Genetics of Ischemic Stroke in Young Adults
Ischemic stroke (IS) is a complex genetic disorder caused by a combination of multiple genetic and environmental factors. Despite the enormous burden associated with stroke, we know little about its underlying pathogenesis. Unlike many other common age-related diseases (eg, diabetes mellitus and heart disease), there are no good preclinical biomarkers that can provide a foothold for studying the molecular and physiological processes leading up to a stroke event. Because a genetic predisposition to stroke is widely acknowledged, 1 current strategy to study stroke pathogenesis is to start by identifying genes associated with stroke and then to investigate the function of these genes. Toward this goal, numerous candidate gene and genome-wide association studies (GWAS) of stroke have been performed.
A strategy successfully used to identify genetic determinants of other common complex diseases has been to focus on subtypes, such as early-onset disease which may be enriched for high-penetrance variants. Variants that are highly penetrant or highly predictive of diseases may be easier to detect and also produce useful insights about disease pathways, even if the same variants play a lesser role in late-onset disease.
The goal of this review is to assess the evidence for a genetic basis to early-onset IS. We mainly focus on early-onset stroke occurring between the ages of 15 and 49 years but specify age ranges considered by other studies as they are discussed. We begin with an epidemiological characterization of early-onset stroke, comparing and contrasting risk factors and the heterogeneity of stroke subtypes between early- and late-onset IS. We then review the evidence for a genetic basis of early-onset stroke, contrasting where possible the magnitude of the genetic contribution in younger versus older IS through familial aggregation studies. Finally, we review current status and prospects for identifying genes contributing to susceptibility to early-onset stroke. Throughout the …