A transcriptome-wide association study identifies novel candidate susceptibility genes for pancreatic cancer

Jun Zhong; Ashley Jermusyk; Lang Wu; Jason W. Hoskins; Irene Collins; Evelina Mocci; Mingfeng Zhang; Lei Song; Charles C. Chung; Tongwu Zhang; Wenming Xiao; Demetrius Albanes; Gabriella Andreotti; Alan A. Arslan; Ana Babic; William R. Bamlet; Laura Beane-Freeman; Sonja Berndt; Ayelet Borgida; Paige M. Bracci; Lauren Brais; Paul Brennan; Bas Bueno-De-Mesquita; Julie Buring; Federico Canzian; Erica J. Childs; Michelle Cotterchio; Mengmeng Du; Eric J. Duell; Charles Fuchs; Steven Gallinger; J. Michael Gaziano; Graham G. Giles; Edward Giovannucci; Michael Goggins; Gary E. Goodman; Phyllis J. Goodman; Christopher Haiman; Patricia Hartge; Manal Hasan; Kathy J. Helzlsouer; Elizabeth A. Holly; Eric A. Klein; Manolis Kogevinas; Robert J. Kurtz; Loic LeMarchand; Núria Malats; Satu Männistö; Roger Milne; Rachel E. Neale; Kimmie Ng; Ofure Obazee; Ann L. Oberg; Irene Orlow; Alpa V. Patel; Ulrike Peters; Miquel Porta; Nathaniel Rothman; Ghislaine Scelo; Howard D. Sesso; Gianluca Severi; Sabina Sieri; Debra Silverman; Malin Sund; Anne Tjønneland; Mark D. Thornquist; Geoffrey S. Tobias; Antonia Trichopoulou; Stephen K. van Den Eeden; Kala Visvanathan; Jean Wactawski-Wende; Nicolas Wentzensen; Emily White; Herbert Yu; Chen Yuan; Anne Zeleniuch-Jacquotte; Robert Hoover; Kevin Brown; Charles Kooperberg; Harvey A. Risch; Eric J. Jacobs; Donghui Li; Kai Yu; Xiao Ou Shu; Stephen J. Chanock; Brian M. Wolpin; Rachael Z. Stolzenberg-Solomon; Nilanjan Chatterjee; Alison P. Klein; Jill P. Smith; Peter Kraft; Jianxin Shi; Gloria M. Petersen; Wei Zheng; Laufey T. Amundadottir

doi:10.1093/jnci/djz246

A transcriptome-wide association study identifies novel candidate susceptibility genes for pancreatic cancer

Jun Zhong, Ashley Jermusyk, Lang Wu, Jason W. Hoskins, Irene Collins, Evelina Mocci, Mingfeng Zhang, Lei Song, Charles C. Chung, Tongwu Zhang, Wenming Xiao, Demetrius Albanes, Gabriella Andreotti, Alan A. Arslan, Ana Babic, William R. Bamlet, Laura Beane-Freeman, Sonja Berndt, Ayelet Borgida, Paige M. BracciLauren Brais, Paul Brennan, Bas Bueno-De-Mesquita, Julie Buring, Federico Canzian, Erica J. Childs, Michelle Cotterchio, Mengmeng Du, Eric J. Duell, Charles Fuchs, Steven Gallinger, J. Michael Gaziano, Graham G. Giles, Edward Giovannucci, Michael Goggins, Gary E. Goodman, Phyllis J. Goodman, Christopher Haiman, Patricia Hartge, Manal Hasan, Kathy J. Helzlsouer, Elizabeth A. Holly, Eric A. Klein, Manolis Kogevinas, Robert J. Kurtz, Loic LeMarchand, Núria Malats, Satu Männistö, Roger Milne, Rachel E. Neale, Kimmie Ng, Ofure Obazee, Ann L. Oberg, Irene Orlow, Alpa V. Patel, Ulrike Peters, Miquel Porta, Nathaniel Rothman, Ghislaine Scelo, Howard D. Sesso, Gianluca Severi, Sabina Sieri, Debra Silverman, Malin Sund, Anne Tjønneland, Mark D. Thornquist, Geoffrey S. Tobias, Antonia Trichopoulou, Stephen K. van Den Eeden, Kala Visvanathan, Jean Wactawski-Wende, Nicolas Wentzensen, Emily White, Herbert Yu, Chen Yuan, Anne Zeleniuch-Jacquotte, Robert Hoover, Kevin Brown, Charles Kooperberg, Harvey A. Risch, Eric J. Jacobs, Donghui Li, Kai Yu, Xiao Ou Shu, Stephen J. Chanock, Brian M. Wolpin, Rachael Z. Stolzenberg-Solomon, Nilanjan Chatterjee, Alison P. Klein, Jill P. Smith, Peter Kraft, Jianxin Shi, Gloria M. Petersen, Wei Zheng, Laufey T. Amundadottir

