael ; Hallmans, Göran ; Hankinson, Susan E. ; Hoffman Bolton, Judith A. ; Hunter, David J. ; Hutchinson, Amy ; Jacobs, Kevin B. ; Jenab, Mazda ; Khaw, Kay Tee ; Kraft, Peter ; Krogh, Vittorio ; Kurtz, Robert C. ; Robert, R. McWilliams ; Mendelsohn, Julie B. ; Patel, Alpa V. ; Rabe, Kari G. ; Riboli, Elio ; Shu, Xiao Ou ; Tjønneland, A. ; Tobias, Geoffrey S. ; Trichopoulos, Dimitrios ; Virtamo, Jarmo ; Visvanathan, Kala ; Watters, Joanne ; Yu, Herbert ; Zeleniuch-Jacquotte, Anne ; Amundadottir, Laufey ; Stolzenberg-Solomon, Rachael Z. / Pathway analysis of genome-wide association study data highlights pancreatic development genes as susceptibility factors for pancreatic cancer. In: Carcinogenesis. 2012 ; Vol. 33, No. 7. pp. 1384-1390.
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title = "Pathway analysis of genome-wide association study data highlights pancreatic development genes as susceptibility factors for pancreatic cancer",
abstract = "Four loci have been associated with pancreatic cancer through genome-wide association studies (GWAS). Pathway-based analysis of GWAS data is a complementary approach to identify groups of genes or biological pathways enriched with disease-associated single-nucleotide polymorphisms (SNPs) whose individual effect sizes may be too small to be detected by standard single-locus methods. We used the adaptive rank truncated product method in a pathway-based analysis of GWAS data from 3851 pancreatic cancer cases and 3934 control participants pooled from 12 cohort studies and 8 case-control studies (PanScan). We compiled 23 biological pathways hypothesized to be relevant to pancreatic cancer and observed a nominal association between pancreatic cancer and five pathways (P < 0.05), i.e. pancreatic development, Helicobacter pylori lacto/neolacto, hedgehog, Th1/Th2 immune response and apoptosis (P = 2.0 × 10 -6, 1.6 × 10 -5, 0.0019, 0.019 and 0.023, respectively). After excluding previously identified genes from the original GWAS in three pathways (NR5A2, ABO and SHH), the pancreatic development pathway remained significant (P = 8.3 × 10 -5), whereas the others did not. The most significant genes (P < 0.01) in the five pathways were NR5A2, HNF1A, HNF4G and PDX1 for pancreatic development; ABO for H.pylori lacto/neolacto; SHH for hedgehog; TGFBR2 and CCL18 for Th1/Th2 immune response and MAPK8 and BCL2L11 for apoptosis. Our results provide a link between inherited variation in genes important for pancreatic development and cancer and show that pathway-based approaches to analysis of GWAS data can yield important insights into the collective role of genetic risk variants in cancer.",
author = "Donghui Li and Duell, {Eric J.} and Kai Yu and Risch, {Harvey A.} and Olson, {Sara H.} and Charles Kooperberg and Wolpin, {Brian M.} and Li Jiao and Xiaoqun Dong and Bill Wheeler and Arslan, {Alan A.} and Bueno-de-Mesquita, {H. Bas} and Fuchs, {Charles S.} and Steven Gallinger and Myron Gross and Patricia Hartge and Hoover, {Robert N.} and Holly, {Elizabeth A.} and Jacobs, {Eric J.} and Klein, {Alison P.} and Andrea LaCroix and Mandelson, {Margaret T.} and Gloria Petersen and Wei Zheng and Ilir Agalliu and Demetrius Albanes and Boutron-Ruault, {Marie Christine} and Bracci, {Paige M.} and Buring, {Julie E.} and Federico Canzian and Kenneth Chang and Chanock, {Stephen J.} and Michelle Cotterchio and Gaziano, {J. Michael} and Giovannucci, {Edward L.} and Michael Goggins and G{\"o}ran Hallmans and Hankinson, {Susan E.} and {Hoffman Bolton}, {Judith A.} and Hunter, {David J.} and Amy Hutchinson and Jacobs, {Kevin B.} and Mazda Jenab and Khaw, {Kay Tee} and Peter Kraft and Vittorio Krogh and Kurtz, {Robert C.} and Robert, {R. McWilliams} and Mendelsohn, {Julie B.} and Patel, {Alpa V.} and Rabe, {Kari G.} and Elio Riboli and Shu, {Xiao Ou} and A. Tj{\o}nneland and Tobias, {Geoffrey S.} and Dimitrios Trichopoulos and Jarmo Virtamo and Kala Visvanathan and Joanne Watters and Herbert Yu and Anne Zeleniuch-Jacquotte and Laufey Amundadottir and Stolzenberg-Solomon, {Rachael Z.}",
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TY - JOUR

T1 - Pathway analysis of genome-wide association study data highlights pancreatic development genes as susceptibility factors for pancreatic cancer

AU - Li, Donghui

AU - Duell, Eric J.

AU - Yu, Kai

AU - Risch, Harvey A.

AU - Olson, Sara H.

AU - Kooperberg, Charles

AU - Wolpin, Brian M.

AU - Jiao, Li

AU - Dong, Xiaoqun

AU - Wheeler, Bill

AU - Arslan, Alan A.

