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

Stroke, vol. 51, pp. 2111–2121

Abstract

Background and Purpose: 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. Methods: 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. Results: In the discovery and replication analysis, for PVWMH only, we found associations on chromosomes 2 ( NBEAL ), 10q23.1 ( TSPAN14/FAM231A ), and 10q24.33 ( SH3PXD2A). 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 ( NOS3 ) 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: CALCRL (2q32.1), KLHL24 (3q27.1), VCAN (5q27.1), and POLR2F (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. Conclusions: 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.

Authors 86

1. Nicola J. Armstrong

   Murdoch University

   Affiliation as printed

   Mathematics and Statistics, Murdoch University, Perth, Australia (N.J.A.)

   Nicola J. Armstrong Mathematics and Statistics, Murdoch University, Perth, Australia (N.J.A.)

2. Karen A. Mather

   UNSW Sydney · Centre for Healthy Brain Ageing · Neuroscience Research Australia

   Affiliation as printed

   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

   Neuroscience Research Australia, Sydney, Australia (K.A.M., P.R.S., A.T.)

   Karen A. Mather 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. Neuroscience Research Australia, Sydney, Australia (K.A.M., P.R.S., A.T.)

3. Muralidharan Sargurupremraj

   Inserm · Bordeaux Population Health

   Affiliation as printed

   University Bordeaux, Inserm, Bordeaux Population Health Research Center, France (M.S., C.T., S.D.)

   Muralidharan Sargurupremraj University Bordeaux, Inserm, Bordeaux Population Health Research Center, France (M.S., C.T., S.D.)

4. Maria J. Knol

   Erasmus MC

   Affiliation as printed

   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.)

   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.)

5. Rainer Malik

   LMU Klinikum · Institut für Schlaganfall- und Demenzforschung · Ludwig-Maximilians-Universität München

   Affiliation as printed

   Institute for Stroke and Dementia Research (ISD), University Hospital, Ludwig-Maximilians-Universität LMU Munich, Germany (R.M., M.D.)

6. Claudia Liliana Satizábal

   Boston University · The University of Texas at San Antonio Health Science Center · Framingham Heart Study

   Affiliation as printed

   Department of Neurology (C.L.S., A.S.B., J.R.R., S.S.), Boston University School of Medicine, MA

   Glenn Biggs Institute for Alzheimer’s & Neurodegenerative Diseases, UT Health San Antonio, San Antonio, TX (C.L.S., S.S.)

   The Framingham Heart Study, MA (C.L.S., A.S.B., J.R.R., S.S.)

   Claudia L. Satizabal Glenn Biggs Institute for Alzheimer's & Neurodegenerative Diseases, UT Health San Antonio, San Antonio, TX (C.L.S., S.S.). The Framingham Heart Study, MA (C.L.S., A.S.B., J.R.R., S.S.). Department of Neurology (C.L.S., A.S.B., J.R.R., S.S.), Boston University School of Medicine, MA

7. Lisa R. Yanek

   Johns Hopkins University · Johns Hopkins Medicine

   Affiliation as printed

   GeneSTAR Research Program (L.R.Y., B.G.K., L.C.B., P.A.N.), Johns Hopkins University School of Medicine, Baltimore, MD

   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

8. Wei Xiong Wen

   UNSW Sydney · Centre for Healthy Brain Ageing

   Affiliation as printed

   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

   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

9. Vilmundur G. Gudnason

   University of Iceland · Icelandic Heart Association

   Affiliation as printed

   Icelandic Heart Association, Kopavogur (V.G.G., S.S.)

   University of Iceland, Reykjavik, Iceland (V.G.G., A.V.S.)

   Vilmundur G. Gudnason Icelandic Heart Association, Kopavogur (V.G.G., S.S.). University of Iceland, Reykjavik, Iceland (V.G.G., A.V.S.)

10. Nicole Dueker

    University of Miami · Dr. John T. Macdonald Foundation

    Affiliation as printed

    Dr. John T. Macdonald Foundation Department of Human Genetics (R.L.S.), University of Miami, FL

    Nicole D. Dueker Dr. John T. Macdonald Foundation Department of Human Genetics (R.L.S.), University of Miami, FL

11. Lloyd T. Elliott

    Simon Fraser University · University of Oxford · Wellcome Centre for Integrative Neuroimaging

    Affiliation as printed

    Department of Statistics and Actuarial Science, Simon Fraser University, Burnaby, BC, Canada (L.T.E.)

