TY - JOUR
T1 - Genomics of perivascular space burden unravels early mechanisms of cerebral small vessel disease
AU - CHARGE Consortium
AU - Duperron, Marie-Gabrielle
AU - Knol, Maria J
AU - Le Grand, Quentin
AU - Evans, Tavia E
AU - Mishra, Aniket
AU - Tsuchida, Ami
AU - Roshchupkin, Gennady
AU - Konuma, Takahiro
AU - Trégouët, David-Alexandre
AU - Romero, Jose Rafael
AU - Frenzel, Stefan
AU - Luciano, Michelle
AU - Hofer, Edith
AU - Bourgey, Mathieu
AU - Dueker, Nicole D
AU - Delgado, Pilar
AU - Hilal, Saima
AU - Tankard, Rick M
AU - Dubost, Florian
AU - Shin, Jean
AU - Saba, Yasaman
AU - Armstrong, Nicola J
AU - Bordes, Constance
AU - Bastin, Mark E
AU - Beiser, Alexa
AU - Brodaty, Henry
AU - Bülow, Robin
AU - Carrera, Caty
AU - Chen, Christopher
AU - Cheng, Ching-Yu
AU - Deary, Ian J
AU - Gampawar, Piyush G
AU - Himali, Jayandra J
AU - Jiang, Jiyang
AU - Kawaguchi, Takahisa
AU - Li, Shuo
AU - Macalli, Melissa
AU - Marquis, Pascale
AU - Morris, Zoe
AU - Muñoz Maniega, Susana
AU - Miyamoto, Susumu
AU - Okawa, Masakazu
AU - Paradise, Matthew
AU - Parva, Pedram
AU - Rundek, Tatjana
AU - Sargurupremraj, Muralidharan
AU - Schilling, Sabrina
AU - Setoh, Kazuya
AU - Soukarieh, Omar
AU - Seshadri, Sudha
N1 - © 2023. The Author(s).
PY - 2023/4
Y1 - 2023/4
N2 - Perivascular space (PVS) burden is an emerging, poorly understood, magnetic resonance imaging marker of cerebral small vessel disease, a leading cause of stroke and dementia. Genome-wide association studies in up to 40,095 participants (18 population-based cohorts, 66.3 ± 8.6 yr, 96.9% European ancestry) revealed 24 genome-wide significant PVS risk loci, mainly in the white matter. These were associated with white matter PVS already in young adults (N = 1,748; 22.1 ± 2.3 yr) and were enriched in early-onset leukodystrophy genes and genes expressed in fetal brain endothelial cells, suggesting early-life mechanisms. In total, 53% of white matter PVS risk loci showed nominally significant associations (27% after multiple-testing correction) in a Japanese population-based cohort (N = 2,862; 68.3 ± 5.3 yr). Mendelian randomization supported causal associations of high blood pressure with basal ganglia and hippocampal PVS, and of basal ganglia PVS and hippocampal PVS with stroke, accounting for blood pressure. Our findings provide insight into the biology of PVS and cerebral small vessel disease, pointing to pathways involving extracellular matrix, membrane transport and developmental processes, and the potential for genetically informed prioritization of drug targets.
AB - Perivascular space (PVS) burden is an emerging, poorly understood, magnetic resonance imaging marker of cerebral small vessel disease, a leading cause of stroke and dementia. Genome-wide association studies in up to 40,095 participants (18 population-based cohorts, 66.3 ± 8.6 yr, 96.9% European ancestry) revealed 24 genome-wide significant PVS risk loci, mainly in the white matter. These were associated with white matter PVS already in young adults (N = 1,748; 22.1 ± 2.3 yr) and were enriched in early-onset leukodystrophy genes and genes expressed in fetal brain endothelial cells, suggesting early-life mechanisms. In total, 53% of white matter PVS risk loci showed nominally significant associations (27% after multiple-testing correction) in a Japanese population-based cohort (N = 2,862; 68.3 ± 5.3 yr). Mendelian randomization supported causal associations of high blood pressure with basal ganglia and hippocampal PVS, and of basal ganglia PVS and hippocampal PVS with stroke, accounting for blood pressure. Our findings provide insight into the biology of PVS and cerebral small vessel disease, pointing to pathways involving extracellular matrix, membrane transport and developmental processes, and the potential for genetically informed prioritization of drug targets.
KW - Humans
KW - Endothelial Cells/pathology
KW - Genome-Wide Association Study
KW - Cerebral Small Vessel Diseases/diagnostic imaging
KW - Stroke
KW - Magnetic Resonance Imaging/methods
KW - Genomics
U2 - 10.1038/s41591-023-02268-w
DO - 10.1038/s41591-023-02268-w
M3 - Article
C2 - 37069360
SN - 1078-8956
VL - 29
SP - 950
EP - 962
JO - Nature Medicine
JF - Nature Medicine
IS - 4
ER -