A novel multivariable Mendelian randomization framework to disentangle highly correlated exposures with application to metabolomics

Abstract

Mendelian randomization (MR) utilizes genome-wide association study (GWAS) summary data to infer causal relationships between exposures and outcomes, offering a valuable tool for identifying disease risk factors. Multivariable MR (MVMR) estimates the direct effects of multiple exposures on an outcome. This study tackles the issue of highly correlated exposures commonly observed in metabolomic data, a situation where existing MVMR methods often face reduced statistical power due to multicollinearity. We propose a robust extension of the MVMR framework that leverages constrained maximum likelihood (cML) and employs a Bayesian approach for identifying independent clusters of exposure signals. Applying our method to the UK Biobank metabolomic data for the largest Alzheimer disease (AD) cohort through a two-sample MR approach, we identified two independent signal clusters for AD: glutamine and lipids, with posterior inclusion probabilities (PIPs) of 95.0% and 81.5%, respectively. Our findings corroborate the hypothesized roles of glutamate and lipids in AD, providing quantitative support for their potential involvement.

Keywords: Alzheimer disease; GWAS; IV; MVMR-cML; SuSiE; cML; causal inference; constrained maximum likelihood; instrumental variable; metabolomics.

Figure 1

The number of instruments used in each step of MVMR-cML-SuSiE

Figure 2

Correlation plots for the 18 metabolites identified in the second cluster (A) Pairwise correlations among the 18 measured metabolite biomarkers. (B) Pairwise genetic correlations among the 18 metabolite biomarkers.