    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

    Lloyd T. Elliott Department of Statistics and Actuarial Science, Simon Fraser University, Burnaby, BC, Canada (L.T.E.). 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

12. Edith Hofer

    Medical University of Graz

    Affiliation as printed

    Clinical Division of Neurogeriatrics, Department of Neurology, Medical University of Graz, Austria (E.H., R.S.)

    Institute for Medical Informatics, Statistics and Documentation, Medical University of Graz, Austria (E.H.)

    Edith Hofer Clinical Division of Neurogeriatrics, Department of Neurology, Medical University of Graz, Austria (E.H., R.S.). Institute for Medical Informatics, Statistics and Documentation, Medical University of Graz, Austria (E.H.)

13. Joshua C. Bis

    University of Washington

    Affiliation as printed

    Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA (J.B., B.P., W.L.)

    Joshua Bis Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA (J.B., B.P., W.L.)

14. Neda Jahanshad

    University of Southern California

    Affiliation as printed

    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.)

    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.)

15. Shuo Li

    Boston University

    Affiliation as printed

    Department of Biostatistics, Boston University School of Public Health, Boston, MA (S.L., M.A.L., A.S.B., Q.Y.)

    Shuo Li Department of Biostatistics, Boston University School of Public Health, Boston, MA (S.L., M.A.L., A.S.B., Q.Y.)

16. Mark Logue

    Boston University · VA Boston Healthcare System

    Affiliation as printed

    Department of Biostatistics, Boston University School of Public Health, Boston, MA (S.L., M.A.L., A.S.B., Q.Y.)

    Department of Psychiatry and Biomedical Genetics Section (M.A.L.), Boston University School of Medicine, MA

    National Center for PTSD: Behavioral Science Division, VA Boston Healthcare System, Boston, MA (M.A.L.)

    Mark A. Logue Department of Psychiatry and Biomedical Genetics Section (M.A.L.), Boston University School of Medicine, MA. Department of Biostatistics, Boston University School of Public Health, Boston, MA (S.L., M.A.L., A.S.B., Q.Y.). National Center for PTSD: Behavioral Science Division, VA Boston Healthcare System, Boston, MA (M.A.L.)

17. Michelle Luciano

    University of Edinburgh

    Affiliation as printed

    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.)

    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.)

18. Markus R. Scholz
    Affiliation as printed

    Institute for Medical Informatics, Statistics and Epidemiology (M.S.)

    Markus Scholz Institute for Medical Informatics, Statistics and Epidemiology (M.S.)

19. Albert V. Smith

    University of Iceland

    Affiliation as printed

    University of Iceland, Reykjavik, Iceland (V.G.G., A.V.S.)

    Albert V. Smith University of Iceland, Reykjavik, Iceland (V.G.G., A.V.S.)

20. Stella Trompet Aachen Department of Cardiology, Leiden University Medical Center Department of Internal Medicine Section of Gerontology and Geriatrics Stella Trompet Department of Internal Medicine

    Leiden University · Leiden University Medical Center

    Affiliation as printed

    Department of Cardiology (S.T.), Leiden University Medical Center, the Netherlands

    Department of Internal Medicine, Section of Gerontology and Geriatrics (S.T.), Leiden University Medical Center, the Netherlands

    Stella Trompet Department of Internal Medicine, Section of Gerontology and Geriatrics (S.T.), Leiden University Medical Center, the Netherlands. Department of Cardiology (S.T.), Leiden University Medical Center, the Netherlands

21. Dina Vojinović

    Erasmus MC

    Affiliation as printed

    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.)

    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.)

22. Rui Xia

    Brown Foundation Institute of Molecular Medicine for the Prevention of Human Diseases · The University of Texas Health Science Center at Houston

    Affiliation as printed

    Brown Foundation Institute of Molecular Medicine, McGovern Medical School, University of Texas Health Science Center at Houston, TX (R.X., M.F.)

    Rui Xia Brown Foundation Institute of Molecular Medicine, McGovern Medical School, University of Texas Health Science Center at Houston, TX (R.X., M.F.)

23. Fidel Alfaro‐Almagro

    University of Oxford · Wellcome Centre for Integrative Neuroimaging

    Affiliation as printed

    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

    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

24. David Ames

    The University of Melbourne · National Ageing Research Institute

    Affiliation as printed

    Academic Unit for Psychiatry of Old Age, University of Melbourne, St George’s Hospital, Kew, Australia (D.A.)

