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A robust and efficient method for Mendelian randomization with hundreds of genetic variants.

Accepted version
Peer-reviewed

Type

Article

Change log

Authors

Foley, Christopher N 
Staley, James R 

Abstract

Mendelian randomization (MR) is an epidemiological technique that uses genetic variants to distinguish correlation from causation in observational data. The reliability of a MR investigation depends on the validity of the genetic variants as instrumental variables (IVs). We develop the contamination mixture method, a method for MR with two modalities. First, it identifies groups of genetic variants with similar causal estimates, which may represent distinct mechanisms by which the risk factor influences the outcome. Second, it performs MR robustly and efficiently in the presence of invalid IVs. Compared to other robust methods, it has the lowest mean squared error across a range of realistic scenarios. The method identifies 11 variants associated with increased high-density lipoprotein-cholesterol, decreased triglyceride levels, and decreased coronary heart disease risk that have the same directions of associations with various blood cell traits, suggesting a shared mechanism linking lipids and coronary heart disease risk mediated via platelet aggregation.

Description

Keywords

Body Mass Index, Cholesterol, HDL, Cholesterol, LDL, Coronary Disease, Diabetes Mellitus, Type 2, Genetic Association Studies, Genetic Pleiotropy, Genetic Predisposition to Disease, Genetic Variation, Humans, Mendelian Randomization Analysis, Models, Genetic, Molecular Epidemiology, Phenotype, Reproducibility of Results, Research Design, Risk Factors, Triglycerides

Journal Title

Nat Commun

Conference Name

Journal ISSN

2041-1723
2041-1723

Volume Title

11

Publisher

Springer Science and Business Media LLC

Rights

All rights reserved
Sponsorship
Wellcome Trust (204623/Z/16/Z)
Medical Research Council (MR/L003120/1)
British Heart Foundation (None)
Medical Research Council (MC_UU_00002/7)
British Heart Foundation (RG/18/13/33946)