scholarly journals Genetic factors in cerebral small vessel disease and their impact on stroke and dementia

2015 ◽  
Vol 36 (1) ◽  
pp. 158-171 ◽  
Author(s):  
Christof Haffner ◽  
Rainer Malik ◽  
Martin Dichgans
Keyword(s):  
Small Vessel Disease ◽  
Association Studies ◽  
Cerebral Small Vessel Disease ◽  
Small Vessel ◽  
Genome Wide Association Studies ◽  
Major Theme ◽  
Vessel Disease ◽  
Type Iv ◽  
Genome Wide ◽  
Substantial Progress

Cerebral small vessel disease (SVD) is among the most frequent causes of both stroke and dementia. There is a growing list of genes known to be implicated in Mendelian forms of SVD. Also, genome-wide association studies have identified common variants at a number of genetic loci that are associated with manifestations of SVD, among them loci for white matter hyperintensities, small vessel stroke, and deep intracerebral hemorrhage. Driven by these discoveries and new animal models substantial progress has been made in elucidating the molecular, cellular, and physiologic mechanisms underlying SVD. A major theme emerging from these studies is the extracellular matrix (ECM). Recent findings include a role of structural constituents of the ECM such as type IV collagens in hereditary and sporadic SVD, the sequestration of proteins with a known role in ECM maintenance into aggregates of NOTCH3, and altered signaling through molecules known to interact with the ECM. Here, we review recent progress in the identification of genes involved in SVD and discuss mechanistic concepts with a particular focus on the ECM.

scholarly journals Association of common genetic variants with brain microbleeds

Neurology ◽  
2020 ◽  
Vol 95 (24) ◽  
pp. e3331-e3343 ◽  
Author(s):  
Maria J. Knol ◽  
Dongwei Lu ◽  
Matthew Traylor ◽  
Hieab H.H. Adams ◽  
José Rafael J. Romero ◽  
...  
Keyword(s):  
Genetic Variants ◽  
Small Vessel Disease ◽  
Association Studies ◽  
Cerebral Small Vessel Disease ◽  
Small Vessel ◽  
White Matter Hyperintensity ◽  
Genome Wide Association Studies ◽  
Vessel Disease ◽  
Genome Wide ◽  
Common Genetic Variants

ObjectiveTo identify common genetic variants associated with the presence of brain microbleeds (BMBs).MethodsWe performed genome-wide association studies in 11 population-based cohort studies and 3 case–control or case-only stroke cohorts. Genotypes were imputed to the Haplotype Reference Consortium or 1000 Genomes reference panel. BMBs were rated on susceptibility-weighted or T2*-weighted gradient echo MRI sequences, and further classified as lobar or mixed (including strictly deep and infratentorial, possibly with lobar BMB). In a subset, we assessed the effects of APOE ε2 and ε4 alleles on BMB counts. We also related previously identified cerebral small vessel disease variants to BMBs.ResultsBMBs were detected in 3,556 of the 25,862 participants, of which 2,179 were strictly lobar and 1,293 mixed. One locus in the APOE region reached genome-wide significance for its association with BMB (lead single nucleotide polymorphism rs769449; odds ratio [OR]any BMB [95% confidence interval (CI)] 1.33 [1.21–1.45]; p = 2.5 × 10−10). APOE ε4 alleles were associated with strictly lobar (OR [95% CI] 1.34 [1.19–1.50]; p = 1.0 × 10−6) but not with mixed BMB counts (OR [95% CI] 1.04 [0.86–1.25]; p = 0.68). APOE ε2 alleles did not show associations with BMB counts. Variants previously related to deep intracerebral hemorrhage and lacunar stroke, and a risk score of cerebral white matter hyperintensity variants, were associated with BMB.ConclusionsGenetic variants in the APOE region are associated with the presence of BMB, most likely due to the APOE ε4 allele count related to a higher number of strictly lobar BMBs. Genetic predisposition to small vessel disease confers risk of BMB, indicating genetic overlap with other cerebral small vessel disease markers.