    National Ageing Research Institute, Parkville, Victoria, Australia (D.A.)

    David Ames National Ageing Research Institute, Parkville, Victoria, Australia (D.A.). Academic Unit for Psychiatry of Old Age, University of Melbourne, St George's Hospital, Kew, Australia (D.A.)

25. Najaf Amin

    Erasmus MC

    Affiliation as printed

    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.)

    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.)

26. Philippe Amouyel

    Inserm · Institut Pasteur de Lille · Centre Hospitalier Universitaire de Lille · LabEx DISTALZ

    Affiliation as printed

    Lille University, Inserm, CHU Lille, Institut Pasteur de Lille, RID-AGE (P.A.)

    Lille University, Inserm, Institut Pasteur de Lille, RID-AGE - Risk Factors and Molecular Determinants of Aging-Related Diseases and Labex Distalz, France (P.A.)

    Philippe Amouyel Lille University, Inserm, Institut Pasteur de Lille, RID-AGE - Risk Factors and Molecular Determinants of Aging-Related Diseases and Labex Distalz, France (P.A.). Lille University, Inserm, CHU Lille, Institut Pasteur de Lille, RID-AGE (P.A.)

27. Alexa S. Beiser

    Boston University · Framingham Heart Study

    Affiliation as printed

    Department of Biostatistics, Boston University School of Public Health, Boston, MA (S.L., M.A.L., A.S.B., Q.Y.)

    Department of Neurology (C.L.S., A.S.B., J.R.R., S.S.), Boston University School of Medicine, MA

    The Framingham Heart Study, MA (C.L.S., A.S.B., J.R.R., S.S.)

    Alexa S. Beiser The Framingham Heart Study, MA (C.L.S., A.S.B., J.R.R., S.S.). Department of Neurology (C.L.S., A.S.B., J.R.R., S.S.), Boston University School of Medicine, MA. Department of Biostatistics, Boston University School of Public Health, Boston, MA (S.L., M.A.L., A.S.B., Q.Y.)

28. Henry Brodaty

    UNSW Sydney · Dementia Collaborative Research Centres · Centre for Healthy Brain Ageing

    Affiliation as printed

    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

    Dementia Centre for Research Collaboration (H.B.), University of New South Wales, Sydney, Australia

    Henry Brodaty 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. Dementia Centre for Research Collaboration (H.B.), University of New South Wales, Sydney, Australia

29. Ian J. Deary

    University of Edinburgh

    Affiliation as printed

    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.)

    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.)

30. Christine Fennema‐Notestine

    University of California San Diego

    Affiliation as printed

    Center for Behavior Genetics of Aging (C.F.-N.), University of California, San Diego, La Jolla, CA

    Department of Psychiatry (C.F.-N.), University of California, San Diego, La Jolla, CA

    Christine Fennema-Notestine Department of Psychiatry (C.F.-N.), University of California, San Diego, La Jolla, CA. Center for Behavior Genetics of Aging (C.F.-N.), University of California, San Diego, La Jolla, CA

31. Piyush G. Gampawar

    Medical University of Graz

    Affiliation as printed

    Gottfried Schatz Research Center (for Cell Signaling, Metabolism and Aging), Medical University of Graz, Austria (P.G.G., H.S.)

    Piyush G. Gampawar Gottfried Schatz Research Center (for Cell Signaling, Metabolism and Aging), Medical University of Graz, Austria (P.G.G., H.S.)

32. Rebecca Gottesman

    Johns Hopkins University · Johns Hopkins Medicine

    Affiliation as printed

    Department of Neurology, Cerebrovascular and stroke Division (R.G.), Johns Hopkins University School of Medicine, Baltimore, MD

    Rebecca Gottesman Department of Neurology, Cerebrovascular and stroke Division (R.G.), Johns Hopkins University School of Medicine, Baltimore, MD

33. Ludovica Griffanti

    University of Oxford · Wellcome Centre for Integrative Neuroimaging

    Affiliation as printed

    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

    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

34. Clifford R. Jack

    Mayo Clinic

    Affiliation as printed

    Department of Radiology, Mayo Clinic, Rochester, MN (C.R.J.J.)

    Clifford R. Jack Jr Department of Radiology, Mayo Clinic, Rochester, MN (C.R.J.J.)

