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 ance...

Descripción completa

Detalles Bibliográficos
Autores: Duperron, Marie-Gabrielle|||0000-0001-7408-7792, Knol, Maria J.|||0000-0002-3597-1531, Le Grand, Quentin|||0000-0002-9299-0747, Evans, Tavia E.|||0000-0003-2390-286X, Mishra, Aniket|||0000-0002-8141-1543, Tsuchida, Ami|||0000-0001-5160-6203, Roshchupkin, Gennady V.|||0000-0002-3403-2313, Konuma, Takahiro, Trégouët, David-Alexandre|||0000-0001-9084-7800, Romero, Jose Rafael|||0000-0002-1101-2950, Frenzel, Stefan|||0000-0001-5087-5970, Luciano, Michelle|||0000-0002-7306-3008, Hofer, Edith, Bourgey, Mathieu|||0000-0002-8432-834X, Dueker, Nicole D., Delgado Martínez, María Pilar|||0000-0002-1628-4488, Hilal, Saima, Tankard, Rick M.|||0000-0002-8847-9401, Dubost, Florian, Shin, Jean|||0000-0001-7353-5178, Saba, Yasaman|||0000-0002-3549-2493, Armstrong, Nicola|||0000-0002-4477-293X, Bordes, Constance|||0000-0003-3367-1778, Bastin, Mark E., Beiser, Alexa, Brodaty, Henry|||0000-0001-9487-6617, Bülow, Robin|||0000-0003-1884-5784, Carrera, Caty|||0000-0002-0804-0969, Chen, Christopher, Cheng, Ching-Yu|||0000-0003-0655-885X, Deary, Ian J.|||0000-0002-1733-263X, Gampawar, Piyush G., Himali, Jayandra J.|||0000-0003-1391-9481, Jiang, Jiyang|||0000-0002-2147-6302, Kawaguchi, Takahisa, Li, Shuo|||0000-0003-2331-2448, Macalli, Melissa|||0000-0003-3008-8720, Marquis, Pascale, Morris, Zoe, Muñoz Maniega, Susana|||0000-0001-5185-6384, Miyamoto, Susumu, Okawa, Masakazu|||0000-0002-5414-1293, Paradise, Matthew, Parva, Pedram, Rundek, Tatjana|||0000-0002-7115-9815, Sargurupremraj, Muralidharan|||0000-0003-1684-3750, Schilling, Sabrina, Setoh, Kazuya, Soukarieh, Omar, Tabara, Yasuharu, Teumer, Alexander|||0000-0002-8309-094X, Thalamuthu, Anbupalam|||0000-0002-7114-1260, Trollor, Julian|||0000-0002-7685-2977, Valdés Hernández, Maria C., Vernooij, Meike W., Völker, Uwe|||0000-0002-5689-3448, Wittfeld, Katharina|||0000-0003-4383-5043, Wong, Tien Yin|||0000-0002-8448-1264, Wright, Margaret J.|||0000-0001-7133-4970, Zhang, Junyi, Zhao, Wanting, Zhu, Yi-Cheng, Schmidt, Helena|||0000-0001-9773-9992, Sachdev, Perminder S.|||0000-0002-9595-3220, Wen, Wei|||0000-0003-2753-3870, Yoshida, Kazumichi, Joutel, Anne, Satizabal, Claudia L.|||0000-0002-1115-4430, Sacco, Ralph L., Bourque, Guillaume|||0000-0002-3933-9656, Lathrop, Mark, Paus, Tomas|||0000-0003-1495-9338, Fernández Cadenas, Israel|||0000-0003-4821-2363, Yang, Qiong|||0000-0002-3658-1375, Mazoyer, Bernard|||0000-0003-0970-2837, Boutinaud, Philippe, Okada, Yukinori|||0000-0002-0311-8472, Grabe, Hans J.|||0000-0003-3684-4208, Mather, Karen A.|||0000-0003-4143-8941, Schmidt, Reinhold, Joliot, Marc|||0000-0001-7792-308X, Ikram, M. Arfan|||0000-0003-0372-8585, Matsuda, Fumihiko, Tzourio, Christophe|||0000-0002-6517-2984, Wardlaw, Joanna|||0000-0002-9812-6642, Seshadri, Sudha|||0000-0001-6135-2622, Adams, Hieab H. H.|||0000-0003-3687-2508, Debette, Stéphanie|||0000-0001-8675-7968
Tipo de recurso: artículo
Fecha de publicación:2023
País:España
Institución:Universitat Autònoma de Barcelona
Repositorio:Dipòsit Digital de Documents de la UAB
Idioma:inglés
OAI Identifier:oai:ddd.uab.cat:280931
Acceso en línea:https://ddd.uab.cat/record/280931
https://dx.doi.org/urn:doi:10.1038/s41591-023-02268-w
Access Level:acceso abierto
Palabra clave:Neurology
Stroke
Genome-wide association studies
Descripción
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. Genomic analyses of large population-based cohorts uncover the genetic determinants of perivascular space burden, an MRI marker of cerebral small vessel disease, across the lifespan, and reveal potential pathways implicated in the etiology of stroke and dementia.

Similares en LA Referencia