| Title: |
Genomics of perivascular space burden unravels early mechanisms of cerebral small vessel disease |
| Authors: |
Duperron, MG; Knol, MJ; Le Grand, Q; Evans, TE; Mishra, A; Tsuchida, A; Roshchupkin, G; Konuma, T; Trégouët, 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; Bülow, R; Carrera, C; Chen, C; Cheng, CY; Deary, IJ; Gampawar, PG; Himali, JJ; 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, JN; Valdés Hernández, MC; Vernooij, MW; Völker, U; Wittfeld, K; Wong, TY; Wright, MJ; Zhang, J; Zhao, W; 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 |
| Source: |
urn:ISSN:1078-8956 ; urn:ISSN:1546-170X ; Nature Medicine, 29, 4, 950-962 |
| Publisher Information: |
Springer Nature |
| Publication Year: |
2023 |
| Collection: |
UNSW Sydney (The University of New South Wales): UNSWorks |
| Subject Terms: |
42 Health Sciences; Brain Disorders; Genetics; Alzheimer's Disease Related Dementias (ADRD); Cerebrovascular; Human Genome; Vascular Cognitive Impairment/Dementia; Dementia; Prevention; Clinical Research; Minority Health; Neurosciences; Neurodegenerative; Acquired Cognitive Impairment; Aging; Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD); Stroke; Health Disparities and Racial or Ethnic Minority Health Research; 2.1 Biological and endogenous factors; Neurological; Humans; Endothelial Cells; Genome-Wide Association Study; Cerebral Small Vessel Diseases; Magnetic Resonance Imaging; Genomics; CHARGE consortium; anzsrc-for: 42 Health Sciences; anzsrc-for: 11 Medical and Health Sciences; anzsrc-for: 32 Biomedical and clinical sciences |
| Description: |
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. |
| Document Type: |
article in journal/newspaper |
| Language: |
unknown |
| Relation: |
http://purl.org/au-research/grants/nhmrc/APP1093083; http://purl.org/au-research/grants/nhmrc/APP1115462; http://purl.org/au-research/grants/nhmrc/APP1025243; http://purl.org/au-research/grants/nhmrc/APP1024224; http://purl.org/au-research/grants/nhmrc/APP1045325; http://purl.org/au-research/grants/nhmrc/APP1085606; http://purl.org/au-research/grants/nhmrc/APP1115575; https://hdl.handle.net/1959.4/unsworks_83299 |
| DOI: |
10.1038/s41591-023-02268-w |
| Availability: |
https://hdl.handle.net/1959.4/unsworks_83299; https://doi.org/10.1038/s41591-023-02268-w |
| Rights: |
open access ; https://purl.org/coar/access_right/c_abf2 ; CC BY ; https://creativecommons.org/licenses/by/4.0/ |
| Accession Number: |
edsbas.4FD75CB0 |
| Database: |
BASE |