35. Mark Jenkinson

    University of Oxford · Wellcome Centre for Integrative Neuroimaging

    Affiliation as printed

    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

    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

36. Jiyang Jiang

    UNSW Sydney · Centre for Healthy Brain Ageing

    Affiliation as printed

    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

    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

37. Brian G. Kral

    Johns Hopkins University · Johns Hopkins Medicine

    Affiliation as printed

    GeneSTAR Research Program (L.R.Y., B.G.K., L.C.B., P.A.N.), Johns Hopkins University School of Medicine, Baltimore, MD

    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

38. John B. Kwok

    The University of Sydney · UNSW Sydney

    Affiliation as printed

    Brain and Mind Centre - The University of Sydney, Camperdown, NSW, Australia (J.B.K.)

    School of Medical Sciences (J.B.K., P.R.S.), University of New South Wales, Sydney, Australia

    John B. Kwok School of Medical Sciences (J.B.K., P.R.S.), University of New South Wales, Sydney, Australia. Brain and Mind Centre - The University of Sydney, Camperdown, NSW, Australia (J.B.K.)

39. Leonie Lampe

    Max Planck Institute for Human Cognitive and Brain Sciences

    Affiliation as printed

    Department of Neurology, Max-Planck-Institute for Human Cognitive and Brain Sciences, Leipzig, Germany (L.L., V.A.W.)

    Leonie Lampe Department of Neurology, Max-Planck-Institute for Human Cognitive and Brain Sciences, Leipzig, Germany (L.L., V.A.W.)

40. David C M Liewald

    University of Edinburgh

    Affiliation as printed

    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.)

    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.)

41. Pauline Maillard

    University of California, Davis

    Affiliation as printed

    Imaging of Dementia and Aging (IDeA) Laboratory, Department of Neurology, University of California-Davis, Davis, CA (P.M.)

    Pauline Maillard Imaging of Dementia and Aging (IDeA) Laboratory, Department of Neurology, University of California-Davis, Davis, CA (P.M.)

42. Jonathan Marchini

    Regeneron (United States)

    Affiliation as printed

    Statistical Genetics and Methods at Regeneron Pharmaceuticals, Inc, New York, NY (J.M.)

    Jonathan Marchini Statistical Genetics and Methods at Regeneron Pharmaceuticals, Inc, New York, NY (J.M.)

43. Mark E. Bastin

    University of Edinburgh

    Affiliation as printed

    Centre for Clinical Brain Sciences, Edinburgh Imaging, Centre for Cognitive Ageing, University of Edinburgh, United Kingdom (M.E.B., J.M.W.)

    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.)

    Mark E. Bastin 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.). Centre for Clinical Brain Sciences, Edinburgh Imaging, Centre for Cognitive Ageing, University of Edinburgh, United Kingdom (M.E.B., J.M.W.)

44. Bernard M. Mazoyer

    Université de Bordeaux · Institut des Maladies Neurodégénératives

    Affiliation as printed

    Institut des Maladies Neurodégénératives, University of Bordeaux, France (B.M.)

45. Lukas Pirpamer

    Medical University of Graz

    Affiliation as printed

    Clinical Division of Neurogeriatrics, Department of Neurology, Medical University of Graz, Austria (L.P.)

    Lukas Pirpamer Clinical Division of Neurogeriatrics, Department of Neurology, Medical University of Graz, Austria (L.P.)

46. Jose Rafael Romero

    Boston University · Framingham Heart Study

    Affiliation as printed

    Department of Neurology (C.L.S., A.S.B., J.R.R., S.S.), Boston University School of Medicine, MA

    The Framingham Heart Study, MA (C.L.S., A.S.B., J.R.R., S.S.)

47. Gennady V. Roshchupkin

    Erasmus MC · Erasmus University Rotterdam

    Affiliation as printed

    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.)

    Department of Radiology and Nuclear Medicine (G.V.R., M.W.V., H.H.H.A.)

    Gennady V. Roshchupkin 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.). Department of Radiology and Nuclear Medicine (G.V.R., M.W.V., H.H.H.A.)

48. Peter R. Schofield

    UNSW Sydney · Neuroscience Research Australia

    Affiliation as printed

    Neuroscience Research Australia, Sydney, Australia (K.A.M., P.R.S., A.T.)

    School of Medical Sciences (J.B.K., P.R.S.), University of New South Wales, Sydney, Australia

    Peter R. Schofield School of Medical Sciences (J.B.K., P.R.S.), University of New South Wales, Sydney, Australia. Neuroscience Research Australia, Sydney, Australia (K.A.M., P.R.S., A.T.)

