New Results
Common genetic variation indicates separate etiologies for periventricular and deep white matter hyperintensities
Nicola J Armstrong, Karen A Mather, Muralidharan Sargurupremraj, Maria J Knol, Rainer Malik, View ORCID ProfileClaudia L Satizabal, Lisa R Yanek, Wen Wei, Vilmundur Gudnason, Nicole D Deuker, Lloyd T Elliott, Edith Hofer, Neda Jahanshad, Shuo Li, Mark A Logue, Michelle Luciano, Markus Scholz, Albert Smith, Stella S Trompet, Dina Vojinovic, Rui Xia, Fidel Alfaro-Almagro, David Ames, Najaf Amin, Philippe Amouyel, Alexa S Beiser, Henry Brodaty, Ian J Deary, Christine Fennema-Notestine, Piyush G Gampwar, Rebecca Gottesman, Ludovica Griffanti, Clifford R Jack, Mark Jenkinson, Jiyang Jain, Brian G Kral, View ORCID ProfileJohn W Kwok, Leonie Lampe, David CM Liewald, Pauline Maillard, Jonathan Marchini, Mark E Bastin, Bernard Mazoyer, Lukas Pirpamer, José Rafael Romero, Gennady V Roshchupkin, View ORCID ProfilePeter R Schofield, Matthias L Schroeter, David J Stott, Anbupalam Thalamuth, Julian Trollor, Christophe Tzourio, Jeroen van der Grond, Meike W Vernooij, Veronica A Witte, Maragret J Wright, Qiong Yang, Moris Zoe, Siggi Siggurdsson, Arno Villringer, Helena Schmidt, Asta L Haberg, Cornelia M Van Duijn, J Wouter Jukema, Martin Dichigans, Ralph L Sacco, Clinton B Wright, William S Kremen, Lewis C Becker, Paul M Thompson, Lenore Launer, Thomas H Mosley, Joanna M Wardlaw, M Afran Ikram, Hieab HH Adams, Reinhold Schmidt, Stephen M Smith, Charles Decarli, Perminder S Sachdev, Myriam Fornage, Stephanie Debbette, Sudha Seshadri, Paul A Nyquist
doi: https://doi.org/10.1101/683367
Nicola J Armstrong
Mathematics and Statistics, Murdoch University, Perth, Australia
Karen A Mather
Centre for Healthy Brain Ageing, School of Psychiatry, University of New South Wales, Sydney, Australia
Neurosciences Research, School of Medical Sciences, University of New South Wales, Sydney Australia
Muralidharan Sargurupremraj
Univ. Bordeaux, Inserm, Bordeaux Population Health Research Center, Bordeaux, France
Maria J Knol
Department of Epidemiology, Erasmus MC, University Medical Center, Rotterdam, the Netherlands
Rainer Malik
Institute for Stroke and Dementia Research (ISD), University Hospital, Ludwig-Maximilians-Universität LMU Munich, Germany
Claudia L Satizabal
Glenn Biggs Institute for Alzheimer’s & Neurodegenerative Diseases, UT Health San Antonio, San Antonio, TX, USA
The Framingham Heart Study, Framingham, MA, USA
Department of Neurology, Boston University School of Medicine, Boston, MA, USA
Lisa R Yanek
GeneSTAR Research Program, Johns Hopkins University School of Medicine, Baltimore, MD, USA
Wen Wei
Centre for Healthy Brain Ageing, School of Psychiatry, University of New South Wales, Sydney, Australia
Vilmundur Gudnason
Icelandic Heart Association, Kopavogur, Iceland
University of Iceland, Reykjavik, Iceland
Nicole D Deuker
John P. Hussman Institute for Human Genomics, University of Miami, Miami, FL, USA
Lloyd T Elliott
Department of Statistics and Actuarial Science, Simon Fraser University, Burnaby, BC, Canada
Wellcome Centre for Integrative Neuroimaging (WIN FMRIB), University of Oxford, Oxford, United Kingdom
Edith Hofer
Clinical Division of Neurogeriatrics, Department of Neurology, Medical University of Graz, Austria
Institute for Medical Informatics, Statistics and Documentation, Medical University of Graz, Austria
Neda Jahanshad
Mark and Mary Neuroimaging and Informatics Institute, Keck School of Medicine of USC, University of Southern California, Marina del Rey, CA, USA
Shuo Li
Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA
Mark A Logue
Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA
National Center for PTSD: Behavioral Science Division, VA Boston Healthcare System, Boston, MA, USA
Department of Psychiatry and Biomedical Genetics Section, Boston University School of Medicine, Boston, MA, USA
Michelle Luciano
