MR-TRYX: Exploiting horizontal pleiotropy to infer novel causal pathways

Yoonsu Cho, Philip C Haycock, Tom R Gaunt, Jie Zheng, Andrew P Morris, George Davey Smith, Gibran Hemani

Dec 28, 2018

Received Date: 26th November 18

In Mendelian randomization (MR) analysis, variants that exert horizontal pleiotropy are typically treated as a nuisance. However, they could be valuable in identifying novel pathways to the traits under investigation. Here, we developed the MR-TRYX framework, following the advice of William Bateson to “TReasure Your eXceptions”. We begin by detecting outliers in a single exposure-outcome MR analysis, hypothesising they are due to horizontal pleiotropy. We search across thousands of complete GWAS summary datasets in the MR-Base database to systematically identify other (“candidate”) traits that associate with the outliers. We developed a LASSO-based multivariable MR approach to model the heterogeneity in the exposure-outcome analysis due to pathways through candidate traits. Through detailed investigation of several causal relationships, many pleiotropic pathways were uncovered with already established causal effects, validating the approach, but also novel putative causal pathways. Adjustment for pleiotropic pathways reduced the heterogeneity across the analyses.

Read in full at bioRxiv.

This is an abstract of a preprint hosted on an independent third party site. It has not been peer reviewed but is currently under consideration at Nature Communications.

Nature Communications

Nature Research, Springer Nature