PuSH - Publication Server of Helmholtz Zentrum München

Schmidt, A.W.* ; Kühnapfel, A.* ; Kirsten, H.* ; Grallert, H. ; Hellerbrand, C.* ; Kiefer, F.* ; Mann, K.* ; Mueller, S.* ; Nöthen, M.M.* ; Peters, A. ; Ridinger, M.* ; Frank, J.* ; Rietschel, M.* ; Soranzo, N.* ; Soyka, M.* ; Wodarz, N.* ; Malerba, G.* ; Gambaro, G.* ; Gieger, C. ; Scholz, M.* ; Krug, S.* ; Michl, P.* ; Ewers, M.* ; Witt, H.* ; Laumen, H.* ; Rosendahl, J.*

Colocalization analysis of pancreas eQTLs with risk loci from alcoholic and novel non-alcoholic chronic pancreatitis GWAS suggests potential disease causing mechanisms.

Pancreatol. 22, 449-456 (2022)
Postprint DOI PMC
Open Access Green
Background: Previous genome-wide association studies (GWAS) identified genome-wide significant risk loci in chronic pancreatitis and investigated underlying disease causing mechanisms by simple overlaps with expression quantitative trait loci (eQTLs), a procedure which may often result in false positive conclusions. Methods: We conducted a GWAS in 584 non-alcoholic chronic pancreatitis (NACP) patients and 6040 healthy controls. Next, we applied Bayesian colocalization analysis of identified genome-wide significant risk loci from both, our recently published alcoholic chronic pancreatitis (ACP) and the novel NACP dataset, with pancreas eQTLs from the GTEx V8 European cohort to prioritize candidate causal genes and extracted credible sets of shared causal variants. Results: Variants at the CTRC (p = 1.22 × 10−21) and SPINK1 (p = 6.59 × 10−47) risk loci reached genome-wide significance in NACP. CTRC risk variants colocalized with CTRC eQTLs in ACP (PP4 = 0.99, PP4/PP3 = 95.51) and NACP (PP4 = 0.99, PP4/PP3 = 95.46). For both diseases, the 95% credible set of shared causal variants consisted of rs497078 and rs545634. CLDN2-MORC4 risk variants colocalized with CLDN2 eQTLs in ACP (PP4 = 0.98, PP4/PP3 = 42.20) and NACP (PP4 = 0.67, PP4/PP3 = 7.18), probably driven by the shared causal variant rs12688220. Conclusions: A shared causal CTRC risk variant might unfold its pathogenic effect in ACP and NACP by reducing CTRC expression, while the CLDN2-MORC4 shared causal variant rs12688220 may modify ACP and NACP risk by increasing CLDN2 expression.
Altmetric
Additional Metrics?
[➜Log in]
Edit extra informations Login
Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords Bayesian Colocalization Analysis ; Chronic Pancreatitis ; Eqtl ; Gtex ; Gwas
ISSN (print) / ISBN 1424-3903
e-ISSN 1424-3911
Journal Pancreatology
Quellenangaben Volume: 22, Issue: 4, Pages: 449-456 Article Number: , Supplement: ,
Publisher Elsevier
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute of Epidemiology II (EPI2)
Grants Else Kroner-Fresenius-Stiftung
Deutsche Forschungsgemeinschaft