RT Journal Article
SR Electronic
T1 A novel Mendelian randomization method identifies causal relationships between gene expression and low-density lipoprotein cholesterol levels
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 671537
DO 10.1101/671537
A1 Adriaan van der Graaf
A1 Annique Claringbould
A1 Antoine Rimbert
A1 BIOS consortium
A1 Harm-Jan Westra
A1 Yang Li
A1 Cisca Wijmenga
A1 Serena Sanna
YR 2019
UL http://biorxiv.org/content/early/2019/06/18/671537.abstract
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.