Simultaneous estimation of bi-directional causal effects and heritable confounding from GWAS summary statistics

Mendelian Randomisation (MR), an increasingly popular method that estimates the causal effects of risk factors on complex human traits, has seen several extensions that relax its basic assumptions. However, most of these extensions suffer from two major limitations; their under-exploitation of genome-wide markers, and sensitivity to the presence of a heritable confounder of the exposure-outcome relationship. To overcome these limitations, we propose a Latent Heritable Confounder MR (LHC-MR) method applicable to association summary statistics, which estimates bi-directional causal effects, direct heritabilities, and confounder effects while accounting for sample overlap. We demonstrate that LHC-MR out-performs several existing MR methods in a wide range of simulation settings and apply it to summary statistics of 13 complex traits. Besides several concordant results, LHC-MR unravelled new mechanisms (how being diagnosed for certain diseases might lead to improved lifestyle) and revealed new causal effects (e.g. HDL cholesterol being protective against high systolic blood pressure), hidden from standard MR methods due to a heritable confounder of opposite direction. Phenome-wide MR search suggested that the confounders indicated by LHC-MR for the birth weight-diabetes pair are likely to be obesity traits. Finally, LHC-MR results indicated that genetic correlations are predominantly driven by bi-directional causal effects and much less so by heritable confounders.