Genomics of perivascular space burden unravels early mechanisms of cerebral small vessel disease

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 an...

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Autores: Duperron, MG; Knol, MJ; Le Grand, Q; Evans, TE; Mishra, A; Tsuchida, A; Roshchupkin, G; Konuma, T; Tregouet, DA; Romero, JR; Frenzel, S; Luciano, M; Hofer, E; Bourgey, M; Dueker, ND; Delgado, P; Hilal, S; Tankard, RM; Dubost, F; Shin, J; Saba, Y; Armstrong, NJ; Bordes, C; Bastin, ME; Beiser, A; Brodaty, H; Bulow, R; Carrera, C; Chen, CSP; Cheng, CY; Deary, IJ; Gampawar, PG; Himali, JJ; Jiang, JY; Kawaguchi, T; Li, S; Macalli, M; Marquis, P; Morris, Z; Maniega, SM; 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, JN; Hernandez, MCV; Vernooij, MW; Volker, U; Wittfeld, K; Wong, TY; Wright, MJ; Zhang, JY; Zhao, WT; Zhu, YC; Schmidt, H; Sachdev, PS; Wen, W; Yoshida, K; Joutel, A; Satizabal, CL; Sacco, RL; Bourque, G; Lathrop, M; Paus, T; Fernandez-Cadenas, I; Yang, Q; Mazoyer, B; Boutinaud, P; Okada, Y; Grabe, HJ; Mather, KA; Schmidt, R; Joliot, M; Ikram, MA; Matsuda, F; Tzourio, C; Wardlaw, JM; Seshadri, S; Adams, HHH; Debette, S
Tipo de documento: Artículo
Estado:Published version
Fecha de publicación:2023
País:España
Institución:Institut d’Investigació Biomèdica Sant Pau (IIB Sant Pau)
Repositorio:r-IIB SANT PAU. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica Sant Pau
OAI Identifier:oai:iibsantpau.fundanetsuite.com:p16466
Acceso en línea:https://iibsantpau.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=16466
https://www.scopus.com/inward/record.uri?eid=2-s2.0-85153120261&doi=10.1038%2fs41591-023-02268-w&partnerID=40&md5=e3a7ebd88f68944059c6a53c7f7898df
Nivel de acceso:Acceso abierto
Sumario: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.

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