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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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

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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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Arfan} and Tim Spector and J{\"a}rvelin, {Marjo Riitta} and Andres Metspalu and Christian Kubisch and Strachan, {David P.} and Ferrari, {Michel D.} and Belin, {Andrea C.} and Martin Dichgans and Maija Wessman and {van den Maagdenberg}, {Arn M.J.M.} and Zwart, {John Anker} and Boomsma, {Dorret I.} and {Davey Smith}, George and Kari Stefansson and Nicholas Eriksson and Daly, {Mark J.} and Neale, {Benjamin M.} and Jes Olesen and Chasman, {Daniel I.} and Nyholt, {Dale R.} and Aarno Palotie and Ikram, {Mohammad A.} and Wei Wen and Charles DeCarli and Srikanth, {Velandai K.} and Jukema, {J. 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year = "2020",

month = dec,

day = "8",

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

language = "English",

volume = "11",

pages = "1--18",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

}

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

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

AU - Le Grand, Quentin

AU - Duperron, Marie Gabrielle

AU - Smith, Albert V.

AU - Knopman, David S.

AU - Schreiner, Pamela J.

AU - Evans, Denis A.

AU - Rotter, Jerome I.

AU - Beiser, Alexa S.

AU - Maniega, Susana Muñoz

AU - Beekman, Marian

AU - Trollor, Julian

AU - Stott, David J.

AU - Vernooij, Meike W.

AU - Wittfeld, Katharina

AU - Niessen, Wiro J.

AU - Soumaré, Aicha

AU - Boerwinkle, Eric

AU - Sidney, Stephen

AU - Turner, Stephen T.

AU - Davies, Gail

AU - Thalamuthu, Anbupalam

AU - Völker, Uwe

AU - van Buchem, Mark A.

AU - Bryan, R. Nick

AU - Dupuis, Josée

AU - Bastin, Mark E.

AU - Ames, David

AU - Teumer, Alexander

AU - Amouyel, Philippe

AU - Kwok, John B.

AU - Bülow, Robin

AU - Deary, Ian J.

AU - Schofield, Peter R.

AU - Brodaty, Henry

AU - Jiang, Jiyang

AU - Tabara, Yasuharu

AU - Setoh, Kazuya

AU - Miyamoto, Susumu

AU - Yoshida, Kazumichi

AU - Nagata, Manabu

AU - Kamatani, Yoichiro

AU - Matsuda, Fumihiko

AU - Psaty, Bruce M.

AU - Bennett, David A.

AU - De Jager, Philip L.

AU - Mosley, Thomas H.

AU - Sachdev, Perminder S.

AU - Schmidt, Reinhold

AU - Warren, Helen R.

AU - Evangelou, Evangelos

AU - Trégouët, David Alexandre

AU - Amouyel, Philippe

AU - de Andrade, Mariza

AU - Basu, Saonli

AU - Berr, Claudine

AU - Brody, Jennifer A.

AU - Chasman, Daniel I.

AU - Dartigues, Jean Francois

AU - Folsom, Aaron R.

AU - Germain, Marine

AU - de Haan, Hugoline

AU - Heit, John

AU - Houwing-Duitermaat, Jeanine

AU - Kabrhel, Christopher

AU - Kraft, Peter

AU - Legal, Grégoire

AU - Lindström, Sara

AU - Monajemi, Ramin

AU - Morange, Pierre Emmanuel

AU - Psaty, Bruce M.

AU - Reitsma, Pieter H.

AU - Ridker, Paul M.

AU - Rose, Lynda M.

AU - Rosendaal, Frits R.

AU - Saut, Noémie

AU - Slagboom, Eline P.

AU - Smadja, David

AU - Smith, Nicholas L.

AU - Suchon, Pierre

AU - Tang, Weihong

AU - Taylor, Kent D.

AU - Trégouët, David Alexandre

AU - Tzourio, Christophe

AU - de Visser, Marieke C.H.

AU - van Hylckama Vlieg, Astrid

AU - Weng, Lu Chen

AU - Wiggins, Kerri L.

AU - Gormley, Padhraig

AU - Anttila, Verneri

AU - Winsvold, Bendik S.

AU - Palta, Priit

AU - Esko, Tonu

AU - Pers, Tune H.

