Alternate approach to stroke phenotyping identifies a genetic risk locus for small vessel stroke

Berg, von; Laan, Sander W. van der; McArdle, Patrick F.; Malik, Rainer; Kittner,; Mitchell, Braxton D.; Worrall,; Pulit, Sara L.

doi:10.1101/718221

Cited by 2 publications

(3 citation statements)

References 28 publications

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“…Work by large international consortia, such as the International Stroke Genetics Consortium (ISGC), has led to substantial progress in the discovery of genes that underlie cSVD-related stroke. To date, GWAS have identified two risk loci for the occurrence of ICH (one for lobar ICH and one for non-lobar ICH), two risk loci associated with ICH volume (one for lobar ICH and one for non-lobar ICH) [31][32][33] and seven risk loci for SVS [34][35][36][37][38] at the genome wide significance level (P <5 × 10 -8 ). The majority of these loci have been identified in populations of European ancestry (Table 1).…”

Section: [H1] Discovery Of Genetic Risk Locimentioning

confidence: 99%

“…g SVS was defined according to Causative Classification of Stroke 181 , which is based on imaging evidence of a clinically relevant acute infarction (≤20 mm in diameter) and the absence of other causes of stroke. Von Berg et al35 used an intersect phenotype (an individual must be assigned the same subtype across all subtyping systems). Traylor et al34 re-analyzed cases of lacunar stroke, identified with the TOAST system, with MRI confirmation.…”

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confidence: 99%

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Genetics of common cerebral small vessel disease

et al. 2022

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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.

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Section: [H1] Discovery Of Genetic Risk Locimentioning

confidence: 99%

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confidence: 99%

Genetics of common cerebral small vessel disease

et al. 2022

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“…In total, 56 independent genetic loci were found to be associated with any stroke or a specific stroke subtype, with several loci showing significant associations with 2 or more stroke types. 40,41,51,61–63,64–68,69-71,72–76,79 Loci showing the largest number of associations with distinct stroke subtypes are those associated with cSVD, reaching genome-wide significance with SVS, all strokes, any IS, and sometimes ICH (eg, at COL4A1/2 , ICA1L-CARF-NBEAL1 , or SLC25A44-PMF1-BGLAP ). The largest number of independent genome-wide significant associations was observed for all strokes or any IS, 60 while fewer signals were observed for IS subtypes or ICH, 40,60,76 in great part because the sample size available for the latter is more limited.…”

Section: Multifactorial Strokementioning

confidence: 99%

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

Debette

Markus

2022

Circulation Research

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Stroke is the second leading cause of death worldwide and a complex, heterogeneous condition. In this review, we provide an overview of the current knowledge on monogenic and multifactorial forms of stroke, highlighting recent insight into the continuum between these. We describe how, in recent years, large-scale genome-wide association studies have enabled major progress in deciphering the genetic basis for stroke and its subtypes, although more research is needed to interpret these findings. We cover the potential of stroke genetics to reveal novel pathophysiological processes underlying stroke, to accelerate the discovery of new therapeutic approaches, and to identify individuals in the population who are at high risk of stroke and could be targeted for tailored preventative interventions.

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Alternate approach to stroke phenotyping identifies a genetic risk locus for small vessel stroke

Cited by 2 publications

References 28 publications

Genetics of common cerebral small vessel disease

Genetics of common cerebral small vessel disease

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

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