Common Genetic Variation Indicates Separate Causes 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; Wei Wen; Vilmundur G Gudnason; Nicole D Dueker; Lloyd T Elliott; Edith Hofer; Joshua Bis; Neda Jahanshad; Shuo Li; Mark A Logue; Michelle Luciano; Markus Scholz; Albert V Smith; Stella 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 Gampawar; Rebecca Gottesman; Ludovica Griffanti; Clifford R Jack, Jr; Mark Jenkinson; Jiyang Jiang; Brian G Kral; John B Kwok; Leonie Lampe; David C M 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 Thalamuthu; Julian Trollor; Christophe Tzourio; Jeroen van der Grond; Meike W Vernooij; Veronica A Witte; Margaret J Wright; Qiong Yang; Zoe Morris; Siggi Siggurdsson; Bruce Psaty; Arno Villringer; Helena Schmidt; Asta K Haberg; Cornelia M van Duijn; J Wouter Jukema; Martin Dichgans; Ralph L Sacco; Clinton B Wright; William S Kremen; Lewis C Becker; Paul M Thompson; Thomas H Mosley; Joanna M Wardlaw; M Arfan Ikram; Hieab H H Adams; Sudha Seshadri; Perminder S Sachdev; Stephen M Smith; Lenore Launer; William Longstreth; Charles DeCarli; Reinhold Schmidt; Myriam Fornage; Stephanie Debette; Paul A Nyquist

doi:10.1161/STROKEAHA.119.027544

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Common Genetic Variation Indicates Separate Causes for Periventricular and Deep White Matter Hyperintensities

Journal article

Open access

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Common Genetic Variation Indicates Separate Causes 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, Wei Wen, Vilmundur G Gudnason, Nicole D Dueker, …

Stroke (1970), Vol.51(7), pp.2111-2121

2020-07

DOI: https://doi.org/10.1161/STROKEAHA.119.027544

PMID: 32517579

Abstract

Brain - diagnostic imaging

Cerebral Small Vessel Diseases - genetics

Genetic Predisposition to Disease - genetics

Genome-Wide Association Study

Humans

Middle Aged

Male

Cerebral Small Vessel Diseases - pathology

White Matter - pathology

White Matter - diagnostic imaging

Cerebral Small Vessel Diseases - diagnostic imaging

Brain - pathology

Female

Aged

Periventricular white matter hyperintensities (WMH; PVWMH) and deep WMH (DWMH) are regional classifications of WMH and reflect proposed differences in cause. In the first study, to date, we undertook genome-wide association analyses of DWMH and PVWMH to show that these phenotypes have different genetic underpinnings. Participants were aged 45 years and older, free of stroke and dementia. We conducted genome-wide association analyses of PVWMH and DWMH in 26,654 participants from CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology), ENIGMA (Enhancing Neuro-Imaging Genetics Through Meta-Analysis), and the UKB (UK Biobank). Regional correlations were investigated using the genome-wide association analyses -pairwise method. Cross-trait genetic correlations between PVWMH, DWMH, stroke, and dementia were estimated using LDSC. In the discovery and replication analysis, for PVWMH only, we found associations on chromosomes 2 ( ), 10q23.1 ( ), and 10q24.33 ( In the much larger combined meta-analysis of all cohorts, we identified ten significant regions for PVWMH: chromosomes 2 (3 regions), 6, 7, 10 (2 regions), 13, 16, and 17q23.1. New loci of interest include 7q36.1 ( ) and 16q24.2. In both the discovery/replication and combined analysis, we found genome-wide significant associations for the 17q25.1 locus for both DWMH and PVWMH. Using gene-based association analysis, 19 genes across all regions were identified for PVWMH only, including the new genes: (2q32.1), (3q27.1), (5q27.1), and (22q13.1). Thirteen genes in the 17q25.1 locus were significant for both phenotypes. More extensive genetic correlations were observed for PVWMH with small vessel ischemic stroke. There were no associations with dementia for either phenotype. Our study confirms these phenotypes have distinct and also shared genetic architectures. Genetic analyses indicated PVWMH was more associated with ischemic stroke whilst DWMH loci were implicated in vascular, astrocyte, and neuronal function. Our study confirms these phenotypes are distinct neuroimaging classifications and identifies new candidate genes associated with PVWMH only.

