the association between the risk factor and the outcome. In contrast, LD-score analysis uses variants across the whole genome and is a symmetric (i.e., non-directional) analysis of the risk factor and the outcome, meaning that LD-score regression is not able to ascertain the direction of causation between the risk factor and outcome. Also, the contribution of a variant to a MR analysis is proportional to its association with the exposure, whereas the contribution of a variant to LD-score regression is proportional to its “LD-score”. This means that even if a MR investigation was undertaken using genetic variants from the whole genome, it would differ from LD-score regression. The LD-score does not differ between exposures, meaning there is the potential for systematic bias in LD-score regressions across different phenotypes. Finally, the LD-score is likely to be a weak instrument, meaning a higher possibility of bias.