AU - Farh, Kai How

AU - Cuenca-Leon, Ester

AU - Muona, Mikko

AU - Furlotte, Nicholas A.

AU - Kurth, Tobias

AU - Ingason, Andres

AU - McMahon, George

AU - Ligthart, Lannie

AU - Terwindt, Gisela M.

AU - Kallela, Mikko

AU - Freilinger, Tobias M.

AU - Ran, Caroline

AU - Gordon, Scott G.

AU - Stam, Anine H.

AU - Steinberg, Stacy

AU - Borck, Guntram

AU - Koiranen, Markku

AU - Quaye, Lydia

AU - Adams, Hieab H.

AU - Lehtimäki, Terho

AU - Sarin, Antti Pekka

AU - Wedenoja, Juho

AU - Hinds, David A.

AU - Buring, Julie E.

AU - Schürks, Markus

AU - Ridker, Paul M.

AU - Gudlaug Hrafnsdottir, Maria

AU - Stefansson, Hreinn

AU - Ring, Susan M.

AU - Hottenga, Jouke Jan

AU - Penninx, Brenda W.J.H.

AU - Färkkilä, Markus

AU - Artto, Ville

AU - Kaunisto, Mari

AU - Vepsäläinen, Salli

AU - Malik, Rainer

AU - Heath, Andrew C.

AU - Madden, Pamela A.F.

AU - Martin, Nicholas G.

AU - Montgomery, Grant W.

AU - Kurki, Mitja

AU - Kals, Mart

AU - Mägi, Reedik

AU - Pärn, Kalle

AU - Hämäläinen, Eija

AU - Huang, Hailiang

AU - Byrnes, Andrea E.

AU - Franke, Lude

AU - Huang, Jie

AU - Stergiakouli, Evie

AU - Lee, Phil H.

AU - Sandor, Cynthia

AU - Webber, Caleb

AU - Cader, Zameel

AU - Muller-Myhsok, Bertram

AU - Schreiber, Stefan

AU - Meitinger, Thomas

AU - Eriksson, Johan G.

AU - Salomaa, Veikko

AU - Heikkilä, Kauko

AU - Loehrer, Elizabeth

AU - Uitterlinden, Andre G.

AU - Hofman, Albert

AU - Van Duijn, Cornelia M.

AU - Cherkas, Lynn

AU - Pedersen, Linda M.

AU - Stubhaug, Audun

AU - Nielsen, Christopher S.

AU - Männikkö, Minna

AU - Mihailov, Evelin

AU - Milani, Lili

AU - Göbel, Hartmut

AU - Esserlind, Ann Louise

AU - Francke Christensen, Anne

AU - Folkmann Hansen, Thomas

AU - Werge, Thomas

AU - Kaprio, Jaakko

AU - Aromaa, Arpo J.

AU - Raitakari, Olli

AU - Ikram, M. Arfan

AU - Spector, Tim

AU - Järvelin, Marjo Riitta

AU - Metspalu, Andres

AU - Kubisch, Christian

AU - Strachan, David P.

AU - Ferrari, Michel D.

AU - Belin, Andrea C.

AU - Dichgans, Martin

AU - Wessman, Maija

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

AU - Zwart, John Anker

AU - Boomsma, Dorret I.

AU - Davey Smith, George

AU - Stefansson, Kari

AU - Eriksson, Nicholas

AU - Daly, Mark J.

AU - Neale, Benjamin M.

AU - Olesen, Jes

AU - Chasman, Daniel I.

AU - Nyholt, Dale R.

AU - Palotie, Aarno

AU - Ikram, Mohammad A.

AU - Wen, Wei

AU - DeCarli, Charles

AU - Srikanth, Velandai K.

AU - Jukema, J. Wouter

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.

UR - http://www.scopus.com/inward/record.url?scp=85097295783&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85097295783&partnerID=8YFLogxK

U2 - 10.1038/s41467-020-19111-2

DO - 10.1038/s41467-020-19111-2

M3 - Article

C2 - 33293549

SN - 2041-1723

VL - 11

SP - 1

EP - 18

JO - Nature Communications

JF - Nature Communications

M1 - 6285

ER -

Cerebral small vessel disease genomics and its implications across the lifespan

Abstract

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