Genomics of perivascular space burden unravels early mechanisms of cerebral small vessel disease

Perivascular space (PVS) burden is an emerging, poorly understood, magnetic resonance imaging marker of cerebral small vessel disease, a leading cause of stroke and dementia. Genome-wide association studies in up to 40,095 participants (18 population-based cohorts, 66.3 ± 8.6 yr, 96.9% European ance...

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Autores: Duperron, Marie-Gabrielle|||0000-0001-7408-7792, Knol, Maria J.|||0000-0002-3597-1531, Le Grand, Quentin|||0000-0002-9299-0747, Evans, Tavia E.|||0000-0003-2390-286X, Mishra, Aniket|||0000-0002-8141-1543, Tsuchida, Ami|||0000-0001-5160-6203, Roshchupkin, Gennady V.|||0000-0002-3403-2313, Konuma, Takahiro, Trégouët, David-Alexandre|||0000-0001-9084-7800, Romero, Jose Rafael|||0000-0002-1101-2950, Frenzel, Stefan|||0000-0001-5087-5970, Luciano, Michelle|||0000-0002-7306-3008, Hofer, Edith, Bourgey, Mathieu|||0000-0002-8432-834X, Dueker, Nicole D., Delgado Martínez, María Pilar|||0000-0002-1628-4488, Hilal, Saima, Tankard, Rick M.|||0000-0002-8847-9401, Dubost, Florian, Shin, Jean|||0000-0001-7353-5178, Saba, Yasaman|||0000-0002-3549-2493, Armstrong, Nicola|||0000-0002-4477-293X, Bordes, Constance|||0000-0003-3367-1778, Bastin, Mark E., Beiser, Alexa, Brodaty, Henry|||0000-0001-9487-6617, Bülow, Robin|||0000-0003-1884-5784, Carrera, Caty|||0000-0002-0804-0969, Chen, Christopher, Cheng, Ching-Yu|||0000-0003-0655-885X, Deary, Ian J.|||0000-0002-1733-263X, Gampawar, Piyush G., Himali, Jayandra J.|||0000-0003-1391-9481, Jiang, Jiyang|||0000-0002-2147-6302, Kawaguchi, Takahisa, Li, Shuo|||0000-0003-2331-2448, Macalli, Melissa|||0000-0003-3008-8720, Marquis, Pascale, Morris, Zoe, Muñoz Maniega, Susana|||0000-0001-5185-6384, Miyamoto, Susumu, Okawa, Masakazu|||0000-0002-5414-1293, Paradise, Matthew, Parva, Pedram, Rundek, Tatjana|||0000-0002-7115-9815, Sargurupremraj, Muralidharan|||0000-0003-1684-3750, Schilling, Sabrina, Setoh, Kazuya, Soukarieh, Omar, Tabara, Yasuharu, Teumer, Alexander|||0000-0002-8309-094X, Thalamuthu, Anbupalam|||0000-0002-7114-1260, Trollor, Julian|||0000-0002-7685-2977, Valdés Hernández, Maria C., Vernooij, Meike W., Völker, Uwe|||0000-0002-5689-3448, Wittfeld, Katharina|||0000-0003-4383-5043, Wong, Tien Yin|||0000-0002-8448-1264, Wright, Margaret J.|||0000-0001-7133-4970, Zhang, Junyi, Zhao, Wanting, Zhu, Yi-Cheng, Schmidt, Helena|||0000-0001-9773-9992, Sachdev, Perminder S.|||0000-0002-9595-3220, Wen, Wei|||0000-0003-2753-3870, Yoshida, Kazumichi, Joutel, Anne, Satizabal, Claudia L.|||0000-0002-1115-4430, Sacco, Ralph L., Bourque, Guillaume|||0000-0002-3933-9656, Lathrop, Mark, Paus, Tomas|||0000-0003-1495-9338, Fernández Cadenas, Israel|||0000-0003-4821-2363, Yang, Qiong|||0000-0002-3658-1375, Mazoyer, Bernard|||0000-0003-0970-2837, Boutinaud, Philippe, Okada, Yukinori|||0000-0002-0311-8472, Grabe, Hans J.|||0000-0003-3684-4208, Mather, Karen A.|||0000-0003-4143-8941, Schmidt, Reinhold, Joliot, Marc|||0000-0001-7792-308X, Ikram, M. Arfan|||0000-0003-0372-8585, Matsuda, Fumihiko, Tzourio, Christophe|||0000-0002-6517-2984, Wardlaw, Joanna|||0000-0002-9812-6642, Seshadri, Sudha|||0000-0001-6135-2622, Adams, Hieab H. H.|||0000-0003-3687-2508, Debette, Stéphanie|||0000-0001-8675-7968
