| Title: |
MR-link-2:pleiotropy robust cis Mendelian randomization validated in three independent reference datasets of causality |
| Authors: |
van der Graaf,Adriaan; Warmerdam,Robert; Auwerx,Chiara; Xie,Manke; Wood,Andrew R.; Westra,Harm Jan; Weiss,Stefan; Völker,Uwe; Visscher,Peter M.; Viñuela,Ana; Verlouw,Joost; Veldink, Jan; Tokolyi,Alex; Teumer,Alexander; Souto,Juan Carlos; Soria,José Manuel; Slagboom,Eline; Singleton,Andrew; Raitoharju,Emma; Raitakari,Olli T.; Prokisch,Holger; Peters,Annette; Persyn,Elodie; Paul,Dirk S.; Pasaniuc,Bogdan; Ophoff,Roel; Nauck,Matthias; Nagpal,Sini; Montgomery,Grant W.; Milani,Lili; van Meurs,Joyce; McRae,Allan F.; Martinez-Perez,Angel; Mägi,Reedik; Lehtimäki,Terho; Lapinska,Sandra; Kukushkina,Viktorija; Kähönen,Mika; Jansen,Rick; Inouye,Michael; Ikram,M. Arfan; Mishra,Binisha Hamal; van Greevenbroek,Marleen; Gieger,Christian; Gibson,Greg; Frayling,Timothy M.; Ferrucci,Luigi; Farzeen,Aiman; Esko,Tõnu; Dupuis,Théo; eQTLGen Consortium; Neurologen; Brain; Genetic Risks |
| Publication Year: |
2025 |
| Subject Terms: |
General Chemistry; General Biochemistry,Genetics and Molecular Biology; General; General Physics and Astronomy |
| Description: |
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 (α̂ = 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. |
| Document Type: |
article in journal/newspaper |
| File Description: |
application/pdf |
| Language: |
English |
| ISSN: |
2041-1723 |
| Relation: |
https://dspace.library.uu.nl/handle/1874/467326 |
| Availability: |
https://dspace.library.uu.nl/handle/1874/467326 |
| Rights: |
info:eu-repo/semantics/OpenAccess |
| Accession Number: |
edsbas.F2CDD895 |
| Database: |
BASE |