AU - Bueno-de-Mesquita, H. Bas

AU - Fuchs, Charles S.

AU - Gallinger, Steven

AU - Gross, Myron

AU - Hartge, Patricia

AU - Hoover, Robert N.

AU - Holly, Elizabeth A.

AU - Jacobs, Eric J.

AU - Klein, Alison P.

AU - LaCroix, Andrea

AU - Mandelson, Margaret T.

AU - Petersen, Gloria

AU - Zheng, Wei

AU - Agalliu, Ilir

AU - Albanes, Demetrius

AU - Boutron-Ruault, Marie Christine

AU - Bracci, Paige M.

AU - Buring, Julie E.

AU - Canzian, Federico

AU - Chang, Kenneth

AU - Chanock, Stephen J.

AU - Cotterchio, Michelle

AU - Gaziano, J. Michael

AU - Giovannucci, Edward L.

AU - Goggins, Michael

AU - Hallmans, Göran

AU - Hankinson, Susan E.

AU - Hoffman Bolton, Judith A.

AU - Hunter, David J.

AU - Hutchinson, Amy

AU - Jacobs, Kevin B.

AU - Jenab, Mazda

AU - Khaw, Kay Tee

AU - Kraft, Peter

AU - Krogh, Vittorio

AU - Kurtz, Robert C.

AU - Robert, R. McWilliams

AU - Mendelsohn, Julie B.

AU - Patel, Alpa V.

AU - Rabe, Kari G.

AU - Riboli, Elio

AU - Shu, Xiao Ou

AU - Tjønneland, A.

AU - Tobias, Geoffrey S.

AU - Trichopoulos, Dimitrios

AU - Virtamo, Jarmo

AU - Visvanathan, Kala

AU - Watters, Joanne

AU - Yu, Herbert

AU - Zeleniuch-Jacquotte, Anne

AU - Amundadottir, Laufey

AU - Stolzenberg-Solomon, Rachael Z.

PY - 2012/7

Y1 - 2012/7

N2 - Four loci have been associated with pancreatic cancer through genome-wide association studies (GWAS). Pathway-based analysis of GWAS data is a complementary approach to identify groups of genes or biological pathways enriched with disease-associated single-nucleotide polymorphisms (SNPs) whose individual effect sizes may be too small to be detected by standard single-locus methods. We used the adaptive rank truncated product method in a pathway-based analysis of GWAS data from 3851 pancreatic cancer cases and 3934 control participants pooled from 12 cohort studies and 8 case-control studies (PanScan). We compiled 23 biological pathways hypothesized to be relevant to pancreatic cancer and observed a nominal association between pancreatic cancer and five pathways (P < 0.05), i.e. pancreatic development, Helicobacter pylori lacto/neolacto, hedgehog, Th1/Th2 immune response and apoptosis (P = 2.0 × 10 -6, 1.6 × 10 -5, 0.0019, 0.019 and 0.023, respectively). After excluding previously identified genes from the original GWAS in three pathways (NR5A2, ABO and SHH), the pancreatic development pathway remained significant (P = 8.3 × 10 -5), whereas the others did not. The most significant genes (P < 0.01) in the five pathways were NR5A2, HNF1A, HNF4G and PDX1 for pancreatic development; ABO for H.pylori lacto/neolacto; SHH for hedgehog; TGFBR2 and CCL18 for Th1/Th2 immune response and MAPK8 and BCL2L11 for apoptosis. Our results provide a link between inherited variation in genes important for pancreatic development and cancer and show that pathway-based approaches to analysis of GWAS data can yield important insights into the collective role of genetic risk variants in cancer.

AB - Four loci have been associated with pancreatic cancer through genome-wide association studies (GWAS). Pathway-based analysis of GWAS data is a complementary approach to identify groups of genes or biological pathways enriched with disease-associated single-nucleotide polymorphisms (SNPs) whose individual effect sizes may be too small to be detected by standard single-locus methods. We used the adaptive rank truncated product method in a pathway-based analysis of GWAS data from 3851 pancreatic cancer cases and 3934 control participants pooled from 12 cohort studies and 8 case-control studies (PanScan). We compiled 23 biological pathways hypothesized to be relevant to pancreatic cancer and observed a nominal association between pancreatic cancer and five pathways (P < 0.05), i.e. pancreatic development, Helicobacter pylori lacto/neolacto, hedgehog, Th1/Th2 immune response and apoptosis (P = 2.0 × 10 -6, 1.6 × 10 -5, 0.0019, 0.019 and 0.023, respectively). After excluding previously identified genes from the original GWAS in three pathways (NR5A2, ABO and SHH), the pancreatic development pathway remained significant (P = 8.3 × 10 -5), whereas the others did not. The most significant genes (P < 0.01) in the five pathways were NR5A2, HNF1A, HNF4G and PDX1 for pancreatic development; ABO for H.pylori lacto/neolacto; SHH for hedgehog; TGFBR2 and CCL18 for Th1/Th2 immune response and MAPK8 and BCL2L11 for apoptosis. Our results provide a link between inherited variation in genes important for pancreatic development and cancer and show that pathway-based approaches to analysis of GWAS data can yield important insights into the collective role of genetic risk variants in cancer.

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