Cerebral small vessel disease genomics and its implications across the lifespan.
Nat Commun
; 11(1): 6285, 2020 12 08.
Article
em En
| MEDLINE
| ID: mdl-33293549
ABSTRACT
White matter hyperintensities (WMH) are the most common brain-imaging feature of cerebral small vessel disease (SVD), hypertension being the main known risk factor. Here, we identify 27 genome-wide loci for WMH-volume in a cohort of 50,970 older individuals, accounting for modification/confounding by hypertension. Aggregated WMH risk variants were associated with altered white matter integrity (p = 2.5×10-7) in brain images from 1,738 young healthy adults, providing insight into the lifetime impact of SVD genetic risk. Mendelian randomization suggested causal association of increasing WMH-volume with stroke, Alzheimer-type dementia, and of increasing blood pressure (BP) with larger WMH-volume, notably also in persons without clinical hypertension. Transcriptome-wide colocalization analyses showed association of WMH-volume with expression of 39 genes, of which four encode known drug targets. Finally, we provide insight into BP-independent biological pathways underlying SVD and suggest potential for genetic stratification of high-risk individuals and for genetically-informed prioritization of drug targets for prevention trials.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Acidente Vascular Cerebral
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Doença de Alzheimer
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Doenças de Pequenos Vasos Cerebrais
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Hipertensão
Tipo de estudo:
Clinical_trials
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Diagnostic_studies
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Etiology_studies
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Prognostic_studies
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Risk_factors_studies
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Systematic_reviews
Limite:
Adult
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Aged
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Aged80
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Female
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Humans
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Male
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Middle aged
Idioma:
En
Revista:
Nat Commun
Ano de publicação:
2020
Tipo de documento:
Article