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van der Graaf, A.* ; Warmerdam, R.* ; Auwerx, C.* ; Võsa, U.* ; Borges, M.C.* ; Franke, L.* ; eQTLGen Consortium (Farzeen, A. ; Gieger, C. ; Peters, A.)

MR-link-2: Pleiotropy robust cis Mendelian randomization validated in three independent reference datasets of causality.

Nat. Commun. 16:6112 (2025)
Publ. Version/Full Text Research data DOI PMC
Open Access Gold
Creative Commons Lizenzvertrag
Mendelian randomization (MR) identifies causal relationships from observational data but has increased Type 1 error rates (T1E) when genetic instruments are limited to a single associated region, a typical scenario for molecular exposures. We developed MR-link-2, which leverages summary statistics and linkage disequilibrium (LD) to estimate causal effects and pleiotropy in a single region. We compare MR-link-2 to other cis MR methods: i) In simulations, MR-link-2 has calibrated T1E and high power. ii) We reidentify metabolic reactions from three metabolic pathway references using four independent metabolite quantitative trait locus studies. MR-link-2 often (76%) outperforms other methods in area under the receiver operator characteristic curve (AUC) (up to 0.80). iii) For canonical causal relationships between complex traits, MR-link-2 has lower per-locus T1E (0.096 vs. min. 0.142, at 5% level), identifying all but one of the true causal links, reducing cross-locus causal effect heterogeneity to almost half. iv) Testing causal direction between blood cell compositions and marker gene expression shows MR-link-2 has superior AUC (0.82 vs. 0.68). Finally, analyzing causality between metabolites not directly connected by canonical reactions, only MR-link-2 identifies the causal relationship between pyruvate and citrate ( α ̂  = 0.11, P =  7.2⋅10-7), a key citric acid cycle reaction. Overall, MR-link-2 identifies pleiotropy-robust causality from summary statistics in single associated regions, making it well suited for applications to molecular phenotypes.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Coronary-heart-disease; Cholesterol; Risk; Acetoacetate; Metabolism; Variants; Genetics; Glucose; Health; Genes
ISSN (print) / ISBN 2041-1723
e-ISSN 2041-1723
Journal Nature Communications
Quellenangaben Volume: 16, Issue: 1, Pages: , Article Number: 6112 Supplement: ,
Publisher Springer
Publishing Place London
Reviewing status Peer reviewed
Institute(s) Institute of Epidemiology (EPI)
Grants Swiss National Science Foundation
European Union's Horizon Europe research and innovation programme
Dutch Cancer Society
Biogen - Oncode Institute
Dutch Research Council
UK Medical Research Council