Cerebral small vessel disease genomics and its implications across the lifespan
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Published:2020-12
Issue:1
Volume:11
Page:
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ISSN:2041-1723
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Container-title:Nature Communications
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language:en
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Short-container-title:Nat Commun
Author:
Sargurupremraj Muralidharan, , Suzuki Hideaki, Jian XueqiuORCID, Sarnowski ChloéORCID, Evans Tavia E., Bis Joshua C., Eiriksdottir Gudny, Sakaue SaoriORCID, Terzikhan Natalie, Habes Mohamad, Zhao WeiORCID, Armstrong Nicola J., Hofer Edith, Yanek Lisa R.ORCID, Hagenaars Saskia P., Kumar Rajan B., van den Akker Erik B., McWhirter Rebekah E.ORCID, Trompet Stella, Mishra AniketORCID, Saba Yasaman, Satizabal Claudia L.ORCID, Beaudet Gregory, Petit Laurent, Tsuchida AmiORCID, Zago LaureORCID, Schilling Sabrina, Sigurdsson Sigurdur, Gottesman Rebecca F., Lewis Cora E., Aggarwal Neelum T., Lopez Oscar L., Smith Jennifer A.ORCID, Valdés Hernández Maria C., van der Grond Jeroen, Wright Margaret J.ORCID, Knol Maria J.ORCID, Dörr Marcus, Thomson Russell J., Bordes Constance, Le Grand QuentinORCID, Duperron Marie-Gabrielle, Smith Albert V.ORCID, Knopman David S., Schreiner Pamela J., Evans Denis A., Rotter Jerome I.ORCID, Beiser Alexa S., Maniega Susana Muñoz, Beekman MarianORCID, Trollor JulianORCID, Stott David J., Vernooij Meike W., Wittfeld KatharinaORCID, Niessen Wiro J., Soumaré AichaORCID, Boerwinkle Eric, Sidney Stephen, Turner Stephen T., Davies Gail, Thalamuthu Anbupalam, Völker UweORCID, van Buchem Mark A., Bryan R. Nick, Dupuis JoséeORCID, Bastin Mark E., Ames David, Teumer AlexanderORCID, Amouyel PhilippeORCID, Kwok John B., Bülow Robin, Deary Ian J., Schofield Peter R.ORCID, Brodaty HenryORCID, Jiang JiyangORCID, Tabara Yasuharu, Setoh Kazuya, Miyamoto Susumu, Yoshida Kazumichi, Nagata Manabu, Kamatani YoichiroORCID, Matsuda Fumihiko, Psaty Bruce M., Bennett David A., De Jager Philip L.ORCID, Mosley Thomas H., Sachdev Perminder S.ORCID, Schmidt Reinhold, Warren Helen R.ORCID, Evangelou EvangelosORCID, Trégouët David-Alexandre, Ikram Mohammad A.ORCID, Wen WeiORCID, DeCarli Charles, Srikanth Velandai K., Jukema J. WouterORCID, Slagboom Eline P.ORCID, Kardia Sharon L. R., Okada YukinoriORCID, Mazoyer BernardORCID, Wardlaw Joanna M.ORCID, Nyquist Paul A., Mather Karen A., Grabe Hans J.ORCID, Schmidt Helena, Van Duijn Cornelia M.ORCID, Gudnason VilmundurORCID, Longstreth William T., Launer Lenore J., Lathrop Mark, Seshadri Sudha, Tzourio Christophe, Adams Hieab H.ORCID, Matthews Paul M.ORCID, Fornage MyriamORCID, Debette StéphanieORCID,
Abstract
AbstractWhite 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.
Publisher
Springer Science and Business Media LLC
Subject
General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry
Reference86 articles.
1. Debette, S. & Markus, H. S. The clinical importance of white matter hyperintensities on brain magnetic resonance imaging: systematic review and meta-analysis. BMJ 341, c3666 (2010). 2. Shi, Y. et al. Cerebral blood flow in small vessel disease: a systematic review and meta-analysis. J. Cereb. Blood Flow. Metab. 36, 1653–1667 (2016). 3. Debette, S., Schilling, S., Duperron, M. G., Larsson, S. C. & Markus, H. S. Clinical significance of magnetic resonance imaging markers of vascular brain injury: a systematic review and meta-analysis. JAMA Neurol. 76, 81–94 (2019). 4. Corriveau, R. A. et al. Alzheimer’s disease-related Dementias Summit 2016: National research priorities. Neurology 89, 2381–2391 (2017). 5. The Lancet, N. Vascular disease and neurodegeneration: advancing together. Lancet Neurol. 16, 333 (2017).
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