Genomics of perivascular space burden unravels early mechanisms of cerebral small vessel disease
Copyright policy )Genomics of perivascular space burden unravels early mechanisms of cerebral small vessel disease
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.
- Osaka University Graduate School of Medicine Japan
- UNSW Sydney Australia
- National University of Singapore Singapore
- University of Edinburgh United Kingdom
- University of Toronto Canada
FOS: Computer and information sciences, Aging, Genetic variants, Cerebrovascular, CHARGE consortium, TÉCNICAS Y EQUIPOS ANALÍTICOS, DIAGNÓSTICOS Y TERAPÉUTICOS::diagnóstico::técnicas y procedimientos diagnósticos::diagnóstico por imagen::tomografía::imagen por resonancia magnética, Malalties cerebrovasculars - Aspectes genètics, Neurodegenerative, Genome-wide association studies, Gene, Magnetic Resonance Imaging/methods, methods [Magnetic Resonance Imaging], Vascular Cognitive Impairment/Dementia, Pathology, 2.1 Biological and endogenous factors, Disease, Alzheimer's Disease Related Dementias (ADRD), Malalties cerebrovasculars - Imatgeria per ressonància magnètica, Single-nucleotide polymorphism, anzsrc-for: 42 Health Sciences, Genome, Endothelial Cells/pathology, White matter, ENFERMEDADES::enfermedades del sistema nervioso::enfermedades del sistema nervioso central::enfermedades cerebrales::trastornos cerebrovasculares::enfermedades de los pequeños vasos cerebrales, Genomics, Magnetic Resonance Imaging, Stroke, Environmental health, Neurology, complications [Cerebral Small Vessel Diseases], Neurological, Medicine, diagnostic imaging [Cerebral Small Vessel Diseases], DISCIPLINES AND OCCUPATIONS::Natural Science Disciplines::Biological Science Disciplines::Biology::Computational Biology::Genomics, Radiology, Pulmonary and Respiratory Medicine, Genome-wide association study, Candidate gene, Genotype, Bioinformatics, DISEASES::Nervous System Diseases::Central Nervous System Diseases::Brain Diseases::Cerebrovascular Disorders::Cerebral Small Vessel Diseases, Population, 610, pathology [Endothelial Cells], Article, Magnetic resonance imaging, Rheumatology, Clinical Research, Health Sciences, Acquired Cognitive Impairment, Mendelian randomization, Genetics, Humans, Cerebral Small Vessel Diseases/diagnostic imaging, Biology, Prevention, Human Genome, Neurosciences, DISCIPLINAS Y OCUPACIONES::disciplinas de las ciencias naturales::disciplinas de las ciencias biológicas::biología::biología computacional::genómica, Moyamoya Disease and Syndrome, 42 Health Sciences, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Endothelial Cells, Perivascular space, Diagnosis and Treatment of Renal Artery Stenosis, Brain Disorders, anzsrc-for: 32 Biomedical and clinical sciences, Genòmica, Neurosonography, anzsrc-for: 11 Medical and Health Sciences, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, Cerebral Small Vessel Diseases, FOS: Biological sciences, Pediatrics, Perinatology and Child Health, genetics [Cerebral Small Vessel Diseases], Genetic association, Dementia, ANALYTICAL, DIAGNOSTIC AND THERAPEUTIC TECHNIQUES, AND EQUIPMENT::Diagnosis::Diagnostic Techniques and Procedures::Diagnostic Imaging::Tomography::Magnetic Resonance Imaging, Development and Disorders of Fetal Brain, Genome-Wide Association Study, Neuroscience, ddc: ddc:610
FOS: Computer and information sciences, Aging, Genetic variants, Cerebrovascular, CHARGE consortium, TÉCNICAS Y EQUIPOS ANALÍTICOS, DIAGNÓSTICOS Y TERAPÉUTICOS::diagnóstico::técnicas y procedimientos diagnósticos::diagnóstico por imagen::tomografía::imagen por resonancia magnética, Malalties cerebrovasculars - Aspectes genètics, Neurodegenerative, Genome-wide association studies, Gene, Magnetic Resonance Imaging/methods, methods [Magnetic Resonance Imaging], Vascular Cognitive Impairment/Dementia, Pathology, 2.1 Biological and endogenous factors, Disease, Alzheimer's Disease Related Dementias (ADRD), Malalties cerebrovasculars - Imatgeria per ressonància magnètica, Single-nucleotide polymorphism, anzsrc-for: 42 Health Sciences, Genome, Endothelial Cells/pathology, White matter, ENFERMEDADES::enfermedades del sistema nervioso::enfermedades del sistema nervioso central::enfermedades cerebrales::trastornos cerebrovasculares::enfermedades de los pequeños vasos cerebrales, Genomics, Magnetic Resonance Imaging, Stroke, Environmental health, Neurology, complications [Cerebral Small Vessel Diseases], Neurological, Medicine, diagnostic imaging [Cerebral Small Vessel Diseases], DISCIPLINES AND OCCUPATIONS::Natural Science Disciplines::Biological Science Disciplines::Biology::Computational Biology::Genomics, Radiology, Pulmonary and Respiratory Medicine, Genome-wide association study, Candidate gene, Genotype, Bioinformatics, DISEASES::Nervous System Diseases::Central Nervous System Diseases::Brain Diseases::Cerebrovascular Disorders::Cerebral Small Vessel Diseases, Population, 610, pathology [Endothelial Cells], Article, Magnetic resonance imaging, Rheumatology, Clinical Research, Health Sciences, Acquired Cognitive Impairment, Mendelian randomization, Genetics, Humans, Cerebral Small Vessel Diseases/diagnostic imaging, Biology, Prevention, Human Genome, Neurosciences, DISCIPLINAS Y OCUPACIONES::disciplinas de las ciencias naturales::disciplinas de las ciencias biológicas::biología::biología computacional::genómica, Moyamoya Disease and Syndrome, 42 Health Sciences, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Endothelial Cells, Perivascular space, Diagnosis and Treatment of Renal Artery Stenosis, Brain Disorders, anzsrc-for: 32 Biomedical and clinical sciences, Genòmica, Neurosonography, anzsrc-for: 11 Medical and Health Sciences, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, Cerebral Small Vessel Diseases, FOS: Biological sciences, Pediatrics, Perinatology and Child Health, genetics [Cerebral Small Vessel Diseases], Genetic association, Dementia, ANALYTICAL, DIAGNOSTIC AND THERAPEUTIC TECHNIQUES, AND EQUIPMENT::Diagnosis::Diagnostic Techniques and Procedures::Diagnostic Imaging::Tomography::Magnetic Resonance Imaging, Development and Disorders of Fetal Brain, Genome-Wide Association Study, Neuroscience, ddc: ddc:610
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