Transcriptome-wide association study and Mendelian randomization in pancreatic cancer identifies susceptibility genes and causal relationships with type 2 diabetes and venous thromboembolism

Abstract

Background: Two important questions regarding the genetics of pancreatic adenocarcinoma (PDAC) are 1. Which germline genetic variants influence the incidence of this cancer; and 2. Whether PDAC causally predisposes to associated non-malignant phenotypes, such as type 2 diabetes (T2D) and venous thromboembolism (VTE).

Methods: In this study of 8803 patients with PDAC and 67,523 controls, we first performed a large-scale transcriptome-wide association study to investigate the association between genetically determined gene expression in normal pancreas tissue and PDAC risk. Secondly, we used Mendelian Randomization (MR) to analyse the causal relationships among PDAC, T2D (74,124 cases and 824,006 controls) and VTE (30,234 cases and 172,122 controls).

Findings: Sixteen genes showed an association with PDAC risk (FDR <0.10), including six genes not yet reported for PDAC risk (PPIP5K2, TFR2, HNF4G, LRRC10B, PRC1 and FBXL20) and ten previously reported genes (INHBA, SMC2, ABO, PDX1, MTMR6, ACOT2, PGAP3, STARD3, GSDMB, ADAM33). MR provided support for a causal effect of PDAC on T2D using genetic instruments in the HNF4G and PDX1 loci, and unidirectional causality of VTE on PDAC involving the ABO locus (OR 2.12, P < 1e^-7). No evidence of a causal effect of PDAC on VTE was found.

Interpretation: These analyses identified candidate susceptibility genes and disease relationships for PDAC that warrant further investigation. HNF4G and PDX1 may induce PDAC-associated diabetes, whereas ABO may induce the causative effect of VTE on PDAC.

Funding: National Institutes of Health (USA).

Keywords: Case-control studies; Genetic; Genome-wide association study; Mendelian randomization analysis; Models; Polymorphism; Single nucleotide.

Fig. 1

Summary of study cohort. 8803 patients with PDAC and 67523 controls were included. PDAC, pancreatic adenocarcinoma; T2D, type 2 diabetes; VTE, venous thromboembolism; JTI, Joint-Tissue Imputation; UTMOST, unified test for molecular signatures.

Fig. 2

Manhattan plot of association results from the PDAC TWAS. Each dot represents the genetically predicted gene expression of one specific gene by pancreatic tissue prediction models. The x-axis represents the genomic position of the corresponding gene, and the y-axis represents the negative logarithm of the association P-value. The 16 genes that were significantly associated with PDAC at FDR <0.1 have been labelled.

Fig. 3

Mendelian Randomization of PDAC and T2D using the WME method. A: MR analysis using all SNPS with P < 5e-8; B and C: MR analysis only using IVs within 1 Mb from HNF4G and PDX1, respectively. IVs, instrumental variables. Red denotes significant causal effect.

Fig. 4

Causal inference testing of the 16 genes whose genetically predicted expression was associated with PDAC risk using three different methods. Hollow circle, hollow triangle, and solid triangle denote results that were non-significant, only nominally significant (P < 0.05), and significant after Bonferroni correction, respectively. Up (positive) and down (negative) triangles indicate the direction of the estimated effect sizes.

Fig. 5

Manhattan plot of association results from the pancreatic cancer PheWAS, using genes which showed significant association in MR for PDAC. Each triangle represents a gene and its related traits. Up (positive) and down (negative) triangles indicate the direction of the estimated effect sizes. The x-axis represents disease categories, and the y-axis represents the negative logarithm of the association P-value.

Fig. 6

Mendelian randomization of PDAC and VTE using the WME method. A: MR analysis using all SNPs with P < 5e-8; B: MR analysis only using IVs within 1 Mb from ABO. Red denotes significant causal effect.