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Abstract

Background: Although 20 pancreatic cancer susceptibility loci have been identified through genome-wide association studies in individuals of European ancestry, much of its heritability remains unexplained and the genes responsible largely unknown. Methods: To discover novel pancreatic cancer risk loci and possible causal genes, we performed a pancreatic cancer transcriptome-wide association study in Europeans using three approaches: FUSION, MetaXcan, and Summary-MulTiXcan. We integrated genome-wide association studies summary statistics from 9040 pancreatic cancer cases and 12 496 controls, with gene expression prediction models built using transcriptome data from histologically normal pancreatic tissue samples (NCI Laboratory of Translational Genomics [n = 95] and Genotype-Tissue Expression v7 [n = 174] datasets) and data from 48 different tissues (Genotype-Tissue Expression v7, n = 74-421 samples). Results: We identified 25 genes whose genetically predicted expression was statistically significantly associated with pancreatic cancer risk (false discovery rate <.05), including 14 candidate genes at 11 novel loci (1p36.12: CELA3B; 9q31.1: SMC2, SMC2-AS1; 10q23.31: RP11-80H5.9; 12q13.13: SMUG1; 14q32.33: BTBD6; 15q23: HEXA; 15q26.1: RCCD1; 17q12: PNMT, CDK12, PGAP3; 17q22: SUPT4H1; 18q11.22:RP11-888D10.3; and 19p13.11: PGPEP1) and 11 at six known risk loci (5p15.33: TERT, CLPTM1L, ZDHHC11B; 7p14.1: INHBA; 9q34.2: ABO; 13q12.2: PDX1; 13q22.1: KLF5; and 16q23.1: WDR59, CFDP1, BCAR1, TMEM170A). The association for 12 of these genes (CELA3B, SMC2, and PNMT at novel risk loci and TERT, CLPTM1L, INHBA, ABO, PDX1, KLF5, WDR59, CFDP1, and BCAR1 at known loci) remained statistically significant after Bonferroni correction. Conclusions: By integrating gene expression and genotype data, we identified novel pancreatic cancer risk loci and candidate functional genes that warrant further investigation.

Original language	English
Pages (from-to)	1003-1012
Number of pages	10
Journal	Journal of the National Cancer Institute
Volume	112
Issue number	10
DOIs	https://doi.org/10.1093/jnci/djz246
Publication status	Published - 1 Oct 2020

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Zhong, J., Jermusyk, A., Wu, L., Hoskins, J. W., Collins, I., Mocci, E., Zhang, M., Song, L., Chung, C. C., Zhang, T., Xiao, W., Albanes, D., Andreotti, G., Arslan, A. A., Babic, A., Bamlet, W. R., Beane-Freeman, L., Berndt, S., Borgida, A., ... Amundadottir, L. T. (2020). A transcriptome-wide association study identifies novel candidate susceptibility genes for pancreatic cancer. Journal of the National Cancer Institute, 112(10), 1003-1012. https://doi.org/10.1093/jnci/djz246