Centre for Cognitive Ageing and Cognitive Epidemiology, Psychology, University of Edinburgh, Edinburgh, UK
Markus Scholz
Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany
LIFE Research Center for Civilization Disease, Leipzig, Germany
Albert Smith
University of Iceland, Reykjavik, Iceland
Stella S Trompet
Department of Internal Medicine, section of Gerontology and Geriatrics, Leiden University Medical Center, The Netherlands
Department of Cardiology, Leiden University Medical Center, The Netherlands
Dina Vojinovic
Department of Epidemiology, Erasmus MC, University Medical Center, Rotterdam, the Netherlands
Rui Xia
Brown Foundation Institute of Molecular Medicine, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, USA
Fidel Alfaro-Almagro
Wellcome Centre for Integrative Neuroimaging (WIN FMRIB), University of Oxford, Oxford, United Kingdom
David Ames
National Ageing Research Institute, Parkville, Victoria, Australia
Academic Unit for Psychiatry of Old Age, University of Melbourne, St George’s Hospital, Kew, Australia
Najaf Amin
Department of Epidemiology, Erasmus MC, University Medical Center, Rotterdam, the Netherlands
Philippe Amouyel
Lille University, Inserm, Institut Pasteur de Lille, RID-AGE - Risk factors and molecular determinants of aging-related diseases and Labex Distalz, Lille, France
Alexa S Beiser
The Framingham Heart Study, Framingham, MA, USA
Department of Neurology, Boston University School of Medicine, Boston, MA, USA
Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA
Henry Brodaty
Centre for Healthy Brain Ageing, School of Psychiatry, University of New South Wales, Sydney, Australia
Dementia Centre for Research Collaboration, University of New South Wales, Sydney, Australia
Ian J Deary
Centre for Cognitive Ageing and Cognitive Epidemiology, Psychology, University of Edinburgh, Edinburgh, UK
Christine Fennema-Notestine
Department of Psychiatry, University of California, San Diego, La Jolla, CA, USA
Center for Behavior Genetics of Aging, University of California, San Diego, La Jolla, CA, US
Piyush G Gampwar
Gottfried Schatz Research Center (for Cell Signaling, Metabolism and Aging), Medical University of Graz, Austria
Rebecca Gottesman
Department of Neurology, Cerebrovascular and stroke Division, Johns Hopkins University School of Medicine, Baltimore, MD, USA
Ludovica Griffanti
Wellcome Centre for Integrative Neuroimaging (WIN FMRIB), University of Oxford, Oxford, United Kingdom
Clifford R Jack
Department of Radiology, Mayo Clinic, Rochester, MN, USA
Mark Jenkinson
Wellcome Centre for Integrative Neuroimaging (WIN FMRIB), University of Oxford, Oxford, United Kingdom
Jiyang Jain
Centre for Healthy Brain Ageing, School of Psychiatry, University of New South Wales, Sydney, Australia
Brian G Kral
GeneSTAR Research Program, Johns Hopkins University School of Medicine, Baltimore, MD, USA
John W Kwok
Brain and Mind Centre - The University of Sydney, Camperdown, NSW, Australia
School of Medical Sciences, University of New South Wales, Sydney, Australia
Leonie Lampe
Department of Neurology, Max-Planck-Institute for Human Cognitive and Brain Sciences, Leipzig, Germany
David CM Liewald
Centre for Cognitive Ageing and Cognitive Epidemiology, Psychology, University of Edinburgh, Edinburgh, UK
Pauline Maillard
Imaging of Dementia and Aging (IDeA) Laboratory, Department of Neurology, University of California-Davis, Davis, CA, USA
Jonathan Marchini
Statistical Genetics and Methods at Regeneron Pharmaceuticals, Inc., New York, NY, USA
Mark E Bastin
Centre for Clinical Brain Sciences, University of Edinburgh & Brain Research Imaging Centre, University of Edinburgh, Edinburgh, United Kingdom
Bernard Mazoyer
Univ. Bordeaux, Institut des Maladies Neurodégénératives, Bordeaux, France
Lukas Pirpamer
Clinical Division of Neurogeriatrics, Department of Neurology, Medical University of Graz, Austria
José Rafael Romero
The Framingham Heart Study, Framingham, MA, USA
