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Stroke genetics inf...
Stroke genetics informs drug discovery and risk prediction across ancestries
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- Mishra, A. (author)
- University of Bordeaux
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Malik, R. (author)
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Hachiya, T. (author)
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Jurgenson, T. (author)
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Namba, S. (author)
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Posner, D. C. (author)
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Kamanu, F. K. (author)
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- Koido, M. (author)
- Karolinska Institutet
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Le Grand, Q. (author)
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Shi, M. Y. (author)
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He, Y. Y. (author)
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Georgakis, M. K. (author)
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Caro, I. (author)
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Krebs, K. (author)
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Liaw, Y. C. (author)
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Vaura, F. C. (author)
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Lin, K. (author)
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Winsvold, B. S. (author)
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Srinivasasainagendra, V. (author)
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Parodi, L. (author)
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Bae, H. J. (author)
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Chauhan, G. (author)
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Chong, M. C. R. (author)
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Tomppo, L. (author)
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Akinyemi, R. (author)
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Roshchupkin, G. V. (author)
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Habib, N. (author)
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Thomassen, J. Q. (author)
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Abedi, V. (author)
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Carcel-Marquez, J. (author)
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Nygaard, M. (author)
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Leonard, H. L. (author)
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- Jern, Christina, 1962 (author)
- Gothenburg University,Göteborgs universitet,Institutionen för biomedicin, avdelningen för laboratoriemedicin,Department of Laboratory Medicine
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Yonova-Doing, E. (author)
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Knol, M. J. (author)
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Lewis, A. J. (author)
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- Judy, R. L. (author)
- Gothenburg University,Göteborgs universitet,Institutionen för biomedicin, avdelningen för laboratoriemedicin,Department of Laboratory Medicine
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Ago, T. (author)
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Cho, K. (author)
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Endres, M. (author)
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Gasca, N. C. (author)
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Gudnason, V. (author)
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Jacob, M. A. (author)
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- Jern, Christina, 1962 (author)
- Gothenburg University,Göteborgs universitet,Institutionen för biomedicin, avdelningen för laboratoriemedicin,Department of Laboratory Medicine
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Kamouchi, M. (author)
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Kitazono, T. (author)
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Kittner, S. J. (author)
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Konuma, T. (author)
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Kumar, A. (author)
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- Lacaze, P. (author)
- Karolinska Institutet
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Launer, L. J. (author)
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Li, J. (author)
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- Melander, Olle (author)
- Lund University,Lunds universitet,Kardiovaskulär forskning - hypertoni,Forskargrupper vid Lunds universitet,Cardiovascular Research - Hypertension,Lund University Research Groups
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- Umeå universitet,Allmänmedicin
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- Gothenburg University,Göteborgs universitet,Institutionen för biomedicin, avdelningen för laboratoriemedicin,Department of Laboratory Medicine
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- Putaala, Jukka (author)
- Gothenburg University,Göteborgs universitet,Institutionen för biomedicin, avdelningen för laboratoriemedicin,Department of Laboratory Medicine
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Anderson, C. D. (author)
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- Lemmens, Robin (author)
- Gothenburg University,Göteborgs universitet,Institutionen för biomedicin, avdelningen för laboratoriemedicin,Department of Laboratory Medicine
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van Setten, J. (author)
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van Setten, J. (author)
-
van der Laan, S. W. (author)