@article{bf65327fcad941e3ade96eea03b32ec1,

title = "A transcriptome-wide association study identifies novel candidate susceptibility genes for pancreatic cancer",

abstract = "Background: Although 20 pancreatic cancer susceptibility loci have been identified through genome-wide association studies in individuals of European ancestry, much of its heritability remains unexplained and the genes responsible largely unknown. Methods: To discover novel pancreatic cancer risk loci and possible causal genes, we performed a pancreatic cancer transcriptome-wide association study in Europeans using three approaches: FUSION, MetaXcan, and Summary-MulTiXcan. We integrated genome-wide association studies summary statistics from 9040 pancreatic cancer cases and 12 496 controls, with gene expression prediction models built using transcriptome data from histologically normal pancreatic tissue samples (NCI Laboratory of Translational Genomics [n = 95] and Genotype-Tissue Expression v7 [n = 174] datasets) and data from 48 different tissues (Genotype-Tissue Expression v7, n = 74-421 samples). Results: We identified 25 genes whose genetically predicted expression was statistically significantly associated with pancreatic cancer risk (false discovery rate <.05), including 14 candidate genes at 11 novel loci (1p36.12: CELA3B; 9q31.1: SMC2, SMC2-AS1; 10q23.31: RP11-80H5.9; 12q13.13: SMUG1; 14q32.33: BTBD6; 15q23: HEXA; 15q26.1: RCCD1; 17q12: PNMT, CDK12, PGAP3; 17q22: SUPT4H1; 18q11.22:RP11-888D10.3; and 19p13.11: PGPEP1) and 11 at six known risk loci (5p15.33: TERT, CLPTM1L, ZDHHC11B; 7p14.1: INHBA; 9q34.2: ABO; 13q12.2: PDX1; 13q22.1: KLF5; and 16q23.1: WDR59, CFDP1, BCAR1, TMEM170A). The association for 12 of these genes (CELA3B, SMC2, and PNMT at novel risk loci and TERT, CLPTM1L, INHBA, ABO, PDX1, KLF5, WDR59, CFDP1, and BCAR1 at known loci) remained statistically significant after Bonferroni correction. Conclusions: By integrating gene expression and genotype data, we identified novel pancreatic cancer risk loci and candidate functional genes that warrant further investigation.",

author = "Jun Zhong and Ashley Jermusyk and Lang Wu and Hoskins, {Jason W.} and Irene Collins and Evelina Mocci and Mingfeng Zhang and Lei Song and Chung, {Charles C.} and Tongwu Zhang and Wenming Xiao and Demetrius Albanes and Gabriella Andreotti and Arslan, {Alan A.} and Ana Babic and Bamlet, {William R.} and Laura Beane-Freeman and Sonja Berndt and Ayelet Borgida and Bracci, {Paige M.} and Lauren Brais and Paul Brennan and Bas Bueno-De-Mesquita and Julie Buring and Federico Canzian and Childs, {Erica J.} and Michelle Cotterchio and Mengmeng Du and Duell, {Eric J.} and Charles Fuchs and Steven Gallinger and {Michael Gaziano}, J. and Giles, {Graham G.} and Edward Giovannucci and Michael Goggins and Goodman, {Gary E.} and Goodman, {Phyllis J.} and Christopher Haiman and Patricia Hartge and Manal Hasan and Helzlsouer, {Kathy J.} and Holly, {Elizabeth A.} and Klein, {Eric A.} and Manolis Kogevinas and Kurtz, {Robert J.} and Loic LeMarchand and N{\'u}ria Malats and Satu M{\"a}nnist{\"o} and Roger Milne and Neale, {Rachel E.} and Kimmie Ng and Ofure Obazee and Oberg, {Ann L.} and Irene Orlow and Patel, {Alpa V.} and Ulrike Peters and Miquel Porta and Nathaniel Rothman and Ghislaine Scelo and Sesso, {Howard D.} and Gianluca Severi and Sabina Sieri and Debra Silverman and Malin Sund and Anne Tj{\o}nneland and Thornquist, {Mark D.} and Tobias, {Geoffrey S.} and Antonia Trichopoulou and {van Den Eeden}, {Stephen K.} and Kala Visvanathan and Jean Wactawski-Wende and Nicolas Wentzensen and Emily White and Herbert Yu and Chen Yuan and Anne Zeleniuch-Jacquotte and Robert Hoover and Kevin Brown and Charles Kooperberg and Risch, {Harvey A.} and Jacobs, {Eric J.} and Donghui Li and Kai Yu and Shu, {Xiao Ou} and Chanock, {Stephen J.} and Wolpin, {Brian M.} and Stolzenberg-Solomon, {Rachael Z.} and Nilanjan Chatterjee and Klein, {Alison P.} and Smith, {Jill P.} and Peter Kraft and Jianxin Shi and Petersen, {Gloria M.} and Wei Zheng and Amundadottir, {Laufey T.}",

