PT  - JOURNAL ARTICLE
AU  - Stephen Burgess
AU  - Christopher N Foley
AU  - Elias Allara
AU  - James R Staley
AU  - Joanna MM Howson
TI  - A robust and efficient method for Mendelian randomization with hundreds of genetic variants: unravelling mechanisms linking HDL-cholesterol and coronary heart disease
AID  - 10.1101/566851
DP  - 2019 Jan 01
TA  - bioRxiv
PG  - 566851
4099  - http://biorxiv.org/content/early/2019/03/04/566851.short
4100  - http://biorxiv.org/content/early/2019/03/04/566851.full
AB  - Mendelian randomization (MR) investigations with large numbers of genetic variants are becoming increasingly common. However, the reliability of findings from a MR investigation is dependent on the validity of the genetic variants as instrumental variables. We developed a method to identify groups of genetic variants with similar causal effect estimates, which may represent distinct mechanisms by which the risk factor influences the outcome. Our contamination mixture method is a robust and efficient method for valid MR in the presence of invalid IVs. Compared to other robust methods, our method had the lowest mean squared error across a range of realistic scenarios. The method is fast and efficient, and can perform analysis with hundreds of variants in a fraction of a second. In a MR analysis for high-density lipoprotein (HDL) cholesterol and coronary heart disease (CHD) risk, the method identified 11 variants associated with increased HDL-cholesterol, decreased triglyceride levels, and decreased CHD risk that had the same directions of associations with platelet distribution width and other blood cell traits, suggesting a shared mechanism linking lipids and CHD risk relating to platelet aggregation.