Genomics of perivascular space burden unravels early mechanisms of cerebral small vessel disease
Duperron, Marie-Gabrielle (Bordeaux University Hospital(França))
Knol, Maria J. (Erasmus MC University Medical Center)
Le Grand, Quentin (Bordeaux Population Health Research Center)
Evans, Tavia E. (Erasmus MC University Medical Center)
Mishra, Aniket (University of Bordeaux)
Tsuchida, Ami (University of Bordeaux)
Roshchupkin, Gennady V (Erasmus MC University Medical Center)
Konuma, Takahiro (Osaka University Graduate School of Medicine)
Trégouët, David-Alexandre (University of Bordeaux)
Romero, Jose Rafael (The Framingham Heart Study)
Frenzel, Stefan (University Medicine Greifswald)
Luciano, Michelle (University of Edinburgh)
Hofer, Edith (Medical University of Graz)
Bourgey, Mathieu (McGill University)
Dueker, Nicole D. (University of Miami)
Delgado Martínez, María Pilar (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Hilal, Saima (National University of Singapore and National University Health System)
Tankard, Rick M. (Curtin University)
Dubost, Florian (Erasmus MC University Medical Center)
Shin, Jean (University of Toronto)
Saba, Yasaman (Medical University of Graz)
Armstrong, Nicola (Curtin University)
Bordes, Constance (Bordeaux Population Health Research Center)
Bastin, Mark E. (University of Edinburgh)
Beiser, Alexa (Boston University School of Public Health)
Brodaty, Henry (Dementia Collaborative Research Centre Assessment and Better Care)
Bülow, Robin (University Medicine Greifswald)
Carrera, Caty (Institut d'Investigació Biomèdica Sant Pau)
Chen, Christopher (National University of Singapore)
Cheng, Ching-Yu (Duke-NUS Medical School)
Deary, Ian J. (University of Edinburgh)
Gampawar, Piyush G. (Medical University of Graz)
Himali, Jayandra J. (UT Health San Antonio)
Jiang, Jiyang (University of New South Wales)
Kawaguchi, Takahisa (Kyoto University Graduate School of Medicine)
Li, Shuo (Boston University School of Public Health)
Macalli, Melissa (University of Bordeaux)
Marquis, Pascale (McGill University)
Morris, Zoe (Royal Infirmary of Edinburgh)
Muñoz Maniega, Susana (UK Dementia Research Institute Centre at the University of Edinburgh)
Miyamoto, Susumu (Kyoto University Hospital)
Okawa, Masakazu (Kyoto University Graduate School of Medicine)
Paradise, Matthew (University of New South Wales)
Parva, Pedram (Harvard Medical School)
Rundek, Tatjana (University of Miami)
Sargurupremraj, Muralidharan (University of Bordeaux)
Schilling, Sabrina (University of Bordeaux)
Setoh, Kazuya (Shizuoka Graduate University of Public Health)
Soukarieh, Omar (University of Bordeaux)
Tabara, Yasuharu (Shizuoka Graduate University of Public Health)
Teumer, Alexander (University Medicine Greifswald)
Thalamuthu, Anbupalam (University of New South Wales)
Trollor, Julian (UNSW)
Valdés Hernández, Maria C. (University of Edinburgh)
Vernooij, Meike W. (Erasmus MC University Medical Center)
Völker, Uwe (University Medicine Greifswald)
Wittfeld, Katharina (German Center for Neurodegenerative Diseases)
Wong, Tien Yin (Tsinghua University)
Wright, Margaret J. (University of Queensland)
Zhang, Junyi (Peking Union Medical College Hospital)
Zhao, Wanting (Duke-NUS Medical School)
Zhu, Yi-Cheng (Peking Union Medical College Hospital)
Schmidt, Helena (Medical University of Graz)
Sachdev, Perminder S. (Prince of Wales Hospital (Australia))
Wen, Wei (University of New South Wales)
Yoshida, Kazumichi (Kyoto University Graduate School of Medicine)
Joutel, Anne (Université Paris Cité)
Satizabal, Claudia L. (UT Health San Antonio)
Sacco, Ralph L. (University of Miami)
Bourque, Guillaume (McGill University)
Lathrop, Mark (Victor Phillip Dahdaleh Institute of Genomic Medicine at McGill University)
Paus, Tomas (University of Toronto)
Fernandez-Cadenas, Israel (Institut d'Investigació Biomèdica Sant Pau)
Yang, Qiong (Boston University School of Public Health)
Mazoyer, Bernard (Bordeaux University Hospital (França))
Boutinaud, Philippe (Fealinx)
Okada, Yukinori (University of Tokyo)
Grabe, Hans J. (German Center for Neurodegenerative Diseases)
Mather, Karen A (Neuroscience Research Australia)
Schmidt, Reinhold (Medical University of Graz)
Joliot, Marc (University of Bordeaux)
Ikram, M. Arfan (Erasmus MC University Medical Center)
Matsuda, Fumihiko (Kyoto University Graduate School of Medicine)
Tzourio, Christophe (Bordeaux University Hospital(França))
Wardlaw, Joanna (University of Edinburgh)
Seshadri, Sudha (UT Health San Antonio)
Adams, Hieab (Universidad Adolfo Ibáñez)
Debette, Stéphanie (Bordeaux University Hospital(França))
Universitat Autònoma de Barcelona

Data:	2023
Resum:	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.
Ajuts:	Ministerio de Economía y Competitividad PI14/01535 Instituto de Salud Carlos III PI17/02222
Drets:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Matèria:	Neurology ; Stroke ; Genome-wide association studies
Publicat a:	Nature Medicine, Vol. 29 (april 2023) , p. 950-962, ISSN 1546-170X

DOI: 10.1038/s41591-023-02268-w
PMID: 37069360

32 p, 9.6 MB

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