year = "2020",

month = oct,

day = "1",

doi = "10.1093/jnci/djz246",

language = "English",

volume = "112",

pages = "1003--1012",

journal = "Journal of the National Cancer Institute",

issn = "0027-8874",

number = "10",

}

Zhong, J, Jermusyk, A, Wu, L, Hoskins, JW, Collins, I, Mocci, E, Zhang, M, Song, L, Chung, CC, Zhang, T, Xiao, W, Albanes, D, Andreotti, G, Arslan, AA, Babic, A, Bamlet, WR, Beane-Freeman, L, Berndt, S, Borgida, A, Bracci, PM, Brais, L, Brennan, P, Bueno-De-Mesquita, B, Buring, J, Canzian, F, Childs, EJ, Cotterchio, M, Du, M, Duell, EJ, Fuchs, C, Gallinger, S, Michael Gaziano, J, Giles, GG, Giovannucci, E, Goggins, M, Goodman, GE, Goodman, PJ, Haiman, C, Hartge, P, Hasan, M, Helzlsouer, KJ, Holly, EA, Klein, EA, Kogevinas, M, Kurtz, RJ, LeMarchand, L, Malats, N, Männistö, S, Milne, R, Neale, RE, Ng, K, Obazee, O, Oberg, AL, Orlow, I, Patel, AV, Peters, U, Porta, M, Rothman, N, Scelo, G, Sesso, HD, Severi, G, Sieri, S, Silverman, D, Sund, M, Tjønneland, A, Thornquist, MD, Tobias, GS, Trichopoulou, A, van Den Eeden, SK, Visvanathan, K, Wactawski-Wende, J, Wentzensen, N, White, E, Yu, H, Yuan, C, Zeleniuch-Jacquotte, A, Hoover, R, Brown, K, Kooperberg, C, Risch, HA, Jacobs, EJ, Li, D, Yu, K, Shu, XO, Chanock, SJ, Wolpin, BM, Stolzenberg-Solomon, RZ, Chatterjee, N, Klein, AP, Smith, JP, Kraft, P, Shi, J, Petersen, GM, Zheng, W & Amundadottir, LT 2020, 'A transcriptome-wide association study identifies novel candidate susceptibility genes for pancreatic cancer', Journal of the National Cancer Institute, vol. 112, no. 10, pp. 1003-1012. https://doi.org/10.1093/jnci/djz246

TY - JOUR

T1 - A transcriptome-wide association study identifies novel candidate susceptibility genes for pancreatic cancer

AU - Zhong, Jun

AU - Jermusyk, Ashley

AU - Wu, Lang

AU - Hoskins, Jason W.

AU - Collins, Irene

AU - Mocci, Evelina

AU - Zhang, Mingfeng

AU - Song, Lei

AU - Chung, Charles C.