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Vonk, J. M. J. (author)
-
Kim, B. J. (author)
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Kim, B. J. (author)
-
Curtze, S. (author)
-
Curtze, S. (author)
-
Tiainen, M. (author)
-
Kinnunen, J. (author)
-
Menon, V. (author)
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Menon, V. (author)
-
Sung, Y. J. (author)
-
Yang, C. R. (author)
-
Saillour-Glenisson, F. (author)
-
Gravel, S. (author)
-
Onland-Moret, N. C. (author)
-
Onland-Moret, N. C. (author)
-
Heath, A. K. (author)
-
Millwood, I. Y. (author)
-
Gieger, C. (author)
-
Ninomiya, T. (author)
-
Grabe, H. J. (author)
-
Jukema, J. W. (author)
-
Rissanen, I. L. (author)
-
Strbian, D. (author)
-
Kim, Y. J. (author)
-
Chen, P. H. (author)
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Mayerhofer, E. (author)
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Howson, J. M. M. (author)
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Irvin, M. R. (author)
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Adams, H. (author)
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Wassertheil-Smoller, S. (author)
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Christensen, K. (author)
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Ikram, M. A. (author)
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Rundek, T. (author)
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Worrall, B. B. (author)
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Lathrop, G. M. (author)
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Riaz, M. (author)
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Simonsick, E. M. (author)
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Korv, J. (author)
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Franca, P. H. C. (author)
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Zand, R. (author)
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Prasad, K. (author)
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Frikke-Schmidt, R. (author)
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de Leeuw, F. E. (author)
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Liman, T. (author)
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Haeusler, K. G. (author)
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Ruigrok, Y. M. (author)
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Heuschmann, P. U. (author)
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Longstreth, W. T. (author)
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Jung, K. J. (author)
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Bastarache, L. (author)
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Pare, G. (author)
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Damrauer, S. M. (author)
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Chasman, D. I. (author)
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Rotter, J. I. (author)
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Anderson, C. D. (author)
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Zwart, J. A. (author)
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Niiranen, T. J. (author)
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Fornage, M. (author)
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Liaw, Y. P. (author)
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Seshadri, S. (author)
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Fernandez-Cadenas, I. (author)
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Walters, R. G. (author)
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Ruff, C. T. (author)
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Owolabi, M. O. (author)
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Huffman, J. E. (author)
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Milani, L. (author)
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Kamatani, Y. (author)
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Dichgans, M. (author)
-
- Debette, S. (author)
- University of Bordeaux
-
Compass Consortium, Compass Consortium (author)
-
Invent Consortium, Invent Consortium (author)
-
Estonian, Biobank (author)
-
Preciseq Consortium, Preciseq Consortium (author)
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FinnGen, Consortium (author)
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Megastroke Consortium, Megastroke Consortium (author)
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Siren Consortium, Siren Consortium (author)
-
Biobank, Japan (author)
-
Charge Consortium, Charge Consortium (author)
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Gigastroke Consortium, Gigastroke Consortium (author)
-
Regeneron Genetics, Ctr (author)
-
Odyssey Study, Odyssey Study (author)
-
Sicfail Study, Sicfail Study (author)
-
Generacion, Study (author)
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Smart Study, Smart Study (author)
-
Helsinki Stroke, Project (author)
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Epic,, Epic, (author)
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(creator_code:org_t)
- 2022-09-30
- 2022
- English.
-
In: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 611, s. 115-123
- Related links:
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https://doi.org/10.1...
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https://umu.diva-por... (primary) (Raw object)
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http://dx.doi.org/10... (free)
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https://gup.ub.gu.se...
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https://doi.org/10.1...
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https://urn.kb.se/re...
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https://lup.lub.lu.s...
