PT - JOURNAL ARTICLE AU - Adriaan van der Graaf AU - Annique Claringbould AU - Antoine Rimbert AU - BIOS consortium AU - Harm-Jan Westra AU - Yang Li AU - Cisca Wijmenga AU - Serena Sanna TI - A novel Mendelian randomization method identifies causal relationships between gene expression and low-density lipoprotein cholesterol levels AID - 10.1101/671537 DP - 2019 Jan 01 TA - bioRxiv PG - 671537 4099 - http://biorxiv.org/content/early/2019/06/18/671537.short 4100 - http://biorxiv.org/content/early/2019/06/18/671537.full AB - Robust inference of causal relationships between gene expression and complex traits using Mendelian Randomization (MR) approaches is confounded by pleiotropy and linkage disequilibrium (LD) between gene expression quantitative loci (eQTLs). Here we propose a new MR method, MR-link, that accounts for unobserved pleiotropy and LD by leveraging information from individual-level data. In simulations, MR-link shows false positive rates close to expectation (median 0.05) and high power (up to 0.89), outperforming all other MR methods we tested, even when only one eQTL variant is present. Application of MR-link to low-density lipoprotein cholesterol (LDL-C) measurements in 12,449 individuals and eQTLs summary statistics from whole blood and liver identified 19 genes causally linked to LDL-C. These include the previously functionally validated SORT1 gene, and the PVRL2 gene, located in the APOE locus, for which a causal role in liver was yet unknown. Our results showcase the strength of MR-link for transcriptome-wide causal inferences.