Journal Article

DZNE-2023-00479

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Genomics of perivascular space burden unravels early mechanisms of cerebral small vessel disease.

Duperron, M.-G. ; Knol, M. J. ; Le Grand, Q. ; Evans, T. E. ; Mishra, A. ; Tsuchida, A. ; Roshchupkin, G. ; Konuma, T. ; Trégouët, D.-A. ; Romero, J. R. ; Frenzel, S. ; Luciano, M. ; Hofer, E. ; Bourgey, M. ; Dueker, N. D. ; Delgado, P. ; Hilal, S. ; Tankard, R. M. ; Dubost, F. ; Shin, J. ; Saba, Y. ; Armstrong, N. J. ; Bordes, C. ; Bastin, M. E. ; Beiser, A. ; Brodaty, H. ; Bülow, R. ; Carrera, C. ; Chen, C. ; Cheng, C.-Y. ; Deary, I. J. ; Gampawar, P. G. ; Himali, J. J. ; Jiang, J. ; Kawaguchi, T. ; Li, S. ; Macalli, M. ; Marquis, P. ; Morris, Z. ; Muñoz Maniega, S. ; Miyamoto, S. ; Okawa, M. ; Paradise, M. ; Parva, P. ; Rundek, T. ; Sargurupremraj, M. ; Schilling, S. ; Setoh, K. ; Soukarieh, O. ; Tabara, Y. ; Teumer, A. ; Thalamuthu, A. ; Trollor, J. N. ; Valdés Hernández, M. C. ; Vernooij, M. W. ; Völker, U. ; Wittfeld, K.DZNE* ; Wong, T. Y. ; Wright, M. J. ; Zhang, J. ; Zhao, W. ; Zhu, Y.-C. ; Schmidt, H. ; Sachdev, P. S. ; Wen, W. ; Yoshida, K. ; Joutel, A. ; Satizabal, C. L. ; Sacco, R. L. ; Bourque, G. ; consortium, C. (Collaboration Author) ; Lathrop, M. ; Paus, T. ; Fernandez-Cadenas, I. ; Yang, Q. ; Mazoyer, B. ; Boutinaud, P. ; Okada, Y. ; Grabe, H. J.DZNE* ; Mather, K. A. ; Schmidt, R. ; Joliot, M. ; Ikram, M. A. ; Matsuda, F. ; Tzourio, C. ; Wardlaw, J. M. ; Seshadri, S. ; Adams, H. H. H. ; Debette, S. ; Le Grand, Q. (Contributor)

2023
Nature America Inc. New York, NY

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Please use a persistent id in citations: doi:10.1038/s41591-023-02268-w

Abstract: 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.

Keyword(s): Humans (MeSH) ; Endothelial Cells: pathology (MeSH) ; Genome-Wide Association Study (MeSH) ; Cerebral Small Vessel Diseases: diagnostic imaging (MeSH) ; Cerebral Small Vessel Diseases: genetics (MeSH) ; Cerebral Small Vessel Diseases: complications (MeSH) ; Stroke (MeSH) ; Magnetic Resonance Imaging: methods (MeSH) ; Genomics (MeSH)

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Contributing Institute(s):

1. Translational Health Care Research (AG Hoffmann)
2. Biomarkers of Dementia in the General Population (AG Grabe)

Research Program(s):

1. 352 - Disease Mechanisms (POF4-352) (POF4-352)
2. 353 - Clinical and Health Care Research (POF4-353) (POF4-353)

Appears in the scientific report 2023

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