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

Schmidt AW, Kühnapfel A, Kirsten H, Grallert H, Hellerbrand C, Kiefer F, Mann K, Mueller S, Nöthen MM, 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 (2022)

Publication Type: Journal article

Publication year: 2022

Journal

Pancreatology Karger / Elsevier

DOI: 10.1016/j.pan.2022.03.007

Abstract

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.

Authors with CRIS profile

Claus Hellerbrand Professur für Biochemie und Molekulare Pathobiologie

Involved external institutions

Helmholtz Zentrum München - Deutsches Forschungszentrum für Gesundheit und Umwelt (HMGU) / Helmholtz Munich DE Germany (DE) Universitätsklinikum Mannheim DE Germany (DE) Martin-Luther-Universität Halle-Wittenberg (MLU) DE Germany (DE) Universität Leipzig DE Germany (DE) Universität Regensburg DE Germany (DE) Wellcome Trust (WT) GB United Kingdom (GB) Else Kröner-Fresenius-Zentrum für Ernährungsmedizin DE Germany (DE) Ruprecht-Karls-Universität Heidelberg DE Germany (DE) Rheinische Friedrich-Wilhelms-Universität Bonn DE Germany (DE) Ludwig-Maximilians-Universität (LMU) DE Germany (DE) University of Verona / Università degli Studi di Verona IT Italy (IT)

How to cite

APA:

Schmidt, A.W., Kühnapfel, A., Kirsten, H., Grallert, H., Hellerbrand, C., Kiefer, F.,... Rosendahl, J. (2022). Colocalization analysis of pancreas eQTLs with risk loci from alcoholic and novel non-alcoholic chronic pancreatitis GWAS suggests potential disease causing mechanisms. Pancreatology. https://dx.doi.org/10.1016/j.pan.2022.03.007

MLA:

Schmidt, Andreas W., et al. "Colocalization analysis of pancreas eQTLs with risk loci from alcoholic and novel non-alcoholic chronic pancreatitis GWAS suggests potential disease causing mechanisms." Pancreatology (2022).

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