MR-link-2: pleiotropy robust cis Mendelian randomization validated in three independent reference datasets of causality
Abstract
Abstract 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 ( $$\hat{\alpha }$$ 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.
Article Details
Authors (59)
Adriaan van der Graaf
Robert Warmerdam
Chiara Auwerx
Toni Boltz
Dorret I. Boomsma
Andrew Brown
Evans Cheruiyot
Emma E. Davenport
Théo Dupuis
Tõnu Esko
Aiman Farzeen
Luigi Ferrucci
Timothy M. Frayling
Greg Gibson
Christian Gieger
Marleen van Greevenbroek
Binisha Hamal Mishra
M. Arfan Ikram
Michael Inouye
Rick Jansen
Mika Kähönen
Viktorija Kukushkina
Sandra Lapinska
Terho Lehtimäki
Reedik Mägi
Angel Martinez-Perez
Allan F. McRae
Joyce van Meurs
Lili Milani
Grant W. Montgomery
Sini Nagpal
Matthias Nauck
Roel Ophoff
Bogdan Pasaniuc
Dirk S. Paul
Elodie Persyn
Annette Peters
Holger Prokisch
Olli T. Raitakari
Emma Raitoharju
Andrew Singleton
Eline Slagboom
José Manuel Soria
Juan Carlos Souto
Alexander Teumer
Alex Tokolyi
Jan Veldink
Joost Verlouw
Ana Viñuela
Peter M. Visscher
Uwe Völker
Department of Functional Genomics, Universitätsmedizin Greifswald, Greifswald, Germany
Stefan Weiss
Harm-Jan Westra
Andrew R. Wood
Manke Xie
Urmo Võsa
Maria Carolina Borges
Lude Franke
Zoltán Kutalik