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