Challenges and opportunities in stroke genetics

Abstract

Stroke, ischaemic stroke and subtypes of ischaemic stroke display substantial heritability. When compared with related vascular conditions, the number of established risk loci reaching genome-wide significance for association with stroke is still in the lower range, particularly for aetiological stroke subtypes such as large artery atherosclerotic stroke or small vessel stroke. Nevertheless, for individual loci substantial progress has been made in determining the specific mechanisms mediating stroke risk. In this review, we present a roadmap for functional follow-up of common risk variants associated with stroke. First, we discuss in silico strategies for characterizing signals in non-coding regions and highlight databases providing information on quantitative trait loci for mRNA and protein expression, as well as methylation, focussing on those with presumed relevance for stroke. Next, we discuss experimental strategies for following up on non-coding risk variants and regions such as massively parallel reporter assays, proteome-wide association studies, and chromatin conformation capture (3C) assays. These and other approaches are relevant for gaining insight into the specific variants and mechanisms mediating genetic stroke risk. Finally, we discuss how genetic findings could influence clinical practice by adding to diagnostic algorithms and eventually improve treatment options for stroke.