Cerebral small vessel disease genomics and its implications across the lifespan

Muralidharan Sargurupremraj; Aniket Mishra; Lannie Ligthart; Jouke Jan Hottenga; Dorret I. Boomsma; Stéphanie Debette; International Network against Thrombosis (INVENT) Consortium; International Headache Genomics Consortium (IHGC)

doi:10.1038/s41467-020-19111-2

Cerebral small vessel disease genomics and its implications across the lifespan

Muralidharan Sargurupremraj, Aniket Mishra, Lannie Ligthart, Jouke Jan Hottenga, Dorret I. Boomsma, Stéphanie Debette^*, International Network against Thrombosis (INVENT) Consortium, International Headache Genomics Consortium (IHGC)

^*Corresponding author for this work

Research output: Contribution to Journal › Article › Academic › peer-review

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
Pages (from-to)	1-18
Number of pages	18
Journal	Nature Communications
Volume	11
DOIs	https://doi.org/10.1038/s41467-020-19111-2
Publication status	Published - 8 Dec 2020

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10.1038/s41467-020-19111-2

http://www.nature.com/articles/s41467-020-19111-2

Cite this

Sargurupremraj, M., Mishra, A., Ligthart, L., Hottenga, J. J., Boomsma, D. I., Debette, S., International Network against Thrombosis (INVENT) Consortium, & International Headache Genomics Consortium (IHGC) (2020). Cerebral small vessel disease genomics and its implications across the lifespan. Nature Communications, 11, 1-18. [6285]. https://doi.org/10.1038/s41467-020-19111-2

Sargurupremraj, Muralidharan ; Mishra, Aniket ; Ligthart, Lannie ; Hottenga, Jouke Jan ; Boomsma, Dorret I. ; Debette, Stéphanie ; International Network against Thrombosis (INVENT) Consortium ; International Headache Genomics Consortium (IHGC). / Cerebral small vessel disease genomics and its implications across the lifespan. In: Nature Communications. 2020 ; Vol. 11. pp. 1-18.

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

language = "English",

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journal = "Nature Communications",

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Sargurupremraj, M, Mishra, A, Ligthart, L , Hottenga, JJ , Boomsma, DI, Debette, S, International Network against Thrombosis (INVENT) Consortium & International Headache Genomics Consortium (IHGC) 2020, 'Cerebral small vessel disease genomics and its implications across the lifespan', Nature Communications, vol. 11, 6285, pp. 1-18. https://doi.org/10.1038/s41467-020-19111-2

Cerebral small vessel disease genomics and its implications across the lifespan. / Sargurupremraj, Muralidharan; Mishra, Aniket; Ligthart, Lannie ; Hottenga, Jouke Jan ; Boomsma, Dorret I.; Debette, Stéphanie; International Network against Thrombosis (INVENT) Consortium; International Headache Genomics Consortium (IHGC).

In: Nature Communications, Vol. 11, 6285, 08.12.2020, p. 1-18.

Research output: Contribution to Journal › Article › Academic › peer-review

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, Chloé

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 - Valdés Hernández, Maria C.

AU - van der Grond, Jeroen

AU - Wright, Margaret J.

AU - Knol, Maria J.

AU - Dörr, Marcus

AU - Thomson, Russell J.

AU - Bordes, Constance

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AU - Duperron, Marie Gabrielle

AU - Smith, Albert V.

AU - Knopman, David S.

AU - Schreiner, Pamela J.

AU - Evans, Denis A.

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AU - Bryan, R. Nick

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AU - van den Maagdenberg, Arn M.J.M.

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AU - Boomsma, Dorret I.

AU - Davey Smith, George

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AU - Slagboom, Eline P.

AU - Kardia, Sharon L.R.

AU - Okada, Yukinori

AU - Mazoyer, Bernard

AU - Wardlaw, Joanna M.

AU - Nyquist, Paul A.

AU - Mather, Karen A.

AU - Grabe, Hans J.

AU - Schmidt, Helena

AU - Van Duijn, Cornelia M.

AU - Gudnason, Vilmundur

AU - Longstreth, William T.

AU - Launer, Lenore J.

AU - Lathrop, Mark

AU - Seshadri, Sudha

AU - Tzourio, Christophe

AU - Adams, Hieab H.

AU - Matthews, Paul M.

AU - Fornage, Myriam

AU - Debette, Stéphanie

AU - International Network against Thrombosis (INVENT) Consortium

AU - International Headache Genomics Consortium (IHGC)

PY - 2020/12/8

Y1 - 2020/12/8

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.

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U2 - 10.1038/s41467-020-19111-2

DO - 10.1038/s41467-020-19111-2

M3 - Article

C2 - 33293549

VL - 11

SP - 1

EP - 18

JO - Nature Communications

JF - Nature Communications

SN - 2041-1723

M1 - 6285

ER -

Cerebral small vessel disease genomics and its implications across the lifespan

Abstract

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