A Transcriptome-Wide Association Study Identifies Novel Candidate Susceptibility Genes for Pancreatic Cancer

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

Disclosures

J Natl Cancer Inst. 2020;112(10):1003-1012. 

In This Article

Abstract and Introduction

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.

Introduction

Pancreatic cancer is the third leading cause of cancer deaths in the United States[1] and seventh worldwide.[2] Established risk factors include tobacco smoking, long-standing diabetes, obesity, heavy alcohol consumption, chronic pancreatitis, and family history of pancreatic cancer.[3] Inherited rare mutations in hereditary cancer and pancreatitis genes, identified in families with a high incidence of disease, account for a small percentage of cases.[4] At the other end of the spectrum, common risk variants with low penetrance have been discovered through genome-wide association studies (GWAS).[5–11] However, these loci explain a small fraction of genetic heritability for pancreatic cancer, and the genes underlying the associations at most of these are unknown.[11–14]

Most susceptibility alleles discovered through GWAS reside in noncoding regions of the genome and likely function through allele-specific regulation of gene expression.[15] A transcriptome-wide association study (TWAS) builds on this premise by imputing genetically predicted gene expression levels into GWAS datasets to discover genes whose cis-regulated expression is associated with complex traits.[16–18] This approach has been applied to several common diseases, including melanoma, breast, prostate, and ovarian cancers.[19–24] In this comprehensive TWAS for pancreatic cancer, we leveraged two expression quantitative trait loci (eQTL) datasets generated from histologically normal pancreatic tissue samples from individuals of European ancestry,[25,26] with GWAS summary statistics [Pancreatic Cancer Cohort Consortium (PanScan) I–III and Pancreatic Cancer Case-Control Consortium (PanC4)[6–11]] to identify genes associated with risk of pancreatic cancer.

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