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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 does not manifest as clinical stroke, is highly prevalent in the general population, particularly 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 insights 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, multi-ancestry approaches and integration with other omics data.

Key points

  • Fifty-two independent genetic loci have been associated with cerebral small vessel disease (cSVD) at the genome-wide significance level, including loci associated with cSVD-related stroke and loci associated with covert, MRI-defined cSVD.

  • In silico functional explorations of the observed genetic associations point to a major role of blood pressure-related pathways and mechanisms independent of vascular risk factors, such as extracellular matrix structure and function.

  • Transcriptome-wide association studies have provided evidence for associations between one or several genes at a cSVD risk locus and the corresponding cSVD traits, enabling prioritization of putative causal genes for functional follow-up.

  • Mendelian randomization studies have been conducted to investigate the causal link between various factors and cSVD-related phenotypes; a dedicated systematic review and meta-analysis is required to confirm some causal relationships.

  • Preliminary results provide proof-of-concept that cSVD genomics can inform therapeutic strategies by providing genetic evidence for drug effects, indicating pathways with therapeutic relevance and revealing potential for drug repositioning.

  • Use of high-throughput molecular approaches, such as epigenomics, transcriptomics, proteomics and metabolomics, will enable integration of genetic associations with functional data to decipher the biological roles of genetic risk loci in cSVD.

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Fig. 1: Potential clinical applications of cerebral small vessel disease genomics.
Fig. 2: Shared risk loci for cSVD phenotypes and associations with vascular risk factors.
Fig. 3: Associations between genetically predicted risk factors and the risk of cSVD.

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Acknowledgements

We thank S. Schilling for her editorial assistance. S.D. is supported by a grant overseen by the French National Research Agency (ANR) as part of the “Investment for the Future Programme” ANR-18-RHUS-0002, by the EU Joint Programme–Neurodegenerative Disease Research (JPND), and by funding from the European Research Council (ERC) and the European Union Horizon 2020 research and innovation programme under grant agreement numbers 643417, 640643, 667375, and 754517.

Review criteria

For our literature review, we searched PubMed for papers published between January 2007 and March 2021. We focused on this period because we chose to focus on genome-wide association studies (GWAS), which were not available at earlier time points in the field of cerebral small vessel disease (cSVD). We considered only genetic associations with common cSVD phenotypes that reached genome-wide significance (P < 5 × 10−8). When several genome-wide significant associations on the same locus were reported in several GWAS, we present the lead single nucleotide polymorphism (SNP) and association statistics of the GWAS performed on the largest sample size (largest number of cases for binary traits) but still report references of the other publications. Where several genome-wide significant associations with different SNPs have been identified in the same locus, we report only those that correspond to independent signals (linkage disequilibrium r² < 0.1); for correlated SNPs (r² > 0.1), we selected the SNP with the lowest P value (if reported in the same study) or that from the GWAS performed on the largest sample size (if reported in two different studies). Results of candidate gene association studies were included if the studies were large (n > 500), robust methodology was used and the findings complement or support GWAS findings. Only peer-reviewed papers in English were considered. For Mendelian randomization studies, we searched the literature for publications that relate to cSVD phenotypes and include Mendelian randomization in the title or abstract. We also systematically screened all published GWAS of cSVD-related phenotypes for Mendelian randomization analyses.

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C.B. researched data for the article. All authors made substantial contributions to discussion of the content, wrote the article and edited and/or reviewed the manuscript before submission.

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Glossary

White matter hyperintensity (WMH) of presumed vascular origin

An abnormality of variable size in the white matter seen on MRI as a hyperintensity on T2-weighted images, such as fluid-attenuated inversion recovery, but as isointense or hypointense on T1-weighted images (although not as hypointense as cerebrospinal fluid).

Lacunes of presumed vascular origin

A subcortical, round, fluid-filled cavity (3–15 mm diameter, of similar signal to cerebrospinal fluid) consistent with a previous acute small subcortical infarct or haemorrhage in the territory of one perforating arteriole.

Cerebral microbleeds

A small area (usually 2–5 mm in diameter) that appears as a signal void with associated blooming on T2*-weighted MRI or susceptibility-weighted imaging, which is likely to mostly reflect vascular leakage of blood cells.

Perivascular spaces

Fluid-filled spaces that surround perforating vessels in the brain, with a signal intensity similar to that of cerebrospinal fluid on all MRI sequences (diameter generally smaller than 3 mm).

Genetic variants

A specific region of the genome that differs between individuals in the population.

Alleles

Two or more versions of a polymorphic genetic site; for single nucleotide polymorphisms, alleles correspond to two alternative nucleotides at the given position.

Fractional anisotropy

A scalar measure derived from diffusion tensor imaging that quantifies the overall directionality of water diffusion in brain tissue. The measure is greatest in organized white matter tracts and lowest in the case of free water movement, such as in cerebrospinal fluid. Reduced fractional anisotropy in white matter is seen in cerebral small vessel disease.

Mean diffusivity

A scalar measure obtained from diffusion tensor imaging that quantifies the magnitude of water diffusion regardless of the direction. It is used to study microstructural properties and the structural integrity of brain tissue. Increased mean diffusivity in white matter is seen in cerebral small vessel disease.

Linkage disequilibrium

The non-random association of alleles at two nearby genetic loci, reflecting haplotypes that descend from a common ancestor.

Inversion polymorphism

A type of DNA structural variant that changes the orientation of a genomic segment.

Single nucleotide polymorphisms

A single nucleotide variation in the DNA sequence.

Pleiotropy

A phenomenon in which genes or genetic variants affect multiple, apparently unrelated, phenotypes.

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Bordes, C., Sargurupremraj, M., Mishra, A. et al. Genetics of common cerebral small vessel disease. Nat Rev Neurol 18, 84–101 (2022). https://doi.org/10.1038/s41582-021-00592-8

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