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High-throughput multivariable Mendelian randomization analysis prioritizes apolipoprotein B as key lipid risk factor for coronary artery disease.

Accepted version
Peer-reviewed

Type

Article

Change log

Authors

Langenberg, Claudia  ORCID logo  https://orcid.org/0000-0002-5017-7344
Butterworth, Adam 

Abstract

BACKGROUND: Genetic variants can be used to prioritize risk factors as potential therapeutic targets via Mendelian randomization (MR). An agnostic statistical framework using Bayesian model averaging (MR-BMA) can disentangle the causal role of correlated risk factors with shared genetic predictors. Here, our objective is to identify lipoprotein measures as mediators between lipid-associated genetic variants and coronary artery disease (CAD) for the purpose of detecting therapeutic targets for CAD. METHODS: As risk factors we consider 30 lipoprotein measures and metabolites derived from a high-throughput metabolomics study including 24 925 participants. We fit multivariable MR models of genetic associations with CAD estimated in 453 595 participants (including 113 937 cases) regressed on genetic associations with the risk factors. MR-BMA assigns to each combination of risk factors a model score quantifying how well the genetic associations with CAD are explained. Risk factors are ranked by their marginal score and selected using false-discovery rate (FDR) criteria. We perform supplementary and sensitivity analyses varying the dataset for genetic associations with CAD. RESULTS: In the main analysis, the top combination of risk factors ranked by the model score contains apolipoprotein B (ApoB) only. ApoB is also the highest ranked risk factor with respect to the marginal score (FDR <0.005). Additionally, ApoB is selected in all sensitivity analyses. No other measure of cholesterol or triglyceride is consistently selected otherwise. CONCLUSIONS: Our agnostic genetic investigation prioritizes ApoB across all datasets considered, suggesting that ApoB, representing the total number of hepatic-derived lipoprotein particles, is the primary lipid determinant of CAD.

Description

Keywords

Lipoproteins, Mendelian randomization, apolipoprotein B, blood lipids, coronary artery disease, metabolomics, risk factor selection, Apolipoproteins B, Bayes Theorem, Cholesterol, LDL, Coronary Artery Disease, Humans, Lipids, Mendelian Randomization Analysis, Risk Factors

Journal Title

Int J Epidemiol

Conference Name

Journal ISSN

0300-5771
1464-3685

Volume Title

50

Publisher

Oxford University Press

Rights

All rights reserved
Sponsorship
Wellcome Trust (204623/Z/16/Z)
Alan Turing Institute (BCDSA/100038)
Alan Turing Institute (Unknown)
Medical Research Council (MC_UU_12015/1)
MRC (MC_UU_00006/1)
Medical Research Council (MR/L003120/1)
British Heart Foundation (None)
British Heart Foundation (RG/18/13/33946)
Medical Research Council (MC_UU_00002/7)