Genetics of common cerebral small vessel disease

Abstract

Cerebral small vessel disease (cSVD) is a leading cause of ischaemic and haemorrhagic stroke and a major contributor to dementia. Covert cSVD, which is detectable with brain MRI but not manifest as clinical stroke, is highly prevalent in the general population with increasing age. Advances in technologies and collaborative work have led to substantial progress in the identification of common genetic variants that are associated with cSVD-related stroke (ischaemic and haemorrhagic) and MRI-defined covert cSVD. In this Review, we provide an overview of collaborative studies -mostly genome-wide association studies (GWAS)that have identified >50 independent genetic loci associated with the risk of cSVD. We describe how these associations have provided novel insight into the biological mechanisms involved in cSVD, revealed patterns of shared genetic variation across cSVD traits, and shed new light on the continuum between rare, monogenic and common, multifactorial cSVD. We consider how GWAS summary statistics have been leveraged for Mendelian randomization studies to explore causal pathways in cSVD and provide genetic evidence for drug effects, and how the combination of findings from GWAS with gene expression resources and drug target databases has enabled identification of putative causal genes and provided proof-of-concept for drug repositioning potential. We also discuss opportunities for polygenic risk prediction, multiancestry approaches and integration with other omics data.

ICA1L Is Associated with Small Vessel Disease: A Proteome-Wide Association Study in Small Vessel Stroke and Intracerebral Haemorrhage

“…Different SVD features have been found in post-mortem brains from AD patients, such as small cortical and subcortical infarcts, microbleeds, perivascular spacing, and WMH [ 32 ]. Additionally, ApoE is the major genetic factor associated both with lobar ICH and AD [ 33 ]. The Ica1l results suggest that this protein could also be commonly regulated in AD and SVD.…”

Stroke Genetics: Discovery, Insight Into Mechanisms, and Clinical Perspectives

“…44 Furthermore GWAS studies in multifactorial SVS and MRI-markers of cSVD have identified associations with additional genes associated with vascular ECM function (LOX, SH3PXD2A, GPR126, VCAN, NID2, EFEMP1, HBEGF ). 40,42,43,45…”

“…GWAS of MRI-markers of cSVD have for instance been more powerful than GWAS of small vessel disease related stroke (SVS, ICH), possibly in part due to larger sample sizes and the continuous nature of phenotypes such as white matter hyperintensity volume. 42,43 MRI-endophenotypes also enable to study the impact of risk variants on brain microstructure already at a very young age, 43,45 with important potential implications for our understanding of disease mechanisms across the lifespan and for devising efficient and timely preventative strategies. More broadly, combining high-resolution multimodal brain and vascular imaging, machine learning and genomics offers the potential to reveal completely novel insight into mechanisms of stroke risk, stroke outcomes and more broadly of pathways linking vascular and brain health.…”

“…44 Furthermore GWAS studies in multifactorial SVS and MRI-markers of cSVD have identified associations with additional genes associated with vascular ECM function (LOX, SH3PXD2A, GPR126, VCAN, NID2, EFEMP1, HBEGF). 40,42,43,45 Matrisome dysfunction represents a promising target for treatment of cSVD for which there are no specific mechanism-based treatments to date, with initial experimental success in both monogenic 46 and sporadic cSVD, 47 although whether such approaches can be translated into man remains to be tested.…”

What Turns the White Matter White? Metabolomic Clues to the Origin of Age-Related Cerebral White Matter Hyperintensities

“…Preliminary evidence points to associations with genes involved in sphingolipid metabolism, myelination, blood-brain barrier integrity, neurodevelopment, and Wnt signaling. 9…”