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Collaboration types: Industry collaboration; Domestic collaboration; International collaboration
Citation topics: 1 Clinical & Life Sciences; 1.52 Neurodegenerative Diseases; 1.52.60 Dementia
Web Of Science research areas: Clinical Neurology; Peripheral Vascular Disease
ESI research areas: Neuroscience & Behavior

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Title: Common Genetic Variation Indicates Separate Causes for Periventricular and Deep White Matter Hyperintensities
Creators: Nicola J Armstrong - Mathematics and Statistics, Murdoch University, Perth, Australia (N.J.A.)
Karen A Mather - Neuroscience Research Australia, Sydney, Australia (K.A.M., P.R.S., A.T.)
Muralidharan Sargurupremraj - University Bordeaux, Inserm, Bordeaux Population Health Research Center, France (M.S., C.T., S.D.)
Maria J Knol - Department of Epidemiology, Erasmus MC, University Medical Center, Rotterdam, the Netherlands (M.J.K., D.V., N.A., G.V.R., M.W.V., C.M.v.D., M.A.I., H.H.H.A.)
Rainer Malik - Institute for Stroke and Dementia Research (ISD), University Hospital, Ludwig-Maximilians-Universität LMU Munich, Germany (R.M., M.D.)
Claudia L Satizabal - Department of Neurology (C.L.S., A.S.B., J.R.R., S.S.), Boston University School of Medicine, MA
Lisa R Yanek - GeneSTAR Research Program (L.R.Y., B.G.K., L.C.B., P.A.N.), Johns Hopkins University School of Medicine, Baltimore, MD
Wei Wen - Centre for Healthy Brain Ageing, School of Psychiatry (K.A.M., W.W., H.B., J.J., A.T., J.T., P.S.S.), University of New South Wales, Sydney, Australia
Vilmundur G Gudnason - University of Iceland, Reykjavik, Iceland (V.G.G., A.V.S.)
Nicole D Dueker - Dr. John T. Macdonald Foundation Department of Human Genetics (R.L.S.), University of Miami, FL
Lloyd T Elliott - Wellcome Centre for Integrative Neuroimaging (WIN FMRIB) (L.T.E., F.A.-A., L.G., M.J., S.M.S.), University of Oxford, United Kingdom
Edith Hofer - Institute for Medical Informatics, Statistics and Documentation, Medical University of Graz, Austria (E.H.)
Joshua Bis - Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA (J.B., B.P., W.L.)
Neda Jahanshad - Mark and Mary Stevens Neuroimaging and Informatics Institute, Keck School of Medicine of USC, University of Southern California, Marina del Rey (N.J., P.M.T.)
Shuo Li - Department of Biostatistics, Boston University School of Public Health, Boston, MA (S.L., M.A.L., A.S.B., Q.Y.)
Mark A Logue - National Center for PTSD: Behavioral Science Division, VA Boston Healthcare System, Boston, MA (M.A.L.)
Michelle Luciano - Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, United Kingdom (M.L., I.J.D., D.C.M.L., M.E.B., J.M.W.)
Markus Scholz - Institute for Medical Informatics, Statistics and Epidemiology (M.S.)
Albert V Smith - University of Iceland, Reykjavik, Iceland (V.G.G., A.V.S.)
Stella Trompet - Department of Cardiology (S.T.), Leiden University Medical Center, the Netherlands
Dina Vojinovic - Department of Epidemiology, Erasmus MC, University Medical Center, Rotterdam, the Netherlands (M.J.K., D.V., N.A., G.V.R., M.W.V., C.M.v.D., M.A.I., H.H.H.A.)
Rui Xia - Brown Foundation Institute of Molecular Medicine, McGovern Medical School, University of Texas Health Science Center at Houston, TX (R.X., M.F.)
Fidel Alfaro-Almagro - Wellcome Centre for Integrative Neuroimaging (WIN FMRIB) (L.T.E., F.A.-A., L.G., M.J., S.M.S.), University of Oxford, United Kingdom
David Ames - Academic Unit for Psychiatry of Old Age, University of Melbourne, St George's Hospital, Kew, Australia (D.A.)
Najaf Amin - Department of Epidemiology, Erasmus MC, University Medical Center, Rotterdam, the Netherlands (M.J.K., D.V., N.A., G.V.R., M.W.V., C.M.v.D., M.A.I., H.H.H.A.)
Philippe Amouyel - Lille University, Inserm, CHU Lille, Institut Pasteur de Lille, RID-AGE (P.A.)
Alexa S Beiser - Department of Biostatistics, Boston University School of Public Health, Boston, MA (S.L., M.A.L., A.S.B., Q.Y.)
Henry Brodaty - Dementia Centre for Research Collaboration (H.B.), University of New South Wales, Sydney, Australia