Tipo de recurso: artículo
Fecha de publicación:2023
País:España
Institución:Universitat Autònoma de Barcelona
Repositorio:Dipòsit Digital de Documents de la UAB
Idioma:inglés
OAI Identifier:oai:ddd.uab.cat:280931
Acceso en línea:https://ddd.uab.cat/record/280931
https://dx.doi.org/urn:doi:10.1038/s41591-023-02268-w
Access Level:acceso abierto
Palabra clave:Neurology
Stroke
Genome-wide association studies
id ES_bdff9b5080e60f323e5ebadb6cbe89b0
oai_identifier_str oai:ddd.uab.cat:280931
network_acronym_str ES
network_name_str España
repository_id_str
dc.title.none.fl_str_mv Genomics of perivascular space burden unravels early mechanisms of cerebral small vessel disease
title Genomics of perivascular space burden unravels early mechanisms of cerebral small vessel disease
spellingShingle Genomics of perivascular space burden unravels early mechanisms of cerebral small vessel disease
Duperron, Marie-Gabrielle|||0000-0001-7408-7792
Neurology
Stroke
Genome-wide association studies
title_short Genomics of perivascular space burden unravels early mechanisms of cerebral small vessel disease
title_full Genomics of perivascular space burden unravels early mechanisms of cerebral small vessel disease
title_fullStr Genomics of perivascular space burden unravels early mechanisms of cerebral small vessel disease
title_full_unstemmed Genomics of perivascular space burden unravels early mechanisms of cerebral small vessel disease
title_sort Genomics of perivascular space burden unravels early mechanisms of cerebral small vessel disease
dc.creator.none.fl_str_mv Duperron, Marie-Gabrielle|||0000-0001-7408-7792
Knol, Maria J.|||0000-0002-3597-1531
Le Grand, Quentin|||0000-0002-9299-0747
Evans, Tavia E.|||0000-0003-2390-286X
Mishra, Aniket|||0000-0002-8141-1543
Tsuchida, Ami|||0000-0001-5160-6203
Roshchupkin, Gennady V.|||0000-0002-3403-2313
Konuma, Takahiro
Trégouët, David-Alexandre|||0000-0001-9084-7800
Romero, Jose Rafael|||0000-0002-1101-2950
Frenzel, Stefan|||0000-0001-5087-5970
Luciano, Michelle|||0000-0002-7306-3008
Hofer, Edith
Bourgey, Mathieu|||0000-0002-8432-834X
Dueker, Nicole D.
Delgado Martínez, María Pilar|||0000-0002-1628-4488
Hilal, Saima
Tankard, Rick M.|||0000-0002-8847-9401
Dubost, Florian
Shin, Jean|||0000-0001-7353-5178
Saba, Yasaman|||0000-0002-3549-2493
Armstrong, Nicola|||0000-0002-4477-293X
Bordes, Constance|||0000-0003-3367-1778
Bastin, Mark E.
Beiser, Alexa
Brodaty, Henry|||0000-0001-9487-6617
Bülow, Robin|||0000-0003-1884-5784
Carrera, Caty|||0000-0002-0804-0969
Chen, Christopher
Cheng, Ching-Yu|||0000-0003-0655-885X
Deary, Ian J.|||0000-0002-1733-263X
Gampawar, Piyush G.
