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

CHARGE Consortium, Marie-Gabrielle Duperron, Maria J Knol, Quentin Le Grand, Tavia E Evans, Aniket Mishra, Ami Tsuchida, Gennady Roshchupkin, Takahiro Konuma, David-Alexandre Trégouët, Jose Rafael Romero, Stefan Frenzel, Michelle Luciano, Edith Hofer, Mathieu Bourgey, Nicole D Dueker, Pilar Delgado, Saima Hilal, Rick M Tankard, Florian DubostJean Shin, Yasaman Saba, Nicola J Armstrong, Constance Bordes, Mark E Bastin, Alexa Beiser, Henry Brodaty, Robin Bülow, Caty Carrera, Christopher Chen, Ching-Yu Cheng, Ian J Deary, Piyush G Gampawar, Jayandra J Himali, Jiyang Jiang, Takahisa Kawaguchi, Shuo Li, Melissa Macalli, Pascale Marquis, Zoe Morris, Susana Muñoz Maniega, Susumu Miyamoto, Masakazu Okawa, Matthew Paradise, Pedram Parva, Tatjana Rundek, Muralidharan Sargurupremraj, Sabrina Schilling, Kazuya Setoh, Omar Soukarieh, Yasuharu Tabara, Alexander Teumer, Anbupalam Thalamuthu, Julian N Trollor, Maria C Valdés Hernández, Meike W Vernooij, Uwe Völker, Katharina Wittfeld, Tien Yin Wong, Margaret J Wright, Junyi Zhang, Wanting Zhao, Yi-Cheng Zhu, Helena Schmidt, Perminder S Sachdev, Wei Wen, Kazumichi Yoshida, Anne Joutel, Claudia L Satizabal, Ralph L Sacco, Guillaume Bourque, Mark Lathrop, Tomas Paus, Israel Fernandez-Cadenas, Qiong Yang, Bernard Mazoyer, Philippe Boutinaud, Yukinori Okada, Hans J Grabe, Karen A Mather, Reinhold Schmidt, Marc Joliot, M Arfan Ikram, Fumihiko Matsuda, Christophe Tzourio, Joanna M Wardlaw, Sudha Seshadri, Hieab H H Adams, Stéphanie Debette

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

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.

Original languageEnglish
Pages (from-to)950-962
Number of pages13
JournalNature Medicine
Issue number4
Publication statusPublished - 17 Apr 2023

Keywords / Materials (for Non-textual outputs)

  • Humans
  • Endothelial Cells/pathology
  • Genome-Wide Association Study
  • Cerebral Small Vessel Diseases/diagnostic imaging
  • Stroke
  • Magnetic Resonance Imaging/methods
  • Genomics


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