49. Matthias Leopold Schroeter

    University Hospital Leipzig · Max Planck Institute for Human Cognitive and Brain Sciences

    Affiliation as printed

    Day Clinic for Cognitive Neurology, University Hospital Leipzig, Germany (M.L.S., A.V.)

    Department of Neurology, Max-Planck-Institute for Human Cognitive and Brain Sciences, Leipzig, Germany (M.L.S., A.V.)

    LIFE Research Center for Civilization Disease, Leipzig, Germany (M.S.)

    Matthias L. Schroeter LIFE Research Center for Civilization Disease, Leipzig, Germany (M.S.). Department of Neurology, Max-Planck-Institute for Human Cognitive and Brain Sciences, Leipzig, Germany (M.L.S., A.V.). Day Clinic for Cognitive Neurology, University Hospital Leipzig, Germany (M.L.S., A.V.)

50. David J. Stott

    University of Glasgow

    Affiliation as printed

    Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, United Kingdom (D.J.S.)

    David J. Stott Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, United Kingdom (D.J.S.)

51. Anbupalam Thalamuthu

    UNSW Sydney · Centre for Healthy Brain Ageing · Neuroscience Research Australia

    Affiliation as printed

    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

    Neuroscience Research Australia, Sydney, Australia (K.A.M., P.R.S., A.T.)

    Anbupalam Thalamuthu 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. Neuroscience Research Australia, Sydney, Australia (K.A.M., P.R.S., A.T.)

52. Julian Norman Trollor

    UNSW Sydney · Centre for Healthy Brain Ageing

    Affiliation as printed

    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

    Department of Developmental Disability Neuropsychiatry, School of Psychiatry (J.T.), University of New South Wales, Sydney, Australia

    Julian Trollor 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. Department of Developmental Disability Neuropsychiatry, School of Psychiatry (J.T.), University of New South Wales, Sydney, Australia

53. Christophe Tzourio

    Inserm · Centre Hospitalier Universitaire de Bordeaux · Bordeaux Population Health

    Affiliation as printed

    CHU de Bordeaux, Public Health Department, Medical information Department, Bordeaux, France (C.T.)

    University Bordeaux, Inserm, Bordeaux Population Health Research Center, France (M.S., C.T., S.D.)

    Christophe Tzourio University Bordeaux, Inserm, Bordeaux Population Health Research Center, France (M.S., C.T., S.D.). CHU de Bordeaux, Public Health Department, Medical information Department, Bordeaux, France (C.T.)

54. Jeroen van der Grond Aachen Department of Radiology, Leiden University Medical Center

    Leiden University Medical Center

    Affiliation as printed

    Department of Radiology (J.v.d.G.), Leiden University Medical Center, the Netherlands

    Jeroen van der Grond Department of Radiology (J.v.d.G.), Leiden University Medical Center, the Netherlands

55. Meike Willemijn Vernooij

    Erasmus MC · Erasmus University Rotterdam

    Affiliation as printed

    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.)

    Department of Radiology and Nuclear Medicine (G.V.R., M.W.V., H.H.H.A.)

    Meike W. Vernooij 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.). Department of Radiology and Nuclear Medicine (G.V.R., M.W.V., H.H.H.A.)

56. A. Veronica Witte

    Max Planck Institute for Human Cognitive and Brain Sciences · Leipzig University

    Affiliation as printed

    Collaborative Research Center 1052 Obesity Mechanisms, Faculty of Medicine, University of Leipzig, Germany (V.A.W)

    Department of Neurology, Max-Planck-Institute for Human Cognitive and Brain Sciences, Leipzig, Germany (L.L., V.A.W.)

    Veronica A. Witte Collaborative Research Center 1052 Obesity Mechanisms, Faculty of Medicine, University of Leipzig, Germany (V.A.W). Department of Neurology, Max-Planck-Institute for Human Cognitive and Brain Sciences, Leipzig, Germany (L.L., V.A.W.)

57. Margaret J. Wright

    The University of Queensland

    Affiliation as printed

    Centre for Advanced Imaging (M.J.W.), The University of Queensland, St Lucia, QLD, Australia

    Queensland Brain Institute (M.J.W.), The University of Queensland, St Lucia, QLD, Australia

    Margaret J. Wright Queensland Brain Institute (M.J.W.), The University of Queensland, St Lucia, QLD, Australia. Centre for Advanced Imaging (M.J.W.), The University of Queensland, St Lucia, QLD, Australia

58. Qiong Yang

    Boston University

    Affiliation as printed

    Department of Biostatistics, Boston University School of Public Health, Boston, MA (S.L., M.A.L., A.S.B., Q.Y.)