AU - Zhang, Tongwu

AU - Xiao, Wenming

AU - Albanes, Demetrius

AU - Andreotti, Gabriella

AU - Arslan, Alan A.

AU - Babic, Ana

AU - Bamlet, William R.

AU - Beane-Freeman, Laura

AU - Berndt, Sonja

AU - Borgida, Ayelet

AU - Bracci, Paige M.

AU - Brais, Lauren

AU - Brennan, Paul

AU - Bueno-De-Mesquita, Bas

AU - Buring, Julie

AU - Canzian, Federico

AU - Childs, Erica J.

AU - Cotterchio, Michelle

AU - Du, Mengmeng

AU - Duell, Eric J.

AU - Fuchs, Charles

AU - Gallinger, Steven

AU - Michael Gaziano, J.

AU - Giles, Graham G.

AU - Giovannucci, Edward

AU - Goggins, Michael

AU - Goodman, Gary E.

AU - Goodman, Phyllis J.

AU - Haiman, Christopher

AU - Hartge, Patricia

AU - Hasan, Manal

AU - Helzlsouer, Kathy J.

AU - Holly, Elizabeth A.

AU - Klein, Eric A.

AU - Kogevinas, Manolis

AU - Kurtz, Robert J.

AU - LeMarchand, Loic

AU - Malats, Núria

AU - Männistö, Satu

AU - Milne, Roger

AU - Neale, Rachel E.

AU - Ng, Kimmie

AU - Obazee, Ofure

AU - Oberg, Ann L.

AU - Orlow, Irene

AU - Patel, Alpa V.

AU - Peters, Ulrike

AU - Porta, Miquel

AU - Rothman, Nathaniel

AU - Scelo, Ghislaine

AU - Sesso, Howard D.

AU - Severi, Gianluca

AU - Sieri, Sabina

AU - Silverman, Debra

AU - Sund, Malin

AU - Tjønneland, Anne

AU - Thornquist, Mark D.

AU - Tobias, Geoffrey S.

AU - Trichopoulou, Antonia

AU - van Den Eeden, Stephen K.

AU - Visvanathan, Kala

AU - Wactawski-Wende, Jean

AU - Wentzensen, Nicolas

AU - White, Emily

AU - Yu, Herbert

AU - Yuan, Chen

AU - Zeleniuch-Jacquotte, Anne

AU - Hoover, Robert

AU - Brown, Kevin

AU - Kooperberg, Charles

AU - Risch, Harvey A.

AU - Jacobs, Eric J.

AU - Li, Donghui

AU - Yu, Kai

AU - Shu, Xiao Ou

AU - Chanock, Stephen J.

AU - Wolpin, Brian M.

AU - Stolzenberg-Solomon, Rachael Z.

AU - Chatterjee, Nilanjan

AU - Klein, Alison P.

AU - Smith, Jill P.

AU - Kraft, Peter

AU - Shi, Jianxin

AU - Petersen, Gloria M.

AU - Zheng, Wei

AU - Amundadottir, Laufey T.

