Cerebral small vessel disease genomics and its implications across the lifespan

Muralidharan Sargurupremraj; Hideaki Suzuki; Xueqiu Jian; Chloe Sarnowski; Tavia E. Evans; Joshua C. Bis; Gudny Eiriksdottir; Saori Sakaue; Natalie Terzikhan; Mohamad Habes; Wei Zhao; Nicola J. Armstrong; Edith Hofer; Lisa R. Yanek; Saskia P. Hagenaars; Rajan B. Kumar; Erik B. van den Akker; Rebekah E. McWhirter; Stella Trompet; Aniket Mishra; Yasaman Saba; Claudia L. Satizabal; Gregory Beaudet; Laurent Petit; Ami Tsuchida; Laure Zago; Sabrina Schilling; Sigurdur Sigurdsson; Rebecca F. Gottesman; Cora E. Lewis; Neelum T. Aggarwal; Oscar L. Lopez; Jennifer A. Smith; Maria C. Valdes Hernandez; Jeroen van der Grond; Margaret J. Wright; Maria J. Knol; Marcus Dorr; Russell J. Thomson; et al.

doi:10.1038/s41467-020-19111-2

Cerebral small vessel disease genomics and its implications across the lifespan

Muralidharan Sargurupremraj
, Hideaki Suzuki
, Xueqiu Jian
, Chloe Sarnowski
, Tavia E. Evans
, Joshua C. Bis
, Gudny Eiriksdottir
, Saori Sakaue
, Natalie Terzikhan
, Mohamad Habes
, Wei Zhao
, Nicola J. Armstrong
, Edith Hofer
, Lisa R. Yanek
, Saskia P. Hagenaars
, Rajan B. Kumar
, Erik B. van den Akker
, Rebekah E. McWhirter
, Stella Trompet
, Aniket Mishra

Yasaman Saba, Claudia L. Satizabal, Gregory Beaudet, Laurent Petit, Ami Tsuchida, Laure Zago, Sabrina Schilling, Sigurdur Sigurdsson, Rebecca F. Gottesman, Cora E. Lewis, Neelum T. Aggarwal, Oscar L. Lopez, Jennifer A. Smith, Maria C. Valdes Hernandez, Jeroen van der Grond, Margaret J. Wright, Maria J. Knol, Marcus Dorr, Russell J. Thomson, et al.

Western Sydney University

Research output: Contribution to journal › Article › peer-review

169 Citations (Scopus)

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.

Original language	English
Article number	6285
Number of pages	18
Journal	Nature Communications
Volume	11
Issue number	1
DOIs	https://doi.org/10.1038/s41467-020-19111-2
Publication status	Published - Dec 2020

Bibliographical note

Publisher Copyright:
© 2020, The Author(s).

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Â© 2020, The Author(s). Open Access 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/.

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SDG 3 Good Health and Well-being

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10.1038/s41467-020-19111-2

Cite this

Sargurupremraj, M., Suzuki, H., Jian, X., Sarnowski, C., Evans, T. E., Bis, J. C., Eiriksdottir, G., Sakaue, S., Terzikhan, N., Habes, M., Zhao, W., Armstrong, N. J., Hofer, E., Yanek, L. R., Hagenaars, S. P., Kumar, R. B., van den Akker, E. B., McWhirter, R. E., Trompet, S., ... et al. (2020). Cerebral small vessel disease genomics and its implications across the lifespan. Nature Communications, 11(1), Article 6285. https://doi.org/10.1038/s41467-020-19111-2

@article{c79c6076099e40f48ab5dadcbb19dbfc,

title = "Cerebral small vessel disease genomics and its implications across the lifespan",

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{\texttimes}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.",

author = "Muralidharan Sargurupremraj and Hideaki Suzuki and Xueqiu Jian and Chloe Sarnowski and Evans, \{Tavia E.\} and Bis, \{Joshua C.\} and Gudny Eiriksdottir and Saori Sakaue and Natalie Terzikhan and Mohamad Habes and Wei Zhao and Armstrong, \{Nicola J.\} and Edith Hofer and Yanek, \{Lisa R.\} and Hagenaars, \{Saskia P.\} and Kumar, \{Rajan B.\} and \{van den Akker\}, \{Erik B.\} and McWhirter, \{Rebekah E.\} and Stella Trompet and Aniket Mishra and Yasaman Saba and Satizabal, \{Claudia L.\} and Gregory Beaudet and Laurent Petit and Ami Tsuchida and Laure Zago and Sabrina Schilling and Sigurdur Sigurdsson and Gottesman, \{Rebecca F.\} and Lewis, \{Cora E.\} and Aggarwal, \{Neelum T.\} and Lopez, \{Oscar L.\} and Smith, \{Jennifer A.\} and \{Valdes Hernandez\}, \{Maria C.\} and \{van der Grond\}, Jeroen and Wright, \{Margaret J.\} and Knol, \{Maria J.\} and Marcus Dorr and Thomson, \{Russell J.\} and \{et al.\}",

note = "Publisher Copyright: {\textcopyright} 2020, The Author(s).",

year = "2020",

month = dec,

doi = "10.1038/s41467-020-19111-2",

language = "English",

volume = "11",

journal = "Nature Communications",

issn = "2041-1723",

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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, Valdes Hernandez, MC, van der Grond, J, Wright, MJ, Knol, MJ, Dorr, M, Thomson, RJ & et al. 2020, 'Cerebral small vessel disease genomics and its implications across the lifespan', Nature Communications, vol. 11, no. 1, 6285. https://doi.org/10.1038/s41467-020-19111-2

TY - JOUR

T1 - Cerebral small vessel disease genomics and its implications across the lifespan

AU - Sargurupremraj, Muralidharan

AU - Suzuki, Hideaki

AU - Jian, Xueqiu

AU - Sarnowski, Chloe

AU - Evans, Tavia E.

AU - Bis, Joshua C.

AU - Eiriksdottir, Gudny

AU - Sakaue, Saori

AU - Terzikhan, Natalie

AU - Habes, Mohamad

AU - Zhao, Wei

AU - Armstrong, Nicola J.

AU - Hofer, Edith

AU - Yanek, Lisa R.

AU - Hagenaars, Saskia P.

AU - Kumar, Rajan B.

AU - van den Akker, Erik B.

AU - McWhirter, Rebekah E.

AU - Trompet, Stella

AU - Mishra, Aniket

AU - Saba, Yasaman

AU - Satizabal, Claudia L.

AU - Beaudet, Gregory

AU - Petit, Laurent

AU - Tsuchida, Ami

AU - Zago, Laure

AU - Schilling, Sabrina

AU - Sigurdsson, Sigurdur

AU - Gottesman, Rebecca F.

AU - Lewis, Cora E.

AU - Aggarwal, Neelum T.

AU - Lopez, Oscar L.

AU - Smith, Jennifer A.

AU - Valdes Hernandez, Maria C.

AU - van der Grond, Jeroen

AU - Wright, Margaret J.

AU - Knol, Maria J.

AU - Dorr, Marcus

AU - Thomson, Russell J.

AU - et al., null

PY - 2020/12

Y1 - 2020/12

N2 - 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.

AB - 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.

UR - http://hdl.handle.net/1959.7/uws:63036

U2 - 10.1038/s41467-020-19111-2

DO - 10.1038/s41467-020-19111-2

M3 - Article

SN - 2041-1723

VL - 11

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 6285

ER -

Cerebral small vessel disease genomics and its implications across the lifespan

Abstract

Bibliographical note

Open Access - Access Right Statement

UN SDGs

Access to Document

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