Department of Neurology, Boston University School of Medicine, Boston, MA, USA
Gennady V Roshchupkin
Department of Epidemiology, Erasmus MC, University Medical Center, Rotterdam, the Netherlands
Department of Radiology and Nuclear Medicine, Erasmus MC, Rotterdam, the Netherlands
Peter R Schofield
Neurosciences Research, School of Medical Sciences, University of New South Wales, Sydney Australia
Matthias L Schroeter
Department of Neurology, Max-Planck-Institute for Human Cognitive and Brain Sciences, Leipzig, Germany
Day Clinic for Cognitive Neurology, University Hospital Leipzig, Leipzig, Germany
David J Stott
Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, United Kingdom
Anbupalam Thalamuth
Centre for Healthy Brain Ageing, School of Psychiatry, University of New South Wales, Sydney, Australia
Julian Trollor
Centre for Healthy Brain Ageing, School of Psychiatry, University of New South Wales, Sydney, Australia
Department of Developmental Disability Neuropsychiatry, School of Psychiatry, University of New South Wales, Sydney, Australia
Christophe Tzourio
Univ. Bordeaux, Inserm, Bordeaux Population Health Research Center, Bordeaux, France
CHU de Bordeaux, Public Health Department, Medical information Department, Bordeaux, France
Jeroen van der Grond
Department of Radiology, Leiden University Medical Center, The Netherlands
Meike W Vernooij
Department of Epidemiology, Erasmus MC, University Medical Center, Rotterdam, the Netherlands
Department of Radiology and Nuclear Medicine, Erasmus MC, Rotterdam, the Netherlands
Veronica A Witte
Department of Neurology, Max-Planck-Institute for Human Cognitive and Brain Sciences, Leipzig, Germany
Collaborative Research Center 1052 Obesity Mechanisms, Faculty of Medicine, University of Leipzig, Leipzig, Germany
Maragret J Wright
Queensland Brain Institute, The University of Queensland, St Lucia, QLD, Australia
Centre for Advanced Imaging, The University of Queensland, St Lucia, QLD, Australia
Qiong Yang
Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA
Moris Zoe
Centre for Advanced Imaging, The University of Queensland, St Lucia, QLD, Australia
Siggi Siggurdsson
Icelandic Heart Association, Kopavogur, Iceland
Arno Villringer
Department of Neurology, Max-Planck-Institute for Human Cognitive and Brain Sciences, Leipzig, Germany
Day Clinic for Cognitive Neurology, University Hospital Leipzig, Leipzig, Germany
Helena Schmidt
Gottfried Schatz Research Center (for Cell Signaling, Metabolism and Aging), Medical University of Graz, Austria
Asta L Haberg
Department of Neuromedicine and Movement Science, Norwegian University of Science and Technology, Trondheim, Norway
Department of Radiology and Nuclear Medicine, Norwegian University of Science and Technology, Trondheim, Norway
Cornelia M Van Duijn
Department of Epidemiology, Erasmus MC, University Medical Center, Rotterdam, the Netherlands
Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom
J Wouter Jukema
Department of Cardiology, Leiden University Medical Center, The Netherlands
Einthoven Laboratory for Experimental Vascular Medicine, LUMC, Leiden, the Netherlands
Martin Dichigans
Institute for Stroke and Dementia Research (ISD), University Hospital, Ludwig-Maximilians-Universität LMU Munich, Germany
German Center for Neurodegenerative Diseases, Munich, Germany
Munich Cluster for Systems Neurology (SyNergy), Munich, Germany
Ralph L Sacco
Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami, Miami, FL, USA
Department of Public Health Sciences, Miller School of Medicine, University of Miami, Miami, FL USA
Department of Neurology, Miller School of Medicine, University of Miami, Miami, FL USA
Evelyn F. McKnight Brain Institute, Department of Neurology, University of Miami, Miami FL USA
Clinton B Wright
National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA
William S Kremen
Department of Psychiatry, University of California, San Diego, La Jolla, CA, USA
