TY - JOUR
T1 - Mendelian randomization while jointly modeling cis genetics identifies causal relationships between gene expression and lipids
AU - van der Graaf, Adriaan
AU - Claringbould, Annique
AU - Rimbert, Antoine
AU - Heijmans, Bastiaan T.
AU - Hoen, Peter A. C. ’t
AU - van Meurs, Joyce B. J.
AU - BIOS consortium
AU - Jansen, Rick
AU - Franke, Lude
AU - Westra, Harm-Jan
AU - Li, Yang
AU - Wijmenga, Cisca
AU - Sanna, Serena
PY - 2020/12/1
Y1 - 2020/12/1
N2 - Inference of causality between gene expression and complex traits using Mendelian randomization (MR) is confounded by pleiotropy and linkage disequilibrium (LD) of gene-expression quantitative trait loci (eQTL). Here, we propose an MR method, MR-link, that accounts for unobserved pleiotropy and LD by leveraging information from individual-level data, even when only one eQTL variant is present. In simulations, MR-link shows false-positive rates close to expectation (median 0.05) and high power (up to 0.89), outperforming all other tested MR methods and coloc. Application of MR-link to low-density lipoprotein cholesterol (LDL-C) measurements in 12,449 individuals with expression and protein QTL summary statistics from blood and liver identifies 25 genes causally linked to LDL-C. These include the known SORT1 and ApoE genes as well as PVRL2, located in the APOE locus, for which a causal role in liver was not known. Our results showcase the strength of MR-link for transcriptome-wide causal inferences.
AB - Inference of causality between gene expression and complex traits using Mendelian randomization (MR) is confounded by pleiotropy and linkage disequilibrium (LD) of gene-expression quantitative trait loci (eQTL). Here, we propose an MR method, MR-link, that accounts for unobserved pleiotropy and LD by leveraging information from individual-level data, even when only one eQTL variant is present. In simulations, MR-link shows false-positive rates close to expectation (median 0.05) and high power (up to 0.89), outperforming all other tested MR methods and coloc. Application of MR-link to low-density lipoprotein cholesterol (LDL-C) measurements in 12,449 individuals with expression and protein QTL summary statistics from blood and liver identifies 25 genes causally linked to LDL-C. These include the known SORT1 and ApoE genes as well as PVRL2, located in the APOE locus, for which a causal role in liver was not known. Our results showcase the strength of MR-link for transcriptome-wide causal inferences.
UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85091895450&origin=inward
UR - https://www.ncbi.nlm.nih.gov/pubmed/33004804
UR - http://www.scopus.com/inward/record.url?scp=85091895450&partnerID=8YFLogxK
U2 - https://doi.org/10.1038/s41467-020-18716-x
DO - https://doi.org/10.1038/s41467-020-18716-x
M3 - Article
C2 - 33004804
SN - 2041-1723
VL - 11
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 4930
ER -