Himali, Jayandra J.|||0000-0003-1391-9481
Jiang, Jiyang|||0000-0002-2147-6302
Kawaguchi, Takahisa
Li, Shuo|||0000-0003-2331-2448
Macalli, Melissa|||0000-0003-3008-8720
Marquis, Pascale
Morris, Zoe
Muñoz Maniega, Susana|||0000-0001-5185-6384
Miyamoto, Susumu
Okawa, Masakazu|||0000-0002-5414-1293
Paradise, Matthew
Parva, Pedram
Rundek, Tatjana|||0000-0002-7115-9815
Sargurupremraj, Muralidharan|||0000-0003-1684-3750
Schilling, Sabrina
Setoh, Kazuya
Soukarieh, Omar
Tabara, Yasuharu
Teumer, Alexander|||0000-0002-8309-094X
Thalamuthu, Anbupalam|||0000-0002-7114-1260
Trollor, Julian|||0000-0002-7685-2977
Valdés Hernández, Maria C.
Vernooij, Meike W.
Völker, Uwe|||0000-0002-5689-3448
Wittfeld, Katharina|||0000-0003-4383-5043
Wong, Tien Yin|||0000-0002-8448-1264
Wright, Margaret J.|||0000-0001-7133-4970
Zhang, Junyi
Zhao, Wanting
Zhu, Yi-Cheng
Schmidt, Helena|||0000-0001-9773-9992
Sachdev, Perminder S.|||0000-0002-9595-3220
Wen, Wei|||0000-0003-2753-3870
Yoshida, Kazumichi
Joutel, Anne
Satizabal, Claudia L.|||0000-0002-1115-4430
Sacco, Ralph L.
Bourque, Guillaume|||0000-0002-3933-9656
Lathrop, Mark
Paus, Tomas|||0000-0003-1495-9338
Fernández Cadenas, Israel|||0000-0003-4821-2363
Yang, Qiong|||0000-0002-3658-1375
Mazoyer, Bernard|||0000-0003-0970-2837
Boutinaud, Philippe
Okada, Yukinori|||0000-0002-0311-8472
Grabe, Hans J.|||0000-0003-3684-4208
Mather, Karen A.|||0000-0003-4143-8941
Schmidt, Reinhold
Joliot, Marc|||0000-0001-7792-308X
Ikram, M. Arfan|||0000-0003-0372-8585
Matsuda, Fumihiko
Tzourio, Christophe|||0000-0002-6517-2984
Wardlaw, Joanna|||0000-0002-9812-6642
Seshadri, Sudha|||0000-0001-6135-2622
Adams, Hieab H. H.|||0000-0003-3687-2508
Debette, Stéphanie|||0000-0001-8675-7968
author Duperron, Marie-Gabrielle|||0000-0001-7408-7792
author_facet Duperron, Marie-Gabrielle|||0000-0001-7408-7792
Knol, Maria J.|||0000-0002-3597-1531
Le Grand, Quentin|||0000-0002-9299-0747
Evans, Tavia E.|||0000-0003-2390-286X
Mishra, Aniket|||0000-0002-8141-1543
Tsuchida, Ami|||0000-0001-5160-6203
Roshchupkin, Gennady V.|||0000-0002-3403-2313
Konuma, Takahiro
Trégouët, David-Alexandre|||0000-0001-9084-7800
Romero, Jose Rafael|||0000-0002-1101-2950
Frenzel, Stefan|||0000-0001-5087-5970
Luciano, Michelle|||0000-0002-7306-3008
Hofer, Edith
Bourgey, Mathieu|||0000-0002-8432-834X
Dueker, Nicole D.
Delgado Martínez, María Pilar|||0000-0002-1628-4488
Hilal, Saima
Tankard, Rick M.|||0000-0002-8847-9401
Dubost, Florian
Shin, Jean|||0000-0001-7353-5178
Saba, Yasaman|||0000-0002-3549-2493
Armstrong, Nicola|||0000-0002-4477-293X
Bordes, Constance|||0000-0003-3367-1778
Bastin, Mark E.
Beiser, Alexa
Brodaty, Henry|||0000-0001-9487-6617
Bülow, Robin|||0000-0003-1884-5784
Carrera, Caty|||0000-0002-0804-0969
Chen, Christopher
Cheng, Ching-Yu|||0000-0003-0655-885X
Deary, Ian J.|||0000-0002-1733-263X
Gampawar, Piyush G.