Ian J Deary - Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, United Kingdom (M.L., I.J.D., D.C.M.L., M.E.B., J.M.W.)
Christine Fennema-Notestine - Center for Behavior Genetics of Aging (C.F.-N.), University of California, San Diego, La Jolla, CA
Piyush G Gampawar - Gottfried Schatz Research Center (for Cell Signaling, Metabolism and Aging), Medical University of Graz, Austria (P.G.G., H.S.)
Rebecca Gottesman - Department of Neurology, Cerebrovascular and stroke Division (R.G.), Johns Hopkins University School of Medicine, Baltimore, MD
Ludovica Griffanti - Wellcome Centre for Integrative Neuroimaging (WIN FMRIB) (L.T.E., F.A.-A., L.G., M.J., S.M.S.), University of Oxford, United Kingdom
Clifford R Jack, Jr - Department of Radiology, Mayo Clinic, Rochester, MN (C.R.J.J.)
Mark Jenkinson - Wellcome Centre for Integrative Neuroimaging (WIN FMRIB) (L.T.E., F.A.-A., L.G., M.J., S.M.S.), University of Oxford, United Kingdom
Jiyang Jiang - Centre for Healthy Brain Ageing, School of Psychiatry (K.A.M., W.W., H.B., J.J., A.T., J.T., P.S.S.), University of New South Wales, Sydney, Australia
Brian G Kral - GeneSTAR Research Program (L.R.Y., B.G.K., L.C.B., P.A.N.), Johns Hopkins University School of Medicine, Baltimore, MD
John B Kwok - Brain and Mind Centre - The University of Sydney, Camperdown, NSW, Australia (J.B.K.)
Leonie Lampe - Department of Neurology, Max-Planck-Institute for Human Cognitive and Brain Sciences, Leipzig, Germany (L.L., V.A.W.)
David C M Liewald - Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, United Kingdom (M.L., I.J.D., D.C.M.L., M.E.B., J.M.W.)
Pauline Maillard - Imaging of Dementia and Aging (IDeA) Laboratory, Department of Neurology, University of California-Davis, Davis, CA (P.M.)
Jonathan Marchini - Statistical Genetics and Methods at Regeneron Pharmaceuticals, Inc, New York, NY (J.M.)
Mark E Bastin - Centre for Clinical Brain Sciences, Edinburgh Imaging, Centre for Cognitive Ageing, University of Edinburgh, United Kingdom (M.E.B., J.M.W.)
Bernard Mazoyer - Institut des Maladies Neurodégénératives, University of Bordeaux, France (B.M.)
Lukas Pirpamer - Clinical Division of Neurogeriatrics, Department of Neurology, Medical University of Graz, Austria (L.P.)
José Rafael Romero - Department of Neurology (C.L.S., A.S.B., J.R.R., S.S.), Boston University School of Medicine, MA
Gennady V Roshchupkin - Department of Radiology and Nuclear Medicine (G.V.R., M.W.V., H.H.H.A.)
Peter R Schofield - Neuroscience Research Australia, Sydney, Australia (K.A.M., P.R.S., A.T.)
Matthias L Schroeter - Day Clinic for Cognitive Neurology, University Hospital Leipzig, Germany (M.L.S., A.V.)
David J Stott - Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, United Kingdom (D.J.S.)
Anbupalam Thalamuthu - Neuroscience Research Australia, Sydney, Australia (K.A.M., P.R.S., A.T.)
Julian Trollor - Department of Developmental Disability Neuropsychiatry, School of Psychiatry (J.T.), University of New South Wales, Sydney, Australia
Christophe Tzourio - CHU de Bordeaux, Public Health Department, Medical information Department, Bordeaux, France (C.T.)
Jeroen van der Grond - Department of Radiology (J.v.d.G.), Leiden University Medical Center, the Netherlands
Meike W Vernooij - Department of Radiology and Nuclear Medicine (G.V.R., M.W.V., H.H.H.A.)
Veronica A Witte - Department of Neurology, Max-Planck-Institute for Human Cognitive and Brain Sciences, Leipzig, Germany (L.L., V.A.W.)
Margaret J Wright - Centre for Advanced Imaging (M.J.W.), The University of Queensland, St Lucia, QLD, Australia
Qiong Yang - Department of Biostatistics, Boston University School of Public Health, Boston, MA (S.L., M.A.L., A.S.B., Q.Y.)
Zoe Morris - Neuroradiology Department, Department of Clinical Neurosciences, Western General Hospital, Edinburgh, United Kingdom (Z.M.)
Siggi Siggurdsson - Department of Neurology (C.L.S., A.S.B., J.R.R., S.S.), Boston University School of Medicine, MA
Bruce Psaty - Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA (J.B., B.P., W.L.)