Center for Behavior Genetics of Aging, University of California, San Diego, La Jolla, CA, USA
Lewis C Becker
GeneSTAR Research Program, Johns Hopkins University School of Medicine, Baltimore, MD, USA
Paul M Thompson
Mark and Mary Neuroimaging and Informatics Institute, Keck School of Medicine of USC, University of Southern California, Marina del Rey, CA, USA
Lenore Launer
Laboratory of Epidemiology and Population Sciences, National Institute on Aging, Intramural Research Program, National Institutes of Health, Bethesda, MD, USA
Thomas H Mosley
Departemnt of Geriatric Medicine, Memory Impairment and Neurodegenerative Dementia (MIND) Center, University of Mississippi Medical Center, Jackson, MS
Joanna M Wardlaw
Division of Neuroimaging Sciences, Brain Research Imaging Centre, University of Edinburgh. Edinburgh, UK
M Afran Ikram
Department of Epidemiology, Erasmus MC, University Medical Center, Rotterdam, the Netherlands
Hieab HH Adams
Department of Epidemiology, Erasmus MC, University Medical Center, Rotterdam, the Netherlands
Department of Radiology and Nuclear Medicine, Erasmus MC, Rotterdam, the Netherlands
Department of Clinical Genetics, Erasmus MC, Rotterdam, the Netherlands
Reinhold Schmidt
Clinical Division of Neurogeriatrics, Department of Neurology, Medical University of Graz, Austria
Stephen M Smith
Wellcome Centre for Integrative Neuroimaging (WIN FMRIB), University of Oxford, Oxford United Kingdom
Charles Decarli
Alzheimer’s Disease Center and Imaging of Dementia and Aging (IDeA) Laboratory, Department of Neurology and Center for Neuroscience University of California at Davis, Davis, CA USA
Perminder S Sachdev
Centre for Healthy Brain Ageing, School of Psychiatry, University of New South Wales, Sydney, Australia
Neuropsychiatric Institute, Prince of Wales Hospital, Sydney, Australia
Myriam Fornage
Brown Foundation Institute of Molecular Medicine, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, USA
Human Genetics Center, School of Public Health UT, Houston TX, USA
Stephanie Debbette
Univ. Bordeaux, Inserm, Bordeaux Population Health Research Center, Bordeaux, France
CHU de Bordeaux (University Hospital), Department of Neurology, Bordeaux, France
Sudha Seshadri
Glenn Biggs Institute for Alzheimer’s & Neurodegenerative Diseases, UT Health San Antonio, San Antonio, TX, USA
The Framingham Heart Study, Framingham, MA, USA
Department of Neurology, Boston University School of Medicine, Boston, MA, USA
Paul A Nyquist
GeneSTAR Research Program, Johns Hopkins University School of Medicine, Baltimore, MD, USA
Departments of Neurology, Critical Care Medicine, Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA
Critical Care Medicine Department, National Institutes of Health, Bethesda MD, USA
Abstract
We conducted a genome-wide association meta-analysis of two ischemic white matter disease subtypes in the brain, periventricular and deep white matter hyperintensities (PVWMH and DWMH). In 26,654 participants, we found 10 independent genome-wide significant loci only associated with PVWMH, four of which have not been described previously for total WMH burden (16q24.2, 17q21.31, 10q23.1, 7q36.1). Additionally, in both PVWMH and DWMH we observed the previous association of the 17q25.1 locus with total WMH. We found that both phenotypes have shared but also distinct genetic architectures, consistent with both different underlying and related pathophysiology. PVWMH had more extensive genetic overlap with small vessel ischemic stroke, and unique associations with several loci implicated in ischemic stroke. DWMH were characterized by associations with loci previously implicated in vascular as well as astrocytic and neuronal function. Our study confirms the utility of these phenotypes and identifies new candidate genes associated only with PVWMH.
Copyright
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
Posted June 27, 2019.