Himali, Jayandra J.|||0000-0003-1391-9481
Jiang, Jiyang|||0000-0002-2147-6302
Kawaguchi, Takahisa
Li, Shuo|||0000-0003-2331-2448
Macalli, Melissa|||0000-0003-3008-8720
Marquis, Pascale
Morris, Zoe
Muñoz Maniega, Susana|||0000-0001-5185-6384
Miyamoto, Susumu
Okawa, Masakazu|||0000-0002-5414-1293
Paradise, Matthew
Parva, Pedram
Rundek, Tatjana|||0000-0002-7115-9815
Sargurupremraj, Muralidharan|||0000-0003-1684-3750
Schilling, Sabrina
Setoh, Kazuya
Soukarieh, Omar
Tabara, Yasuharu
Teumer, Alexander|||0000-0002-8309-094X
Thalamuthu, Anbupalam|||0000-0002-7114-1260
Trollor, Julian|||0000-0002-7685-2977
Valdés Hernández, Maria C.
Vernooij, Meike W.
Völker, Uwe|||0000-0002-5689-3448
Wittfeld, Katharina|||0000-0003-4383-5043
Wong, Tien Yin|||0000-0002-8448-1264
Wright, Margaret J.|||0000-0001-7133-4970
Zhang, Junyi
Zhao, Wanting
Zhu, Yi-Cheng
Schmidt, Helena|||0000-0001-9773-9992
Sachdev, Perminder S.|||0000-0002-9595-3220
Wen, Wei|||0000-0003-2753-3870
Yoshida, Kazumichi
Joutel, Anne
Satizabal, Claudia L.|||0000-0002-1115-4430
Sacco, Ralph L.
Bourque, Guillaume|||0000-0002-3933-9656
Lathrop, Mark
Paus, Tomas|||0000-0003-1495-9338
Fernández Cadenas, Israel|||0000-0003-4821-2363
Yang, Qiong|||0000-0002-3658-1375
Mazoyer, Bernard|||0000-0003-0970-2837
Boutinaud, Philippe
Okada, Yukinori|||0000-0002-0311-8472
Grabe, Hans J.|||0000-0003-3684-4208
Mather, Karen A.|||0000-0003-4143-8941
Schmidt, Reinhold
Joliot, Marc|||0000-0001-7792-308X
Ikram, M. Arfan|||0000-0003-0372-8585
Matsuda, Fumihiko
Tzourio, Christophe|||0000-0002-6517-2984
Wardlaw, Joanna|||0000-0002-9812-6642
Seshadri, Sudha|||0000-0001-6135-2622
Adams, Hieab H. H.|||0000-0003-3687-2508
Debette, Stéphanie|||0000-0001-8675-7968
author_role author
author2 Knol, Maria J.|||0000-0002-3597-1531
Le Grand, Quentin|||0000-0002-9299-0747
Evans, Tavia E.|||0000-0003-2390-286X
Mishra, Aniket|||0000-0002-8141-1543
Tsuchida, Ami|||0000-0001-5160-6203
Roshchupkin, Gennady V.|||0000-0002-3403-2313
Konuma, Takahiro
Trégouët, David-Alexandre|||0000-0001-9084-7800
Romero, Jose Rafael|||0000-0002-1101-2950
Frenzel, Stefan|||0000-0001-5087-5970
Luciano, Michelle|||0000-0002-7306-3008
Hofer, Edith
Bourgey, Mathieu|||0000-0002-8432-834X
Dueker, Nicole D.
Delgado Martínez, María Pilar|||0000-0002-1628-4488
Hilal, Saima
Tankard, Rick M.|||0000-0002-8847-9401
Dubost, Florian
Shin, Jean|||0000-0001-7353-5178
Saba, Yasaman|||0000-0002-3549-2493
Armstrong, Nicola|||0000-0002-4477-293X
Bordes, Constance|||0000-0003-3367-1778
Bastin, Mark E.
Beiser, Alexa
Brodaty, Henry|||0000-0001-9487-6617
Bülow, Robin|||0000-0003-1884-5784
Carrera, Caty|||0000-0002-0804-0969
Chen, Christopher
Cheng, Ching-Yu|||0000-0003-0655-885X
Deary, Ian J.|||0000-0002-1733-263X
Gampawar, Piyush G.
