Cerebral small vessel disease genomics and its implications across the lifespan

M. Sargurupremraj; H. Suzuki; X. Jian; C. Sarnowski; T.E. Evans; J.C. Bis; G. Eiriksdottir; S. Sakaue; N. Terzikhan; M. Habes; W. Zhao; N.J. Armstrong; E. Hofer; L.R. Yanek; S.P. Hagenaars; R.B. Kumar; E.B. van den Akker; R.E. McWhirter; S. Trompet; A. Mishra; Y. Saba; C.L. Satizabal; G. Beaudet; L. Petit; A. Tsuchida; L. Zago; S. Schilling; S. Sigurdsson; R.F. Gottesman; C.E. Lewis; N.T. Aggarwal; O.L. Lopez; J.A. Smith; M.C. Valdés Hernández; J. Van der Grond; M.J. Wright; M.J. Knol; M. Dörr; R.J. Thomson; C. Bordes; Q. Le Grand; M-G Duperron; A.V. Smith; D.S. Knopman; P.J. Schreiner; D.A. Evans; J.I. Rotter; A.S. Beiser; S.M. Maniega; M. Beekman; J. Trollor; D.J. Stott; M.W. Vernooij; K. Wittfeld; W.J. Niessen; A. Soumaré; E. Boerwinkle; S. Sidney; S.T. Turner; G. Davies; A. Thalamuthu; U. Völker; M.A. van Buchem; R.N. Bryan; J. Dupuis; M.E. Bastin; D. Ames; A. Teumer; P. Amouyel; J.B. Kwok; R. Bülow; I.J. Deary; P.R. Schofield; H. Brodaty; J. Jiang; Y. Tabara; K. Setoh; S. Miyamoto; K. Yoshida; M. Nagata; Y. Kamatani; F. Matsuda; B.M. Psaty; D.A. Bennett; P.L. De Jager; T.H. Mosley; P.S. Sachdev; R. Schmidt; H.R. Warren; E. Evangelou; D-A Trégouët; M.A. Ikram; W. Wen; C. DeCarli; V.K. Srikanth; J.W. Jukema; E.P. Slagboom; S.L.R. Kardia; Y. Okada; B. Mazoyer; J.M. Wardlaw; P.A. Nyquist; K.A. Mather; H.J. Grabe; H. Schmidt; C.M. van Duijn; V. Gudnason; W.T. Longstreth; L. J. Launer; M. Lathrop; S. Seshadri; C. Tzourio; H.H. Adams; P.M. Matthews; M. Fornage; S. Debette

doi:10.1038/s41467-020-19111-2

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Cerebral small vessel disease genomics and its implications across the lifespan

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Cerebral small vessel disease genomics and its implications across the lifespan

M. Sargurupremraj, H. Suzuki, X. Jian, C. Sarnowski, T.E. Evans, J.C. Bis, G. Eiriksdottir, S. Sakaue, N. Terzikhan, M. Habes, …

Nature Communications, Vol.11(1), Art. 6285

2020

DOI: https://doi.org/10.1038/s41467-020-19111-2

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Abstract

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.