PY - 2020/10/1

Y1 - 2020/10/1

N2 - Background: Although 20 pancreatic cancer susceptibility loci have been identified through genome-wide association studies in individuals of European ancestry, much of its heritability remains unexplained and the genes responsible largely unknown. Methods: To discover novel pancreatic cancer risk loci and possible causal genes, we performed a pancreatic cancer transcriptome-wide association study in Europeans using three approaches: FUSION, MetaXcan, and Summary-MulTiXcan. We integrated genome-wide association studies summary statistics from 9040 pancreatic cancer cases and 12 496 controls, with gene expression prediction models built using transcriptome data from histologically normal pancreatic tissue samples (NCI Laboratory of Translational Genomics [n = 95] and Genotype-Tissue Expression v7 [n = 174] datasets) and data from 48 different tissues (Genotype-Tissue Expression v7, n = 74-421 samples). Results: We identified 25 genes whose genetically predicted expression was statistically significantly associated with pancreatic cancer risk (false discovery rate <.05), including 14 candidate genes at 11 novel loci (1p36.12: CELA3B; 9q31.1: SMC2, SMC2-AS1; 10q23.31: RP11-80H5.9; 12q13.13: SMUG1; 14q32.33: BTBD6; 15q23: HEXA; 15q26.1: RCCD1; 17q12: PNMT, CDK12, PGAP3; 17q22: SUPT4H1; 18q11.22:RP11-888D10.3; and 19p13.11: PGPEP1) and 11 at six known risk loci (5p15.33: TERT, CLPTM1L, ZDHHC11B; 7p14.1: INHBA; 9q34.2: ABO; 13q12.2: PDX1; 13q22.1: KLF5; and 16q23.1: WDR59, CFDP1, BCAR1, TMEM170A). The association for 12 of these genes (CELA3B, SMC2, and PNMT at novel risk loci and TERT, CLPTM1L, INHBA, ABO, PDX1, KLF5, WDR59, CFDP1, and BCAR1 at known loci) remained statistically significant after Bonferroni correction. Conclusions: By integrating gene expression and genotype data, we identified novel pancreatic cancer risk loci and candidate functional genes that warrant further investigation.

AB - Background: Although 20 pancreatic cancer susceptibility loci have been identified through genome-wide association studies in individuals of European ancestry, much of its heritability remains unexplained and the genes responsible largely unknown. Methods: To discover novel pancreatic cancer risk loci and possible causal genes, we performed a pancreatic cancer transcriptome-wide association study in Europeans using three approaches: FUSION, MetaXcan, and Summary-MulTiXcan. We integrated genome-wide association studies summary statistics from 9040 pancreatic cancer cases and 12 496 controls, with gene expression prediction models built using transcriptome data from histologically normal pancreatic tissue samples (NCI Laboratory of Translational Genomics [n = 95] and Genotype-Tissue Expression v7 [n = 174] datasets) and data from 48 different tissues (Genotype-Tissue Expression v7, n = 74-421 samples). Results: We identified 25 genes whose genetically predicted expression was statistically significantly associated with pancreatic cancer risk (false discovery rate <.05), including 14 candidate genes at 11 novel loci (1p36.12: CELA3B; 9q31.1: SMC2, SMC2-AS1; 10q23.31: RP11-80H5.9; 12q13.13: SMUG1; 14q32.33: BTBD6; 15q23: HEXA; 15q26.1: RCCD1; 17q12: PNMT, CDK12, PGAP3; 17q22: SUPT4H1; 18q11.22:RP11-888D10.3; and 19p13.11: PGPEP1) and 11 at six known risk loci (5p15.33: TERT, CLPTM1L, ZDHHC11B; 7p14.1: INHBA; 9q34.2: ABO; 13q12.2: PDX1; 13q22.1: KLF5; and 16q23.1: WDR59, CFDP1, BCAR1, TMEM170A). The association for 12 of these genes (CELA3B, SMC2, and PNMT at novel risk loci and TERT, CLPTM1L, INHBA, ABO, PDX1, KLF5, WDR59, CFDP1, and BCAR1 at known loci) remained statistically significant after Bonferroni correction. Conclusions: By integrating gene expression and genotype data, we identified novel pancreatic cancer risk loci and candidate functional genes that warrant further investigation.

UR - http://www.scopus.com/inward/record.url?scp=85079859514&partnerID=8YFLogxK

U2 - 10.1093/jnci/djz246

DO - 10.1093/jnci/djz246

M3 - Article

C2 - 31917448

AN - SCOPUS:85079859514

SN - 0027-8874

VL - 112

SP - 1003

EP - 1012

JO - Journal of the National Cancer Institute

JF - Journal of the National Cancer Institute

IS - 10

ER -

A transcriptome-wide association study identifies novel candidate susceptibility genes for pancreatic cancer

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