Common genetic variation indicates separate etiologies for periventricular and deep white matter hyperintensities
Nicola J Armstrong, Karen A Mather, Muralidharan Sargurupremraj, Maria J Knol, Rainer Malik, Claudia L Satizabal, Lisa R Yanek, Wen Wei, Vilmundur Gudnason, Nicole D Deuker, Lloyd T Elliott, Edith Hofer, Neda Jahanshad, Shuo Li, Mark A Logue, Michelle Luciano, Markus Scholz, Albert Smith, Stella S Trompet, Dina Vojinovic, Rui Xia, Fidel Alfaro-Almagro, David Ames, Najaf Amin, Philippe Amouyel, Alexa S Beiser, Henry Brodaty, Ian J Deary, Christine Fennema-Notestine, Piyush G Gampwar, Rebecca Gottesman, Ludovica Griffanti, Clifford R Jack, Mark Jenkinson, Jiyang Jain, Brian G Kral, John W Kwok, Leonie Lampe, David CM Liewald, Pauline Maillard, Jonathan Marchini, Mark E Bastin, Bernard Mazoyer, Lukas Pirpamer, José Rafael Romero, Gennady V Roshchupkin, Peter R Schofield, Matthias L Schroeter, David J Stott, Anbupalam Thalamuth, Julian Trollor, Christophe Tzourio, Jeroen van der Grond, Meike W Vernooij, Veronica A Witte, Maragret J Wright, Qiong Yang, Moris Zoe, Siggi Siggurdsson, Arno Villringer, Helena Schmidt, Asta L Haberg, Cornelia M Van Duijn, J Wouter Jukema, Martin Dichigans, Ralph L Sacco, Clinton B Wright, William S Kremen, Lewis C Becker, Paul M Thompson, Lenore Launer, Thomas H Mosley, Joanna M Wardlaw, M Afran Ikram, Hieab HH Adams, Reinhold Schmidt, Stephen M Smith, Charles Decarli, Perminder S Sachdev, Myriam Fornage, Stephanie Debbette, Sudha Seshadri, Paul A Nyquist
bioRxiv 683367; doi: https://doi.org/10.1101/683367
Common genetic variation indicates separate etiologies for periventricular and deep white matter hyperintensities
Nicola J Armstrong, Karen A Mather, Muralidharan Sargurupremraj, Maria J Knol, Rainer Malik, Claudia L Satizabal, Lisa R Yanek, Wen Wei, Vilmundur Gudnason, Nicole D Deuker, Lloyd T Elliott, Edith Hofer, Neda Jahanshad, Shuo Li, Mark A Logue, Michelle Luciano, Markus Scholz, Albert Smith, Stella S Trompet, Dina Vojinovic, Rui Xia, Fidel Alfaro-Almagro, David Ames, Najaf Amin, Philippe Amouyel, Alexa S Beiser, Henry Brodaty, Ian J Deary, Christine Fennema-Notestine, Piyush G Gampwar, Rebecca Gottesman, Ludovica Griffanti, Clifford R Jack, Mark Jenkinson, Jiyang Jain, Brian G Kral, John W Kwok, Leonie Lampe, David CM Liewald, Pauline Maillard, Jonathan Marchini, Mark E Bastin, Bernard Mazoyer, Lukas Pirpamer, José Rafael Romero, Gennady V Roshchupkin, Peter R Schofield, Matthias L Schroeter, David J Stott, Anbupalam Thalamuth, Julian Trollor, Christophe Tzourio, Jeroen van der Grond, Meike W Vernooij, Veronica A Witte, Maragret J Wright, Qiong Yang, Moris Zoe, Siggi Siggurdsson, Arno Villringer, Helena Schmidt, Asta L Haberg, Cornelia M Van Duijn, J Wouter Jukema, Martin Dichigans, Ralph L Sacco, Clinton B Wright, William S Kremen, Lewis C Becker, Paul M Thompson, Lenore Launer, Thomas H Mosley, Joanna M Wardlaw, M Afran Ikram, Hieab HH Adams, Reinhold Schmidt, Stephen M Smith, Charles Decarli, Perminder S Sachdev, Myriam Fornage, Stephanie Debbette, Sudha Seshadri, Paul A Nyquist
bioRxiv 683367; doi: https://doi.org/10.1101/683367
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