Arno Villringer - Day Clinic for Cognitive Neurology, University Hospital Leipzig, Germany (M.L.S., A.V.)
Helena Schmidt - Gottfried Schatz Research Center (for Cell Signaling, Metabolism and Aging), Medical University of Graz, Austria (P.G.G., H.S.)
Asta K Haberg - Department of Radiology and Nuclear Medicine (A.K.H.), Norwegian University of Science and Technology, Trondheim, Norway
Cornelia M van Duijn - Nuffield Department of Population Health (C.M.v.D.), University of Oxford, United Kingdom
J Wouter Jukema - Einthoven Laboratory for Experimental Vascular Medicine, LUMC, Leiden, the Netherlands (J.W.J.)
Martin Dichgans - Munich Cluster for Systems Neurology (SyNergy), Germany (M.D.)
Ralph L Sacco - Evelyn F. McKnight Brain Institute, Department of Neurology (R.L.S.), University of Miami, FL
Clinton B Wright - National Institute of Neurological Disorders and Stroke (C.B.W.), National Institutes of Health, Bethesda, MD
William S Kremen - Department of Psychiatry (W.S.K.), University of California, San Diego, La Jolla, CA
Lewis C Becker - GeneSTAR Research Program (L.R.Y., B.G.K., L.C.B., P.A.N.), Johns Hopkins University School of Medicine, Baltimore, MD
Paul M Thompson - Mark and Mary Stevens Neuroimaging and Informatics Institute, Keck School of Medicine of USC, University of Southern California, Marina del Rey (N.J., P.M.T.)
Thomas H Mosley - Department of Geriatric Medicine, Memory Impairment and Neurodegenerative Dementia (MIND) Center, University of Mississippi Medical Center, Jackson (T.H.M.)
Joanna M Wardlaw - Centre for Clinical Brain Sciences, Edinburgh Imaging, Centre for Cognitive Ageing, University of Edinburgh, United Kingdom (M.E.B., J.M.W.)
M Arfan Ikram - Department of Epidemiology, Erasmus MC, University Medical Center, Rotterdam, the Netherlands (M.J.K., D.V., N.A., G.V.R., M.W.V., C.M.v.D., M.A.I., H.H.H.A.)
Hieab H H Adams - Department of Clinical Genetics, Erasmus MC, Rotterdam, the Netherlands (H.H.H.A.)
Sudha Seshadri - Icelandic Heart Association, Kopavogur (V.G.G., S.S.)
Perminder S Sachdev - Neuropsychiatric Institute, Prince of Wales Hospital, Sydney, Australia (P.S.S.)
Stephen M Smith - Wellcome Centre for Integrative Neuroimaging (WIN FMRIB) (L.T.E., F.A.-A., L.G., M.J., S.M.S.), University of Oxford, United Kingdom
Lenore Launer - Laboratory of Epidemiology and Population Sciences, National Institute on Aging, Intramural Research Program (L.L.), National Institutes of Health, Bethesda, MD
William Longstreth - Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA (J.B., B.P., W.L.)
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 (C.D.)
Reinhold Schmidt - Clinical Division of Neurogeriatrics, Department of Neurology, Medical University of Graz, Austria (E.H., R.S.)
Myriam Fornage - Human Genetics Center, School of Public Health UT, Houston, TX (M.F.)
Stephanie Debette - Department of Neurology, CHU de Bordeaux (University Hospital), Bordeaux, France (S.D.)
Paul A Nyquist - Critical Care Medicine Department (P.A.N.), National Institutes of Health, Bethesda, MD
Publication Details: Stroke (1970), Vol.51(7), pp.2111-2121
Publisher: United States
Grant note: MR/M013111/1 / Medical Research Council MR/L023784/2 / Medical Research Council Wellcome Trust R01 AG022381 / NIA NIH HHS R01 AG059874 / NIA NIH HHS U54 EB020403 / NIBIB NIH HHS R01 AG050595 / NIA NIH HHS J-0901 / Parkinson's UK R56 AG058854 / NIA NIH HHS R01 NS062059 / NINDS NIH HHS MC_QA137853 / Medical Research Council G1001245 / Medical Research Council G0700704 / Medical Research Council MC_PC_17228 / Medical Research Council BB/F019394/1 / Biotechnology and Biological Sciences Research Council P41 EB015922 / NIBIB NIH HHS MR/R024065/1 / Medical Research Council MR/N027558/1 / Medical Research Council G0701120 / Medical Research Council
Academic Unit: Leadership Department; Miller School of Medicine; John P. Hussman Institute for Human Genomics; UMMG Department of Neurology
Language: English
Resource Type: Journal article
PMID: 32517579
Record Identifier: 991031578870402976