A multilayered post-GWAS assessment on genetic susceptibility to pancreatic cancer.
3D genomic structure
Genetic susceptibility
Genome-wide association analysis
Local indices of genome spatial autocorrelation
Pancreatic cancer risk
Journal
Genome medicine
ISSN: 1756-994X
Titre abrégé: Genome Med
Pays: England
ID NLM: 101475844
Informations de publication
Date de publication:
01 02 2021
01 02 2021
Historique:
received:
07
08
2020
accepted:
03
12
2020
entrez:
1
2
2021
pubmed:
2
2
2021
medline:
20
1
2022
Statut:
epublish
Résumé
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. 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. 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. 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.
Sections du résumé
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.
Identifiants
pubmed: 33517887
doi: 10.1186/s13073-020-00816-4
pii: 10.1186/s13073-020-00816-4
pmc: PMC7849104
doi:
Substances chimiques
Biomarkers, Tumor
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
15Subventions
Organisme : NCI NIH HHS
ID : HHSN261200800001E
Pays : United States
Organisme : NCI NIH HHS
ID : P50 CA062924
Pays : United States
Organisme : NCI NIH HHS
ID : UG1 CA189974
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA086862
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA008748
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA154823
Pays : United States
Organisme : NCI NIH HHS
ID : UM1 CA182910
Pays : United States
Organisme : NCI NIH HHS
ID : U01 CA247283
Pays : United States
Organisme : NCI NIH HHS
ID : U10 CA037429
Pays : United States
Organisme : NCI NIH HHS
ID : U01 CA182883
Pays : United States
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