A multilayered post-GWAS assessment on genetic susceptibility to pancreatic cancer.
Genome Med
; 13(1): 15, 2021 02 01.
Article
en En
| MEDLINE
| ID: mdl-33517887
ABSTRACT
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.Palabras clave
Texto completo:
1
Colección:
01-internacional
Asunto principal:
Neoplasias Pancreáticas
/
Predisposición Genética a la Enfermedad
/
Estudio de Asociación del Genoma Completo
Tipo de estudio:
Prognostic_studies
Límite:
Humans
Idioma:
En
Revista:
Genome Med
Año:
2021
Tipo del documento:
Article
País de afiliación:
España