A multilayered post-GWAS assessment on genetic susceptibility to pancreatic cancer
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Background: Pancreatic cancer (PC) is a complex disease in which both non-genetic and genetic factors interplay. To date, 40 GWAS hits have been associated with PC risk in individuals of European descent, explaining 4.1% of the phenotypic variance. Methods: We complemented a new conventional PC GWAS (1D) with genome spatial autocorrelation analysis (2D) permitting to prioritize low frequency variants not detected by GWAS. These were further expanded via Hi-C map (3D) interactions to gain additional insight into the inherited basis of PC. In silico functional analysis of public genomic information allowed prioritization of potentially relevant candidate variants. Results: We identified several new variants located in genes for which there is experimental evidence of their implication in the biology and function of pancreatic acinar cells. Among them is a novel independent variant in NR5A2 (rs3790840) with a meta-analysis p value = 5.91E−06 in 1D approach and a Local Moran’s Index (LMI) = 7.76 in 2D approach. We also identified a multi-hit region in CASC8—a lncRNA associated with pancreatic carcinogenesis—with a lowest p value = 6.91E−05. Importantly, two new PC loci were identified both by 2D and 3D approaches: SIAH3 (LMI = 18.24), CTRB2/BCAR1 (LMI = 6.03), in addition to a chromatin interacting region in XBP1—a major regulator of the ER stress and unfolded protein responses in acinar cells—identified by 3D; all of them with a strong in silico functional support. Conclusions: This multi-step strategy, combined with an in-depth in silico functional analysis, offers a comprehensive approach to advance the study of PC genetic susceptibility and could be applied to other diseases.
Originalsprog | Engelsk |
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Artikelnummer | 15 |
Tidsskrift | Genome Medicine |
Vol/bind | 13 |
Udgave nummer | 1 |
Antal sider | 18 |
ISSN | 1756-994X |
DOI | |
Status | Udgivet - 2021 |
Bibliografisk note
Funding Information:
The authors are thankful to the patients, coordinators, field and administrative workers, and technicians of the European Study into Digestive Illnesses and Genetics (PanGenEU) and the Spanish Bladder Cancer (SBC/EPICURO) studies. We also thank Marta Rava former member of the GMEG-CNIO, Guillermo Pita and Anna Gonz?lez-Neira from CGEN-CNIO, and Joe Dennis and Laura Fachal from the University of Cambridge, for genotyping PanGenEU samples, performing variant calling and SNP imputation, and editing data. PanGenEU Study investigators (Additional file 1 : Annex 1) and SBC/EPICURO Investigators (Additional file 1 : Annex 2).
Publisher Copyright:
© 2021, The Author(s).
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