Himali, Jayandra J.|||0000-0003-1391-9481
Jiang, Jiyang|||0000-0002-2147-6302
Kawaguchi, Takahisa
Li, Shuo|||0000-0003-2331-2448
Macalli, Melissa|||0000-0003-3008-8720
Marquis, Pascale
Morris, Zoe
Muñoz Maniega, Susana|||0000-0001-5185-6384
Miyamoto, Susumu
Okawa, Masakazu|||0000-0002-5414-1293
Paradise, Matthew
Parva, Pedram
Rundek, Tatjana|||0000-0002-7115-9815
Sargurupremraj, Muralidharan|||0000-0003-1684-3750
Schilling, Sabrina
Setoh, Kazuya
Soukarieh, Omar
Tabara, Yasuharu
Teumer, Alexander|||0000-0002-8309-094X
Thalamuthu, Anbupalam|||0000-0002-7114-1260
Trollor, Julian|||0000-0002-7685-2977
Valdés Hernández, Maria C.
Vernooij, Meike W.
Völker, Uwe|||0000-0002-5689-3448
Wittfeld, Katharina|||0000-0003-4383-5043
Wong, Tien Yin|||0000-0002-8448-1264
Wright, Margaret J.|||0000-0001-7133-4970
Zhang, Junyi
Zhao, Wanting
Zhu, Yi-Cheng
Schmidt, Helena|||0000-0001-9773-9992
Sachdev, Perminder S.|||0000-0002-9595-3220
Wen, Wei|||0000-0003-2753-3870
Yoshida, Kazumichi
Joutel, Anne
Satizabal, Claudia L.|||0000-0002-1115-4430
Sacco, Ralph L.
Bourque, Guillaume|||0000-0002-3933-9656
Lathrop, Mark
Paus, Tomas|||0000-0003-1495-9338
Fernández Cadenas, Israel|||0000-0003-4821-2363
Yang, Qiong|||0000-0002-3658-1375
Mazoyer, Bernard|||0000-0003-0970-2837
Boutinaud, Philippe
Okada, Yukinori|||0000-0002-0311-8472
Grabe, Hans J.|||0000-0003-3684-4208
Mather, Karen A.|||0000-0003-4143-8941
Schmidt, Reinhold
Joliot, Marc|||0000-0001-7792-308X
Ikram, M. Arfan|||0000-0003-0372-8585
Matsuda, Fumihiko
Tzourio, Christophe|||0000-0002-6517-2984
Wardlaw, Joanna|||0000-0002-9812-6642
Seshadri, Sudha|||0000-0001-6135-2622
Adams, Hieab H. H.|||0000-0003-3687-2508
Debette, Stéphanie|||0000-0001-8675-7968
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dc.contributor.none.fl_str_mv Universitat Autònoma de Barcelona
dc.subject.none.fl_str_mv Neurology
Stroke
Genome-wide association studies
topic Neurology
Stroke
Genome-wide association studies
description Perivascular space (PVS) burden is an emerging, poorly understood, magnetic resonance imaging marker of cerebral small vessel disease, a leading cause of stroke and dementia. Genome-wide association studies in up to 40,095 participants (18 population-based cohorts, 66.3 ± 8.6 yr, 96.9% European ancestry) revealed 24 genome-wide significant PVS risk loci, mainly in the white matter. These were associated with white matter PVS already in young adults (N = 1,748; 22.1 ± 2.3 yr) and were enriched in early-onset leukodystrophy genes and genes expressed in fetal brain endothelial cells, suggesting early-life mechanisms. In total, 53% of white matter PVS risk loci showed nominally significant associations (27% after multiple-testing correction) in a Japanese population-based cohort (N = 2,862; 68.3 ± 5.3 yr). Mendelian randomization supported causal associations of high blood pressure with basal ganglia and hippocampal PVS, and of basal ganglia PVS and hippocampal PVS with stroke, accounting for blood pressure. Our findings provide insight into the biology of PVS and cerebral small vessel disease, pointing to pathways involving extracellular matrix, membrane transport and developmental processes, and the potential for genetically informed prioritization of drug targets. Genomic analyses of large population-based cohorts uncover the genetic determinants of perivascular space burden, an MRI marker of cerebral small vessel disease, across the lifespan, and reveal potential pathways implicated in the etiology of stroke and dementia.