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Title: Cerebral small vessel disease genomics and its implications across the lifespan
Authors/Creators: M. Sargurupremraj (Author/Creator)
H. Suzuki (Author/Creator)
X. Jian (Author/Creator)
C. Sarnowski (Author/Creator)
T.E. Evans (Author/Creator)
J.C. Bis (Author/Creator)
G. Eiriksdottir (Author/Creator)
S. Sakaue (Author/Creator)
N. Terzikhan (Author/Creator)
M. Habes (Author/Creator)
W. Zhao (Author/Creator)
N.J. Armstrong (Author/Creator)
E. Hofer (Author/Creator)
L.R. Yanek (Author/Creator)
S.P. Hagenaars (Author/Creator)
R.B. Kumar (Author/Creator)
E.B. van den Akker (Author/Creator)
R.E. McWhirter (Author/Creator)
S. Trompet (Author/Creator)
A. Mishra (Author/Creator)
Y. Saba (Author/Creator)
C.L. Satizabal (Author/Creator)
G. Beaudet (Author/Creator)
L. Petit (Author/Creator)
A. Tsuchida (Author/Creator)
L. Zago (Author/Creator)
S. Schilling (Author/Creator)
S. Sigurdsson (Author/Creator)
R.F. Gottesman (Author/Creator)
C.E. Lewis (Author/Creator)
N.T. Aggarwal (Author/Creator)
O.L. Lopez (Author/Creator)
J.A. Smith (Author/Creator)
M.C. Valdés Hernández (Author/Creator)
J. Van der Grond (Author/Creator)
M.J. Wright (Author/Creator)
M.J. Knol (Author/Creator)
M. Dörr (Author/Creator)
R.J. Thomson (Author/Creator)
C. Bordes (Author/Creator)
Q. Le Grand (Author/Creator)
M-G Duperron (Author/Creator)
A.V. Smith (Author/Creator)
D.S. Knopman (Author/Creator)
P.J. Schreiner (Author/Creator)
D.A. Evans (Author/Creator)
J.I. Rotter (Author/Creator)
A.S. Beiser (Author/Creator)
S.M. Maniega (Author/Creator)
M. Beekman (Author/Creator)
J. Trollor (Author/Creator)
D.J. Stott (Author/Creator)
M.W. Vernooij (Author/Creator)
K. Wittfeld (Author/Creator)
W.J. Niessen (Author/Creator)
A. Soumaré (Author/Creator)
E. Boerwinkle (Author/Creator)
S. Sidney (Author/Creator)
S.T. Turner (Author/Creator)
G. Davies (Author/Creator)
A. Thalamuthu (Author/Creator)
U. Völker (Author/Creator)
M.A. van Buchem (Author/Creator)
R.N. Bryan (Author/Creator)
J. Dupuis (Author/Creator)
M.E. Bastin (Author/Creator)
D. Ames (Author/Creator)
A. Teumer (Author/Creator)
P. Amouyel (Author/Creator)
J.B. Kwok (Author/Creator)
R. Bülow (Author/Creator)
I.J. Deary (Author/Creator)
P.R. Schofield (Author/Creator)
H. Brodaty (Author/Creator)
J. Jiang (Author/Creator)
Y. Tabara (Author/Creator)
K. Setoh (Author/Creator)
S. Miyamoto (Author/Creator)
K. Yoshida (Author/Creator)
M. Nagata (Author/Creator)
Y. Kamatani (Author/Creator)
F. Matsuda (Author/Creator)
B.M. Psaty (Author/Creator)
D.A. Bennett (Author/Creator)
P.L. De Jager (Author/Creator)
T.H. Mosley (Author/Creator)
P.S. Sachdev (Author/Creator)
R. Schmidt (Author/Creator)
H.R. Warren (Author/Creator)
E. Evangelou (Author/Creator)
D-A Trégouët (Author/Creator)
M.A. Ikram (Author/Creator)
W. Wen (Author/Creator)
C. DeCarli (Author/Creator)
V.K. Srikanth (Author/Creator)
J.W. Jukema (Author/Creator)
E.P. Slagboom (Author/Creator)
S.L.R. Kardia (Author/Creator)
Y. Okada (Author/Creator)
B. Mazoyer (Author/Creator)
J.M. Wardlaw (Author/Creator)
P.A. Nyquist (Author/Creator)
K.A. Mather (Author/Creator)
H.J. Grabe (Author/Creator)
H. Schmidt (Author/Creator)
C.M. van Duijn (Author/Creator)
V. Gudnason (Author/Creator)
W.T. Longstreth (Author/Creator)
L. J. Launer (Author/Creator)
M. Lathrop (Author/Creator)
S. Seshadri (Author/Creator)
C. Tzourio (Author/Creator)
H.H. Adams (Author/Creator)
P.M. Matthews (Author/Creator)
M. Fornage (Author/Creator)
S. Debette (Author/Creator)
Publication Details: Nature Communications, Vol.11(1), Art. 6285
Publisher: Springer Nature
Identifiers: 991005543710307891
Copyright: © 2020 Springer Nature Limited
Murdoch Affiliation: Chemistry and Physics; Information Technology, Mathematics and Statistics
Language: English
Resource Type: Journal article

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Collaboration types: Domestic collaboration; International collaboration
Citation topics: 1 Clinical & Life Sciences; 1.189 Genome Studies; 1.189.455 Genome-Wide Association Studies
Web Of Science research areas: Multidisciplinary Sciences
ESI research areas: Neuroscience & Behavior