| Title: |
Cerebral small vessel disease genomics and its implications across the lifespan |
| Authors: |
Sargurupremraj, M; Suzuki, H; Jian, X; Sarnowski, C; Evans, TE; Bis, JC; Eiriksdottir, G; Sakaue, S; Terzikhan, N; Habes, M; Zhao, W; Armstrong, NJ; Hofer, E; Yanek, LR; Hagenaars, SP; Kumar, RB; van den Akker, EB; McWhirter, RE; Trompet, S; Mishra, A; Saba, Y; Satizabal, CL; Beaudet, G; Petit, L; Tsuchida, A; Zago, L; Schilling, S; Sigurdsson, S; Gottesman, RF; Lewis, CE; Aggarwal, NT; Lopez, OL; Smith, JA; Valdés Hernández, MC; van der Grond, J; Wright, MJ; Knol, MJ; Dörr, M; Thomson, RJ; Bordes, C; Le Grand, Q; Duperron, MG; Smith, AV; Knopman, DS; Schreiner, PJ; Evans, DA; Rotter, JI; Beiser, AS; Maniega, SM; Beekman, M; Trollor, J; Stott, DJ; Vernooij, MW; Wittfeld, K; Niessen, WJ; Soumaré, A; Boerwinkle, E; Sidney, S; Turner, ST; Davies, G; Thalamuthu, A; Völker, U; van Buchem, MA; Bryan, RN; Dupuis, J; Bastin, ME; Ames, D; Teumer, A; Amouyel, P; Kwok, JB; Bülow, R; Deary, IJ; Schofield, PR; Brodaty, H; Jiang, J; Tabara, Y; Setoh, K; Miyamoto, S; Yoshida, K; Nagata, M; Kamatani, Y; Matsuda, F; Psaty, BM; Bennett, DA; De Jager, PL; Mosley, TH; Sachdev, PS; Schmidt, R; Warren, HR; Evangelou, E; Trégouët, DA; de Andrade, M; Basu, S; Berr, C; Brody, JA; Chasman, DI; Dartigues, JF; Folsom, AR; Germain, M; Wen, Wei; Mather, Karen |
| Source: |
urn:ISSN:2041-1723 ; Nature Communications, 11, 1, 6285 |
| Publisher Information: |
Springer Nature |
| Publication Year: |
2020 |
| Collection: |
UNSW Sydney (The University of New South Wales): UNSWorks |
| Subject Terms: |
4202 Epidemiology; 31 Biological Sciences; 42 Health Sciences; 3105 Genetics; Human Genome; Biomedical Imaging; Neurodegenerative; Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD); Genetics; Hypertension; Clinical Trials and Supportive Activities; Aging; Alzheimer's Disease; Brain Disorders; Neurosciences; Alzheimer's Disease Related Dementias (ADRD); Dementia; Stroke; Prevention; Cardiovascular; Cerebrovascular; Biotechnology; Acquired Cognitive Impairment; Clinical Research; Vascular Cognitive Impairment/Dementia; 2.1 Biological and endogenous factors; Neurological; Adult; Aged; 80 and over |
| Description: |
White matter hyperintensities (WMH) are the most common brain-imaging feature of cerebral small vessel disease (SVD), hypertension being the main known risk factor. Here, we identify 27 genome-wide loci for WMH-volume in a cohort of 50,970 older individuals, accounting for modification/confounding by hypertension. Aggregated WMH risk variants were associated with altered white matter integrity (p = 2.5×10-7) in brain images from 1,738 young healthy adults, providing insight into the lifetime impact of SVD genetic risk. Mendelian randomization suggested causal association of increasing WMH-volume with stroke, Alzheimer-type dementia, and of increasing blood pressure (BP) with larger WMH-volume, notably also in persons without clinical hypertension. Transcriptome-wide colocalization analyses showed association of WMH-volume with expression of 39 genes, of which four encode known drug targets. Finally, we provide insight into BP-independent biological pathways underlying SVD and suggest potential for genetic stratification of high-risk individuals and for genetically-informed prioritization of drug targets for prevention trials. |
| Document Type: |
article in journal/newspaper |
| File Description: |
application/pdf |
| Language: |
unknown |
| Relation: |
https://hdl.handle.net/1959.4/unsworks_74672 |
| DOI: |
10.1038/s41467-020-19111-2 |
| Availability: |
https://hdl.handle.net/1959.4/unsworks_74672; https://unsworks.unsw.edu.au/bitstreams/33a5750b-c45e-4cc7-a24b-462c3e6166fe/download; https://doi.org/10.1038/s41467-020-19111-2 |
| Rights: |
open access ; https://purl.org/coar/access_right/c_abf2 ; CC BY ; https://creativecommons.org/licenses/by/4.0/ ; free_to_read |
| Accession Number: |
edsbas.5E08AF02 |
| Database: |
BASE |