scholarly journals Hypertension and Cerebral Microangiopathy (Cerebral Small Vessel Disease): Genetic and Epigenetic Aspects of Their Relationship

Acta Naturae ◽  
2018 ◽  
Vol 10 (2) ◽  
pp. 4-15 ◽  
Author(s):  
L. A. Dobrynina ◽  
M. R. Zabitova ◽  
L. A. Kalashnikova ◽  
E. V. Gnedovskaya ◽  
M. A. Piradov
Keyword(s):  
Antihypertensive Therapy ◽  
Small Vessel Disease ◽  
Association Studies ◽  
Cerebral Small Vessel Disease ◽  
Cerebral Injury ◽  
Small Vessel ◽  
Genome Wide Association Studies ◽  
Vessel Disease ◽  
Cerebral Complications ◽  
Cerebral Microangiopathy

Hypertension (HT) and its cerebral complications are extremely vexing medical and social problems. Despite the obvious association between hypertension and the clinical and neuroimaging features of cerebral microangiopathy (CMA) (also known as cerebral small vessel disease), the causal links between them remain ambiguous. Besides, antihypertensive therapy as the only way to manage these patients does not always prevent brain damage. Knowledge about the key factors and mechanisms involved in HT and CMA development is important for predicting the risk of cerebral complications and developing new approaches to their prevention and treatment. At present, genome-wide association studies and other approaches are used to investigate the common hereditary mechanisms of HT and CMA development, which will explain a large number of CMA cases not associated with hypertension, lack of a correlation between HT severity and the degree of cerebral injury, and failure of antihypertensive therapy to prevent CMA progression. Epigenetic markers likely play a modulating role in the development of these diseases.

scholarly journals Genomics of perivascular space burden unravels early mechanisms of cerebral small vessel disease

2021 ◽  
Author(s):  
Stéphanie Debette ◽  
Marie-Gabrielle Duperron ◽  
Maria Knol ◽  
Quentin Le Grand ◽  
Tavia Evans ◽  
...  
Keyword(s):  
Small Vessel Disease ◽  
Association Studies ◽  
Fetal Brain ◽  
Cognitive Disorders ◽  
Population Based ◽  
Cerebral Small Vessel Disease ◽  
Perivascular Space ◽  
Small Vessel ◽  
Vessel Disease ◽  
Genome Wide

Abstract Perivascular space burden (PVS) is an emerging and possibly the earliest magnetic resonance imaging (MRI)-marker of cerebral small vessel disease (cSVD), a leading cause of stroke and dementia. Its molecular underpinnings are unknown. Genome-wide and whole-exome association studies in 40,095 participants (21 population-based cohorts, 66.3±8.6 years) revealed 24 genome-wide significant PVS risk loci. These showed association with white matter PVS already at age 20, suggesting an important role of early-life factors. PVS loci were enriched in genes causing early-onset leukodystrophies and genes expressed in fetal brain endothelial cells. Mendelian randomization analyses supported causal associations of high blood pressure with basal ganglia (BG) and hippocampal PVS, and of BG PVS with stroke. Transcriptome-wide association studies suggest causal implication of 11 genes, to prioritize for experimental follow-up as putative biotargets for cSVD. Two-thirds of PVS loci point to novel pathways, involving extracellular matrix, membrane transport, and developmental processes, with enrichment in targets of existing drugs for vascular/cognitive disorders.

scholarly journals New insights into mechanisms of small vessel disease stroke from genetics

2017 ◽  
Vol 131 (7) ◽  
pp. 515-531 ◽  
Author(s):  
Rhea Tan ◽  
Matthew Traylor ◽  
Loes Rutten-Jacobs ◽  
Hugh Markus
Keyword(s):  
Small Vessel Disease ◽  
Association Studies ◽  
Small Vessel ◽  
Monogenic Disease ◽  
Genome Wide Association Studies ◽  
Stroke Patients ◽  
Genetic Studies ◽  
Vessel Disease ◽  
Disease Mechanisms ◽  
Shed Light

