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 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

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 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 APOE genotype, hypertension severity and outcomes after intracerebral haemorrhage

2019 ◽  
Vol 1 (1) ◽  
Author(s):  
Alessandro Biffi ◽  
Meredith P Murphy ◽  
Patryk Kubiszewski ◽  
Christina Kourkoulis ◽  
Kristin Schwab ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Systolic Blood Pressure ◽  
Ischaemic Stroke ◽  
Intracerebral Haemorrhage ◽  
Small Vessel Disease ◽  
Apoe Genotype ◽  
Small Vessel ◽  
Gait Impairment ◽  
Vessel Disease ◽  
Recurrent Haemorrhage

Abstract Intracerebral haemorrhage in the elderly is a severe manifestation of common forms of cerebral small vessel disease. Nearly 60% of intracerebral haemorrhage survivors will develop clinical manifestations of small vessel disease progression including recurrent haemorrhage, ischaemic stroke, dementia, late-life depression and gait impairment within 5 years. Blood pressure measurements following intracerebral haemorrhage are strongly associated with this risk. However, aggressive blood pressure lowering in the elderly carries substantial risks. In order to determine whether there might be an opportunity to select individuals at the highest risk for small vessel disease progression for aggressive blood pressure reduction, we investigated whether APOE gene variants ɛ2/ɛ4 modify the association between blood pressure and small vessel disease clinical progression after intracerebral haemorrhage. We conducted a single-centre longitudinal study at a tertiary care referral centre (Massachusetts General Hospital in Boston, MA, USA), analysing 716 consecutive survivors of acute intracerebral haemorrhage, enrolled from January 2006 to December 2016. We conducted research interviews at the time of enrolment and obtained APOE genotypes from peripheral venous blood samples. We followed patients longitudinally by means of validated phone-based research encounters, aimed at gathering measurements of systolic and diastolic blood pressure, as well as information on small vessel disease clinical outcomes (including recurrent haemorrhage, incident ischaemic stroke, incident dementia, incident depression and incident gait impairment). APOE ε4 and systolic blood pressure were associated with the risk of recurrent haemorrhage, ischaemic stroke and post-haemorrhage dementia, depression and gait impairment (all P < 0.05). APOE ε4 and systolic blood pressure interacted to increase the risk of recurrent haemorrhage, ischaemic stroke, dementia and gait impairment (all interaction P < 0.05). Among patients with elevated blood pressure following intracerebral haemorrhage (average systolic blood pressure 120–129 mmHg and diastolic blood pressure <80 mmHg) only those with one or more APOE ε4 copies were at increased risk for one or more small vessel disease outcomes (hazard ratio = 1.97, 95% confidence interval 1.17–3.31). Among haemorrhage survivors with hypertension (stage 1 and beyond) APOE genotype also stratified risk for all small vessel disease outcomes. In conclusion, APOE genotype modifies the already strong association of hypertension with multiple small vessel disease clinical outcomes among intracerebral haemorrhage survivors. These data raise the possibility that genetic screening could inform blood pressure treatment goals in this patient population.

Cerebral small vessel disease: Potential interventions for prevention and treatment

2020 ◽  
pp. 165-188
Author(s):  
Gordon Blair ◽  
Jason P. Appleton ◽  
Joanna M. Wardlaw ◽  
Philip M. Bath
Keyword(s):  
Ischaemic Stroke ◽  
Small Vessel Disease ◽  
Drug Repurposing ◽  
Cerebral Small Vessel Disease ◽  
Small Vessel ◽  
Lipid Lowering ◽  
Perivascular Spaces ◽  
Ageing Population ◽  
Vessel Disease ◽  
Stroke Imaging

Cerebral small vessel disease (SVD) is characterized by lacunar acute ischaemic stroke, imaging findings of recent small subcortical ischaemic stroke which may be symptomatic or silent, white matter hyperintensities, lacunes, microbleeds and visible perivascular spaces, and a substantial proportion of haemorrhagic strokes in older people. It is common, especially in the ageing population and accounts for 25% of all ischaemic strokes and up to 45% of dementias. The pathophysiology of SVD-related stroke is different to that of other stroke subtypes and therefore traditional acute and secondary prevention treatments, such as alteplase, antiplatelets, and lipid-lowering therapy, may not be as effective in most lacunar ischaemic strokes. The chapter reviews the potential targets for management of ischaemic stroke and non-stroke presentations of SVD, current medications and their evidence to date, and future targets, medication, and lifestyle combinations and opportunities for drug repurposing that require further study.

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.

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