publishDate 2023
dc.date.none.fl_str_mv 2
2023-01-01
2023
2023-01-01
dc.type.none.fl_str_mv Article
http://purl.org/coar/resource_type/c_6501
VoR
http://purl.org/coar/version/c_970fb48d4fbd8a85
dc.type.openaire.fl_str_mv info:eu-repo/semantics/article
format article
dc.identifier.none.fl_str_mv https://ddd.uab.cat/record/280931
https://dx.doi.org/urn:doi:10.1038/s41591-023-02268-w
url https://ddd.uab.cat/record/280931
https://dx.doi.org/urn:doi:10.1038/s41591-023-02268-w
dc.language.none.fl_str_mv Inglés
eng
language_invalid_str_mv Inglés
language eng
dc.relation.none.fl_str_mv Ministerio de Economía y Competitividad https://doi.org/10.13039/501100003329 PI14/01535
Instituto de Salud Carlos III https://doi.org/10.13039/501100004587 PI17/02222
dc.rights.none.fl_str_mv open access
http://purl.org/coar/access_right/c_abf2
https://creativecommons.org/licenses/by/4.0/
dc.rights.openaire.fl_str_mv info:eu-repo/semantics/openAccess
rights_invalid_str_mv open access
http://purl.org/coar/access_right/c_abf2
https://creativecommons.org/licenses/by/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.source.none.fl_str_mv reponame:Dipòsit Digital de Documents de la UAB
instname:Universitat Autònoma de Barcelona
instname_str Universitat Autònoma de Barcelona
reponame_str Dipòsit Digital de Documents de la UAB
collection Dipòsit Digital de Documents de la UAB
repository.name.fl_str_mv
repository.mail.fl_str_mv
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spelling Genomics of perivascular space burden unravels early mechanisms of cerebral small vessel diseaseDuperron, Marie-Gabrielle|||0000-0001-7408-7792Knol, Maria J.|||0000-0002-3597-1531Le Grand, Quentin|||0000-0002-9299-0747Evans, Tavia E.|||0000-0003-2390-286XMishra, Aniket|||0000-0002-8141-1543Tsuchida, Ami|||0000-0001-5160-6203Roshchupkin, Gennady V.|||0000-0002-3403-2313Konuma, TakahiroTrégouët, David-Alexandre|||0000-0001-9084-7800Romero, Jose Rafael|||0000-0002-1101-2950Frenzel, Stefan|||0000-0001-5087-5970Luciano, Michelle|||0000-0002-7306-3008Hofer, EdithBourgey, Mathieu|||0000-0002-8432-834XDueker, Nicole D.Delgado Martínez, María Pilar|||0000-0002-1628-4488Hilal, SaimaTankard, Rick M.|||0000-0002-8847-9401Dubost, FlorianShin, Jean|||0000-0001-7353-5178Saba, Yasaman|||0000-0002-3549-2493Armstrong, Nicola|||0000-0002-4477-293XBordes, Constance|||0000-0003-3367-1778Bastin, Mark E.Beiser, AlexaBrodaty, Henry|||0000-0001-9487-6617Bülow, Robin|||0000-0003-1884-5784Carrera, Caty|||0000-0002-0804-0969Chen, ChristopherCheng, Ching-Yu|||0000-0003-0655-885XDeary, Ian J.|||0000-0002-1733-263XGampawar, Piyush G.Himali, Jayandra J.|||0000-0003-1391-9481Jiang, Jiyang|||0000-0002-2147-6302Kawaguchi, TakahisaLi, Shuo|||0000-0003-2331-2448Macalli, Melissa|||0000-0003-3008-8720Marquis, PascaleMorris, ZoeMuñoz Maniega, Susana|||0000-0001-5185-6384Miyamoto, SusumuOkawa, Masakazu|||0000-0002-5414-1293Paradise, MatthewParva, PedramRundek, Tatjana|||0000-0002-7115-9815Sargurupremraj, Muralidharan|||0000-0003-1684-3750Schilling, SabrinaSetoh, KazuyaSoukarieh, OmarTabara, YasuharuTeumer, Alexander|||0000-0002-8309-094XThalamuthu, Anbupalam|||0000-0002-7114-1260Trollor, Julian|||0000-0002-7685-2977Valdés Hernández, Maria C.Vernooij, Meike W.Völker, Uwe|||0000-0002-5689-3448Wittfeld, Katharina|||0000-0003-4383-5043Wong, Tien Yin|||0000-0002-8448-1264Wright, Margaret J.