Stroke Genetics: Turning Discoveries into Clinical Applications

Abstract

The field of medical and population genetics in stroke is moving at a rapid pace and has led to unanticipated opportunities for discovery and clinical applications. Genome-wide association studies have highlighted the role of specific pathways relevant to etiologically defined subtypes of stroke and to stroke as a whole. They have further offered starting points for the exploration of novel pathways and pharmacological strategies in experimental systems. Mendelian randomization studies continue to provide insights in the causal relationships between exposures and outcomes and have become a useful tool for predicting the efficacy and side effects of drugs. Additional applications that have emerged from recent discoveries include risk prediction based on polygenic risk scores and pharmacogenomics. Among the topics currently moving into focus is the genetics of stroke outcome. While still at its infancy, this field is expected to boost the development of neuroprotective agents. We provide a brief overview on recent progress in these areas.

Amplified Risk of Intracranial Artery Stenosis/Occlusion Associated With RNF213 p.R4810K in Familial Hypercholesterolemia

“…Owing to advances in genome analyses, the effects of polygenic changes on developing diseases have gradually been elucidated. 29 , 30 , 31 , 32 Although the influence of individual single nucleotide polymorphisms is weak, the accumulation of multiple common single nucleotide polymorphisms contributes to disease susceptibility. For example, the phosphatase domain containing paladin 1 gene mutation overlaid with RNF213 variants may act synergistically in 2 affected White European families who develop MMD.…”

Whole‐exome sequencing analyses in a Saudi Ischemic Stroke Cohort reveal association signals, and shows polygenic risk scores are related to Modified Rankin Scale Risk

“…While such approaches found causal variants in various genes for monogenic stroke disorders, they had limited value in finding common variants impacting polygenic risk (Ekkert et al 2021;Li et al 2021). Genome-Wide Association Studies (GWAS) utilizing genome-wide genotyping arrays and/or whole exome sequencing (WES) have been successful in elucidating rare and common variants in various stroke subtypes (Li et al 2021;Dichgans et al 2021;Kumar et al 2021).…”

Predicting mortality among ischemic stroke patients using pathways-derived polygenic risk scores

“…Polygenic risk scores (PRSs) based on the effect sizes estimated from the meta/mega-analyses of GWAS, led by the MEGASTROKE consortium, have proven informative for IS risk stratification 4 and augmenting subtyping 5 . The short-term or long-term outcomes have become “The Next Big Thing” in the focus of stroke genetics with a great demand for the development of neuroprotective agents 6 .…”