Cerebral small vessel disease genomics and its implications across the lifespan

Muralidharan Sargurupremraj, Hideaki Suzuki, Xueqiu Jian, Chloé Sarnowski, Tavia E. Evans, Joshua C. Bis, Gudny Eiriksdottir, Saori Sakaue, Natalie Terzikhan, Mohamad Habes, Wei Zhao, Nicola J. Armstrong, Edith Hofer, Lisa R. Yanek, Saskia P. Hagenaars, Rajan B. Kumar, Erik B. Akker, Rebekah E. McWhirter, Stella Trompet, Aniket Mishra, Yasaman Saba, Claudia L. Satizabal, Gregory Beaudet, Laurent Petit, Ami Tsuchida, Laure Zago, Sabrina Schilling, Sigurdur Sigurdsson, Rebecca F. Gottesman, Cora E. Lewis, Neelum T. Aggarwal, Oscar L. Lopez, Jennifer A. Smith, Maria C. Valdés Hernández, Jeroen Grond, Margaret J. Wright, Maria J. Knol, Marcus Dörr, Russell J. Thomson, Constance Bordes, Quentin Grand, Marie-Gabrielle Duperron, Albert V. Smith, David S. Knopman, Pamela J. Schreiner, Denis A. Evans, Jerome I. Rotter, Alexa S. Beiser, Susana Muñoz Maniega, Marian Beekman, Julian Trollor, David J. Stott, Meike W. Vernooij, Katharina Wittfeld, Wiro J. Niessen, Aicha Soumaré, Eric Boerwinkle, Stephen Sidney, Stephen T. Turner, Gail Davies, Anbupalam Thalamuthu, Uwe Völker, Mark A. Buchem, R. Nick Bryan, Josée Dupuis, Mark E. Bastin, David Ames, Alexander Teumer, Philippe Amouyel, John B. Kwok, Robin Bülow, Ian J. Deary, Peter R. Schofield, Henry Brodaty, Jiyang Jiang, Yasuharu Tabara, Kazuya Setoh, Susumu Miyamoto, Kazumichi Yoshida, Manabu Nagata, Yoichiro Kamatani, Fumihiko Matsuda, Bruce M. Psaty, David A. Bennett, Philip L. Jager, Thomas H. Mosley, Perminder S. Sachdev, Reinhold Schmidt, Helen R. Warren, Evangelos Evangelou, David-Alexandre Trégouët, Mohammad A. Ikram, Wei Wen, Charles DeCarli, Velandai K. Srikanth, J. Wouter Jukema, Eline P. Slagboom, Sharon L. R. Kardia, Yukinori Okada, Bernard Mazoyer, Joanna M. Wardlaw, Paul A. Nyquist, Karen A. Mather, Hans J. Grabe, Helena Schmidt, Cornelia M. Duijn, Vilmundur Gudnason, William T. Longstreth, Lenore J. Launer, Mark Lathrop, Sudha Seshadri, Christophe Tzourio, Hieab H. Adams, Paul M. Matthews, Myriam Fornage () and Stéphanie Debette ()
Additional contact information
Muralidharan Sargurupremraj: University of Bordeaux, Inserm, Bordeaux Population Health Research Center
Hideaki Suzuki: Tohoku University, 2-1, Seiryo, Aoba
Xueqiu Jian: University of Texas Health Science Center at Houston McGovern Medical School
Chloé Sarnowski: Boston University School of Public Health
Tavia E. Evans: Erasmus MC
Joshua C. Bis: University of Washington
Gudny Eiriksdottir: Icelandic Heart Association
Saori Sakaue: Osaka University Graduate School of Medicine
Natalie Terzikhan: Erasmus MC
Mohamad Habes: University of Texas Health Sciences Center
Wei Zhao: School of Public Health, University of Michigan
Nicola J. Armstrong: Murdoch University
Edith Hofer: Medical University of Graz
Lisa R. Yanek: Johns Hopkins University School of Medicine
Saskia P. Hagenaars: University of Edinburgh
Rajan B. Kumar: University of California at Davis
Erik B. Akker: Leiden university Medical Center
Rebekah E. McWhirter: University of Tasmania
Stella Trompet: Leiden University Medical Center
Aniket Mishra: University of Bordeaux, Inserm, Bordeaux Population Health Research Center
Yasaman Saba: University of Bordeaux, Inserm, Bordeaux Population Health Research Center
Claudia L. Satizabal: University of Texas Health Sciences Center
Gregory Beaudet: University of Bordeaux, IMN
Laurent Petit: University of Bordeaux, IMN
Ami Tsuchida: University of Bordeaux, IMN
Laure Zago: University of Bordeaux, IMN
Sabrina Schilling: University of Bordeaux, Inserm, Bordeaux Population Health Research Center
Sigurdur Sigurdsson: Icelandic Heart Association
Rebecca F. Gottesman: Johns Hopkins University School of Medicine
Cora E. Lewis: University of Alabama at Birmingham School of Medicine
Neelum T. Aggarwal: Rush University Medical Center
Oscar L. Lopez: University of Pittsburgh
Jennifer A. Smith: School of Public Health, University of Michigan
Maria C. Valdés Hernández: University of Edinburgh
Jeroen Grond: Leiden University medical Center
Margaret J. Wright: The University of Queensland
Maria J. Knol: Erasmus MC
Marcus Dörr: University Medicine Greifswald
Russell J. Thomson: University of Tasmania
Constance Bordes: University of Bordeaux, Inserm, Bordeaux Population Health Research Center
Quentin Grand: University of Bordeaux, Inserm, Bordeaux Population Health Research Center
Marie-Gabrielle Duperron: University of Bordeaux, Inserm, Bordeaux Population Health Research Center
Albert V. Smith: Icelandic Heart Association
David S. Knopman: Mayo Clinic