Cerebral small vessel disease (SVD) is a common cause of lacunar strokes, vascular cognitive impairment (VCI) and vascular dementia. SVD is thought to result in reduced cerebral blood flow, impaired cerebral autoregulation and increased blood–brain barrier (BBB) permeability. However, the molecular mechanisms underlying SVD are incompletely understood. Recent studies in monogenic forms of SVD, such as cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), and ‘sporadic’ SVD have shed light on possible disease mechanisms in SVD. Proteomic and biochemical studies in post-mortem monogenic SVD patients, as well as in animal models of monogenic disease have suggested that disease pathways are shared between different types of monogenic disease, often involving the impairment of extracellular matrix (ECM) function. In addition, genetic studies in ‘sporadic’ SVD have also shown that the disease is highly heritable, particularly among young-onset stroke patients, and that common variants in monogenic disease genes may contribute to disease processes in some SVD subtypes. Genetic studies in sporadic lacunar stroke patients have also suggested distinct genetic mechanisms between subtypes of SVD. Genome-wide association studies (GWAS) have also shed light on other potential disease mechanisms that may be shared with other diseases involving the white matter, or with pathways implicated in monogenic disease. This review brings together recent data from studies in monogenic SVD and genetic studies in ‘sporadic’ SVD. It aims to show how these provide new insights into the pathogenesis of SVD, and highlights the possible convergence of disease mechanisms in monogenic and sporadic SVD.

scholarly journals Genome-wide association study of cerebral small vessel disease reveals established and novel loci

Brain ◽  
2019 ◽  
Vol 142 (10) ◽  
pp. 3176-3189 ◽  
Author(s):  
Jaeyoon Chung ◽  
Sandro Marini ◽  
Joanna Pera ◽  
Bo Norrving ◽  
Jordi Jimenez-Conde ◽  
...  
Keyword(s):  
Ischaemic Stroke ◽  
Intracerebral Haemorrhage ◽  
Genome Wide Association Study ◽  
Small Vessel Disease ◽  
Cerebral Small Vessel Disease ◽  
Genome Wide Association ◽  
Small Vessel ◽  
Vessel Disease ◽  
Genome Wide ◽  
Novel Associations

Intracerebral haemorrhage (ICH) and small vessel ischaemic stroke (SVS) are the most severe manifestations of cerebral small vessel disease. In a cross-phenotype genome-wide association analysis, Chung et al. identify two novel associations at 2q33 and 13q34 plus a previously identified locus at 1q22 for non-lobar ICH and SVS risk.

scholarly journals Hemorrhagic cerebral small vessel disease caused by a novel mutation in 3′ UTR of collagen type IV alpha 1

2019 ◽  
Vol 6 (1) ◽  
pp. e383
Author(s):  
Naoko Sakai ◽  
Masahiro Uemura ◽  
Taisuke Kato ◽  
Hiroaki Nozaki ◽  
Akihide Koyama ◽  
...  
Keyword(s):  
Collagen Type ◽  
Small Vessel Disease ◽  
Novel Mutation ◽  
Cerebral Small Vessel Disease ◽  
Small Vessel ◽  
Collagen Type Iv ◽  
Vessel Disease ◽  
Type Iv

scholarly journals Genome-wide association study of MRI markers of cerebral small vessel disease in 42,310 participants

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Elodie Persyn ◽  
Ken B. Hanscombe ◽  
Joanna M. M. Howson ◽  
Cathryn M. Lewis ◽  
Matthew Traylor ◽  
...  
Keyword(s):  
Association Study ◽  
Genome Wide Association Study ◽  
Small Vessel Disease ◽  
Cerebral Small Vessel Disease ◽  
Genome Wide Association ◽  
Small Vessel ◽  
Vessel Disease ◽  
Genome Wide
Sign in / Sign up

Export Citation Format

Share Document