A Transcriptome-Wide Association Study Identifies Novel Candidate Susceptibility Genes for Pancreatic Cancer
Authors: 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
Journal: JNCI Journal of the National Cancer Institute (2019)

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 &amp;lt; .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.