Pamela J. Schreiner: University of Minnesota School of Public Health
Denis A. Evans: Rush University Medical Center
Jerome I. Rotter: Los Angeles Biomedical Research Institute and Pediatrics at Harbor-UCLA Medical Center
Alexa S. Beiser: Boston University School of Public Health
Susana Muñoz Maniega: University of Edinburgh
Marian Beekman: Leiden university Medical Center
Julian Trollor: University of New South Wales
David J. Stott: Veterinary and Life Sciences, University of Glasgow
Meike W. Vernooij: Erasmus MC
Katharina Wittfeld: German Center for Neurodegenerative Diseases (DZNE), Rostock/Greifswald
Wiro J. Niessen: Erasmus MC
Aicha Soumaré: University of Bordeaux, Inserm, Bordeaux Population Health Research Center
Eric Boerwinkle: University of Texas Health Science Center at Houston School of Public Health
Stephen Sidney: Kaiser Permanente Division of Research
Stephen T. Turner: Division of Nephrology and Hypertension, Mayo Clinic
Gail Davies: Medical University of Graz
Anbupalam Thalamuthu: Los Angeles Biomedical Research Institute and Pediatrics at Harbor-UCLA Medical Center
Uwe Völker: University Medicine Greifswald
Mark A. Buchem: University of Edinburgh
R. Nick Bryan: The University of Texas at Austin Dell Medical School
Josée Dupuis: University of Texas Health Sciences Center
Mark E. Bastin: Medical University of Graz
David Ames: National Ageing Research Institute Royal Melbourne Hospital
Alexander Teumer: Erasmus MC
Philippe Amouyel: Inserm U1167
John B. Kwok: Brain and Mind Centre - The University of Sydney
Robin Bülow: University Medicine Greifswald
Ian J. Deary: Medical University of Graz
Peter R. Schofield: University of New South Wales
Henry Brodaty: Los Angeles Biomedical Research Institute and Pediatrics at Harbor-UCLA Medical Center
Jiyang Jiang: Los Angeles Biomedical Research Institute and Pediatrics at Harbor-UCLA Medical Center
Yasuharu Tabara: Kyoto University Graduate School of Medicine
Kazuya Setoh: Kyoto University Graduate School of Medicine
Susumu Miyamoto: Kyoto University Graduate School of Medicine
Kazumichi Yoshida: Kyoto University Graduate School of Medicine
Manabu Nagata: Kyoto University Graduate School of Medicine
Yoichiro Kamatani: Laboratory for Statistical and Translational Genetics, RIKEN Center for Integrative Medical Sciences, Tsurumi-ku
Fumihiko Matsuda: Kyoto University Graduate School of Medicine
Bruce M. Psaty: University of Washington
David A. Bennett: Rush University Medical Center
Philip L. Jager: Columbia University Medical Center
Thomas H. Mosley: University of Mississippi Medical Center
Perminder S. Sachdev: Los Angeles Biomedical Research Institute and Pediatrics at Harbor-UCLA Medical Center
Reinhold Schmidt: School of Public Health, University of Michigan
Helen R. Warren: Queen Mary University of London
Evangelos Evangelou: School of Public Health, Imperial College London
David-Alexandre Trégouët: University of Bordeaux, Inserm, Bordeaux Population Health Research Center
Mohammad A. Ikram: Erasmus MC
Wei Wen: University of New South Wales
Charles DeCarli: University of California at Davis
Velandai K. Srikanth: University of Tasmania
J. Wouter Jukema: Leiden University Medical Center
Eline P. Slagboom: Leiden university Medical Center
Sharon L. R. Kardia: School of Public Health, University of Michigan
Yukinori Okada: Osaka University Graduate School of Medicine
Bernard Mazoyer: University of Bordeaux, IMN
Joanna M. Wardlaw: University of Edinburgh
Paul A. Nyquist: Johns Hopkins School of Medicine
Karen A. Mather: University of New South Wales
Hans J. Grabe: University Medicine Greifswald
Helena Schmidt: Medical University of Graz
Cornelia M. Duijn: University of Oxford
Vilmundur Gudnason: Icelandic Heart Association
William T. Longstreth: University of Washington
Lenore J. Launer: The National Institutes of Health
Mark Lathrop: University of McGill Genome Center
Sudha Seshadri: University of Texas Health Sciences Center
Christophe Tzourio: University of Bordeaux, Inserm, Bordeaux Population Health Research Center
Hieab H. Adams: Erasmus MC
Paul M. Matthews: Imperial College London
Myriam Fornage: University of Texas Health Science Center at Houston McGovern Medical School
Stéphanie Debette: University of Bordeaux, Inserm, Bordeaux Population Health Research Center

Nature Communications, 2020, vol. 11, issue 1, 1-18

Abstract: 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.

Date: 2020
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-19111-2

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DOI: 10.1038/s41467-020-19111-2

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