MRC Integrative Epidemiology Unit (IEU) Seminar Series

Title: The genetic surroundings of an instrumental variable can be used to correct for pleiotropy in Mendelian randomization.

Abstract: Mendelian randomization (MR) can find causal relationships between gene expression and complex traits but MR is subject to assumptions are hard to meet or to correct for. This is especially true when there are only a limited number of genetic variants available to serve as instrumental variables (IVs). In this seminar, I will elaborate on the progress that we have made in developing a new MR method, we coined MR-link, that tries to correct for pleiotropy even when only a single IV is available. The intended application for MR-link is to find causality between gene expression and complex traits. MR-link is able to correct for certain types of pleiotropy by using the genetic surroundings of the IVs. In simulations that mimic the genetic architecture of gene expression, we find that MR-link has more discriminative ability than all tested MR-methods methods (IVW, MR-Egger, MR-PRESSO and LDA-MR-Egger) as well as the Bayesian colocalization method coloc. Application of MR-link to low-density lipoprotein cholesterol (LDL-C) measurements in 12,449 individuals and expression quantitative trait locus 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.

Biography:

Adriaan van der Graaf, Cisca Wijmenga and Serena Sanna. Department of Genetics, University Medical Center Groningen, University of Groningen 

 

All welcome