Cerebral small vessel disease genomics and its implications across the lifespan

International Headache Genetics Consortium; Lannie Ligthart; Dorret Boomsma; Jouke Jan  Hottenga

doi:10.1038/s41467-020-19111-2

Cerebral small vessel disease genomics and its implications across the lifespan

International Headache Genetics Consortium, Lannie Ligthart, Dorret Boomsma, Jouke Jan Hottenga

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	E-pub ahead of print - 8 Dec 2020

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10.1038/s41467-020-19111-2

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

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@article{c98baeaaca924376aae5b0520460de33,

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 = 2.5×10-7) 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 Chlo{\'e} 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 {Vald{\'e}s Hern{\'a}ndez}, {Maria C.} and {Van Der Grond}, Jeroen and Wright, {Margaret J.} and Knol, {Maria J.} and Marcus D{\"o}rr and Thomson, {Russell J.} and Constance Bordes and {Le Grand}, Quentin and Marie-gabrielle Duperron and Smith, {Albert V.} and Knopman, {David S.} and Schreiner, {Pamela J.} and Evans, {Denis A.} and Rotter, {Jerome I.} and Beiser, {Alexa S.} and Maniega, {Susana Mu{\~n}oz} and Marian Beekman and Julian Trollor and Stott, {David J.} and Vernooij, {Meike W.} and Katharina Wittfeld and Niessen, {Wiro J.} and Aicha Soumar{\'e} and Eric Boerwinkle and Stephen Sidney and Turner, {Stephen T.} and Gail Davies and Anbupalam Thalamuthu and Uwe V{\"o}lker and {Van Buchem}, {Mark A.} and Bryan, {R. Nick} and Jos{\'e}e Dupuis and Bastin, {Mark E.} and David Ames and Alexander Teumer and Philippe Amouyel and Kwok, {John B.} and Robin B{\"u}low and Deary, {Ian J.} and Schofield, {Peter R.} and Henry Brodaty and Jiyang Jiang and Yasuharu Tabara and Kazuya Setoh and Susumu Miyamoto and Kazumichi Yoshida and Manabu Nagata and Yoichiro Kamatani and Fumihiko Matsuda and Psaty, {Bruce M.} and Bennett, {David A.} and {De Jager}, {Philip L.} and Mosley, {Thomas H.} and Sachdev, {Perminder S.} and Reinhold Schmidt and Warren, {Helen R.} and Evangelos Evangelou and David-alexandre Tr{\'e}gou{\"e}t and Ikram, {Mohammad A.} and Wei Wen and Charles Decarli and Srikanth, {Velandai K.} and Jukema, {J. Wouter} and Slagboom, {Eline P.} and Kardia, {Sharon L. R.} and Yukinori Okada and Bernard Mazoyer and Wardlaw, {Joanna M.} and Nyquist, {Paul A.} and Mather, {Karen A.} and Grabe, {Hans J.} and Helena Schmidt and {Van Duijn}, {Cornelia M.} and Vilmundur Gudnason and Longstreth, {William T.} and Launer, {Lenore J.} and Mark Lathrop and Sudha Seshadri and Christophe Tzourio and Adams, {Hieab H.} and Matthews, {Paul M.} and Myriam Fornage and St{\'e}phanie Debette and {International Headache Genetics Consortium} and Lannie Ligthart and Dorret Boomsma and Hottenga, {Jouke Jan}",

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",

}

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 - 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 Headache Genetics Consortium

AU - Ligthart, Lannie

AU - Boomsma, Dorret

AU - Hottenga, Jouke Jan

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.

U2 - 10.1038/s41467-020-19111-2

DO - 10.1038/s41467-020-19111-2

M3 - Article

VL - 11

SP - 1

EP - 18

JO - Nature Communications

JF - Nature Communications

SN - 2041-1723

M1 - 6285

ER -