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Abstract
Subject headings
Close
- Previous genome-wide association studies (GWASs) of stroke - the second leading cause of death worldwide - were conducted predominantly in populations of European ancestry(1,2). Here, in cross-ancestry GWAS meta-analyses of 110,182 patients who have had a stroke (five ancestries, 33% non-European) and 1,503,898 control individuals, we identify association signals for stroke and its subtypes at 89 (61 new) independent loci: 60 in primary inverse-variance-weighted analyses and 29 in secondary meta-regression and multitrait analyses. On the basis of internal cross-ancestry validation and an independent follow-up in 89,084 additional cases of stroke (30% non-European) and 1,013,843 control individuals, 87% of the primary stroke risk loci and 60% of the secondary stroke risk loci were replicated (P < 0.05). Effect sizes were highly correlated across ancestries. Cross-ancestry fine-mapping, in silico mutagenesis analysis(3), and transcriptome-wide and proteome-wide association analyses revealed putative causal genes (such as SH3PXD2A and FURIN) and variants (such as at GRK5 and NOS3). Using a three-pronged approach(4), we provide genetic evidence for putative drug effects, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 and VCAM1 as possible targets, with drugs already under investigation for stroke for F11 and PROC. A polygenic score integrating cross-ancestry and ancestry-specific stroke GWASs with vascular-risk factor GWASs (integrative polygenic scores) strongly predicted ischaemic stroke in populations of European, East Asian and African ancestry(5). Stroke genetic risk scores were predictive of ischaemic stroke independent of clinical risk factors in 52,600 clinical-trial participants with cardiometabolic disease. Our results provide insights to inform biology, reveal potential drug targets and derive genetic risk prediction tools across ancestries.
Subject headings
- NATURVETENSKAP -- Matematik -- Sannolikhetsteori och statistik (hsv//swe)
- NATURAL SCIENCES -- Mathematics -- Probability Theory and Statistics (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Medicinsk genetik (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Medical Genetics (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Neurologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Neurology (hsv//eng)
Keyword
- genome-wide association
- mendelian randomization
- polygenic risk
- heritability
- statistics
- expression
- brain
- atlas
- regularization
- metaanalysis
- Science & Technology - Other Topics
Publication and Content Type
- ref (subject category)
- art (subject category)
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Mishra, A.
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Malik, R.
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Hachiya, T.
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Jurgenson, T.
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Namba, S.
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Posner, D. C.
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Kamanu, F. K.
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Koido, M.
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Le Grand, Q.
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Shi, M. Y.
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He, Y. Y.
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Georgakis, M. K.
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Caro, I.
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Krebs, K.
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Mayerhofer, E.
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Howson, J. M. M.
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Adams, H.
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Wassertheil-Smol ...
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Christensen, K.
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Ikram, M. A.
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Rundek, T.
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Worrall, B. B.
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Lathrop, G. M.
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Riaz, M.
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Simonsick, E. M.
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Korv, J.
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Franca, P. H. C.
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Zand, R.
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Prasad, K.
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Frikke-Schmidt, ...
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Liman, T.
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Haeusler, K. G.
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Ruigrok, Y. M.
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Heuschmann, P. U ...
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Longstreth, W. T ...
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Jung, K. J.
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Bastarache, L.
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Pare, G.
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Damrauer, S. M.
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Chasman, D. I.
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Rotter, J. I.
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Zwart, J. A.
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Niiranen, T. J.
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Fornage, M.
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Liaw, Y. P.
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Seshadri, S.
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Fernandez-Cadena ...
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Walters, R. G.
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Ruff, C. T.
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Owolabi, M. O.
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Huffman, J. E.
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Milani, L.
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Kamatani, Y.
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Dichgans, M.
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Debette, S.
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Compass Consorti ...
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Invent Consortiu ...
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Estonian, Bioban ...
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Preciseq Consort ...
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FinnGen, Consort ...
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Megastroke Conso ...
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Siren Consortium ...
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Biobank, Japan
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Charge Consortiu ...
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Gigastroke Conso ...
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Regeneron Geneti ...
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Odyssey Study, O ...
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Sicfail Study, S ...
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Generacion, Stud ...
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Smart Study, Sma ...
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Helsinki Stroke, ...
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Epic,, Epic
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- About the subject
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- NATURAL SCIENCES
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NATURAL SCIENCES
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and Mathematics
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and Probability Theo ...
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Basic Medicine
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and Medical Genetics
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Clinical Medicin ...
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and Neurology
- Articles in the publication
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Nature
- By the university
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University of Gothenburg
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Umeå University
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Lund University
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Karolinska Institutet