Mendelian Randomization Analysis of Vascular Traits

The MR-base package [40 (link)] was used for two sample MR analyses testing for causality of vascular changes over metabolic traits. MR-base uses instruments SNPs selected on the basis of several hundreds of GWAS summary data sets in its repository and estimates the causal impact of specific traits (exposures) on retinal vasculature phenotype outcomes. These SNPs are all significantly associated with the “exposure” trait and they are meant to be in linkage equilibrium with each other, even if they are located in relative proximity of each other. In all cases, our MR cases were two-sample; the genetic effects were obtained from our GWAS on the four retinal vasculometry traits of interest, and they were compared with effect estimates on other traits from samples that did not include any UK Biobank subjects. Studies in which the UK Biobank had contributed information were specifically removed from the analyses reported here. We are reporting results from different MR tests: the inverse variance weighted, weighted median and MR-Egger tests (both MR and intercept). The results are primarily reported with the reference of the random-effect inverse variance weighted test, but the other tests may be valuable to interpret the relationship between exposure and outcome. In particular, the MR-Egger intercept tests for unbalanced (unidirectional) horizontal pleiotropy, which is usually taken as evidence against causation.