Mendelian Randomization Studies in Stroke: Exploration of Risk Factors and Drug Targets With Human Genetic Data
Marios K. Georgakis, Dipender Gill
Abstract
Elucidating the causes of stroke is key to developing effective preventive strategies. The Mendelian randomization approach leverages genetic variants related to an exposure of interest to investigate the effects of varying that exposure on disease risk. The random allocation of genetic variants at conception reduces confounding from environmental factors and thus strengthens causal inference, analogous to treatment allocation in a randomized controlled trial. With the recent explosion in the availability of human genetic data, Mendelian randomization has proven a valuable tool for studying risk factors for stroke. In this review, we provide an overview of recent developments in the application of Mendelian randomization to unravel the pathophysiology of stroke subtypes and identify therapeutic targets for clinical translation. The approach has offered novel insight into the differential effects of risk factors and antihypertensive, lipid-lowering, and anticoagulant drug classes on risk of stroke subtypes. Analyses have further facilitated the prioritization of novel drug targets, such as for inflammatory pathways underlying large artery atherosclerotic stroke and for the coagulation cascade that contributes to cardioembolic stroke. With continued methodological advances coupled with the rapidly increasing availability of genetic data related to a broad range of stroke phenotypes, the potential for Mendelian randomization in this context is expanding exponentially.