150786 - Cerebral small vessel disease genomics.pdf (2.9 MB)
Cerebral small vessel disease genomics and its implications across the lifespan
journal contribution
posted on 2023-05-21, 09:02 authored by Sargurupremraj, M, Suzuki, H, Jian, X, Sarnowski, C, Rebekah McWhirterRebekah McWhirter, Srikanth, VK, Russell Thomson, 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, 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, de Andrade, M, Hernandez, MCV, van der Grond, J, Wright, MJ, Knol, MJ, Dorr, M, Thomson, RJ, Bordes, C, Le Grand, Q, Duperron, MG, Smith, AV, Knopman, DS, Schreiner, PJ, Evans, DA, Rotter, JI, Beiser, AS, Maniega, SM, Munoz, S, Beekman, M, Trollor, J, Stott, DJ, Vernooij, MW, Wittfeld, K, Niessen, WJ, Soumare, A, Boerwinkle, E, Sidney, S, Turner, ST, Davies, G, Thalamuthu, A, Volker, U, van Buchem, MA, Bryan, RN, Dupuis, J, Bastin, ME, Ames, D, Teumer, A, Amouyel, P, Kwok, JB, Bulow, R, Deary, IJ, Schofield, PR, Brodaty, H, Jiang, J, Tabara, Y, Setoh, K, Miyamoto, S, Yoshid, K, Nagata, M, Kamatani, Y, Matsuda, F, Bennett, DA, De Jager, PL, Mosley, TH, Sachdev, PS, Schmidt, R, Warren, HR, Evangelou, E, Tregouet, DA, Berr, C, Ikram, MA, Wen, W, DeCarli, C, Jukema, JW, Slagboom, EP, Kardia, SLR, Okada, Y, Wardlaw, JM, Mazoyer, B, Nyquist, PA, Mather, KA, Grabe, HJ, Schmidt, H, Van Duijn, CM, Gudnason, V, Esko, T, Longstreth Jr, WT, Launer, LJ, Lathrop, M, Seshadri, S, Tzourio, C, Adams, HH, Matthews, PM, Fornage, M, Debette, SWhite 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.
History
Publication title
Nature CommunicationsVolume
11Issue
2020Article number
6285Number
6285Pagination
1-18ISSN
2041-1723Department/School
Faculty of LawPublisher
Nature Publishing GroupPlace of publication
United KingdomRights statement
© The Author(s) 2020. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.Repository Status
- Open