|||0000-0001-7133-4970Zhang, JunyiZhao, WantingZhu, Yi-ChengSchmidt, Helena|||0000-0001-9773-9992Sachdev, Perminder S.|||0000-0002-9595-3220Wen, Wei|||0000-0003-2753-3870Yoshida, KazumichiJoutel, AnneSatizabal, Claudia L.|||0000-0002-1115-4430Sacco, Ralph L.Bourque, Guillaume|||0000-0002-3933-9656Lathrop, MarkPaus, Tomas|||0000-0003-1495-9338Fernández Cadenas, Israel|||0000-0003-4821-2363Yang, Qiong|||0000-0002-3658-1375Mazoyer, Bernard|||0000-0003-0970-2837Boutinaud, PhilippeOkada, Yukinori|||0000-0002-0311-8472Grabe, Hans J.|||0000-0003-3684-4208Mather, Karen A.|||0000-0003-4143-8941Schmidt, ReinholdJoliot, Marc|||0000-0001-7792-308XIkram, M. Arfan|||0000-0003-0372-8585Matsuda, FumihikoTzourio, Christophe|||0000-0002-6517-2984Wardlaw, Joanna|||0000-0002-9812-6642Seshadri, Sudha|||0000-0001-6135-2622Adams, Hieab H. H.|||0000-0003-3687-2508Debette, Stéphanie|||0000-0001-8675-7968NeurologyStrokeGenome-wide association studiesPerivascular space (PVS) burden is an emerging, poorly understood, magnetic resonance imaging marker of cerebral small vessel disease, a leading cause of stroke and dementia. Genome-wide association studies in up to 40,095 participants (18 population-based cohorts, 66.3 ± 8.6 yr, 96.9% European ancestry) revealed 24 genome-wide significant PVS risk loci, mainly in the white matter. These were associated with white matter PVS already in young adults (N = 1,748; 22.1 ± 2.3 yr) and were enriched in early-onset leukodystrophy genes and genes expressed in fetal brain endothelial cells, suggesting early-life mechanisms. In total, 53% of white matter PVS risk loci showed nominally significant associations (27% after multiple-testing correction) in a Japanese population-based cohort (N = 2,862; 68.3 ± 5.3 yr). Mendelian randomization supported causal associations of high blood pressure with basal ganglia and hippocampal PVS, and of basal ganglia PVS and hippocampal PVS with stroke, accounting for blood pressure. Our findings provide insight into the biology of PVS and cerebral small vessel disease, pointing to pathways involving extracellular matrix, membrane transport and developmental processes, and the potential for genetically informed prioritization of drug targets. Genomic analyses of large population-based cohorts uncover the genetic determinants of perivascular space burden, an MRI marker of cerebral small vessel disease, across the lifespan, and reveal potential pathways implicated in the etiology of stroke and dementia.Universitat Autònoma de Barcelona 22023-01-0120232023-01-01Articlehttp://purl.org/coar/resource_type/c_6501VoRhttp://purl.org/coar/version/c_970fb48d4fbd8a85info:eu-repo/semantics/articleapplication/pdfhttps://ddd.uab.cat/record/280931https://dx.doi.org/urn:doi:10.1038/s41591-023-02268-wreponame:Dipòsit Digital de Documents de la UABinstname:Universitat Autònoma de BarcelonaInglésengMinisterio de Economía y Competitividad https://doi.org/10.13039/501100003329 PI14/01535Instituto de Salud Carlos III https://doi.org/10.13039/501100004587 PI17/02222open accesshttp://purl.org/coar/access_right/c_abf2Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.https://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccessoai:ddd.uab.cat:2809312026-06-06T12:50:31Z
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