    Qiong Yang Department of Biostatistics, Boston University School of Public Health, Boston, MA (S.L., M.A.L., A.S.B., Q.Y.)

59. Zoë Morris

    Western General Hospital

    Affiliation as printed

    Neuroradiology Department, Department of Clinical Neurosciences, Western General Hospital, Edinburgh, United Kingdom (Z.M.)

    Zoe Morris Neuroradiology Department, Department of Clinical Neurosciences, Western General Hospital, Edinburgh, United Kingdom (Z.M.)

60. Siggi Siggurdsson

    Boston University · The University of Texas at San Antonio Health Science Center · Framingham Heart Study

    Affiliation as printed

    Department of Neurology (C.L.S., A.S.B., J.R.R., S.S.), Boston University School of Medicine, MA

    Glenn Biggs Institute for Alzheimer’s & Neurodegenerative Diseases, UT Health San Antonio, San Antonio, TX (C.L.S., S.S.)

    The Framingham Heart Study, MA (C.L.S., A.S.B., J.R.R., S.S.)

    Siggi Siggurdsson Glenn Biggs Institute for Alzheimer's & Neurodegenerative Diseases, UT Health San Antonio, San Antonio, TX (C.L.S., S.S.). The Framingham Heart Study, MA (C.L.S., A.S.B., J.R.R., S.S.). Department of Neurology (C.L.S., A.S.B., J.R.R., S.S.), Boston University School of Medicine, MA

61. Bruce M. Psaty

    University of Washington

    Affiliation as printed

    Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA (J.B., B.P., W.L.)

    Bruce Psaty Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA (J.B., B.P., W.L.)

62. Arno Villringer

    University Hospital Leipzig · Max Planck Institute for Human Cognitive and Brain Sciences

    Affiliation as printed

    Day Clinic for Cognitive Neurology, University Hospital Leipzig, Germany (M.L.S., A.V.)

    Department of Neurology, Max-Planck-Institute for Human Cognitive and Brain Sciences, Leipzig, Germany (M.L.S., A.V.)

    Arno Villringer Department of Neurology, Max-Planck-Institute for Human Cognitive and Brain Sciences, Leipzig, Germany (M.L.S., A.V.). Day Clinic for Cognitive Neurology, University Hospital Leipzig, Germany (M.L.S., A.V.)

63. Helena Schmidt

    Medical University of Graz

    Affiliation as printed

    Gottfried Schatz Research Center (for Cell Signaling, Metabolism and Aging), Medical University of Graz, Austria (P.G.G., H.S.)

    Helena Schmidt Gottfried Schatz Research Center (for Cell Signaling, Metabolism and Aging), Medical University of Graz, Austria (P.G.G., H.S.)

64. Asta Kristine Haberg

    Norwegian University of Science and Technology

    Affiliation as printed

    Department of Neuromedicine and Movement Science (A.K.H.), Norwegian University of Science and Technology, Trondheim, Norway

    Department of Radiology and Nuclear Medicine (A.K.H.), Norwegian University of Science and Technology, Trondheim, Norway

    Asta K. Haberg Department of Neuromedicine and Movement Science (A.K.H.), Norwegian University of Science and Technology, Trondheim, Norway. Department of Radiology and Nuclear Medicine (A.K.H.), Norwegian University of Science and Technology, Trondheim, Norway

65. Cornelia M. van Duijn

    Erasmus MC · University of Oxford

    Affiliation as printed

    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.)

    Nuffield Department of Population Health (C.M.v.D.), University of Oxford, United Kingdom

    Cornelia M. van Duijn 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.). Nuffield Department of Population Health (C.M.v.D.), University of Oxford, United Kingdom

66. J. Wouter Jukema Aachen Department of Cardiology, Leiden University Medical Center Einthoven Laboratory for Experimental Vascular Medicine Netherlands. Einthoven Laboratory for Experimental Vascular Medicine

    Leiden University Medical Center

    Affiliation as printed

    Department of Cardiology (J.W.J.), Leiden University Medical Center, the Netherlands

    Einthoven Laboratory for Experimental Vascular Medicine, LUMC, Leiden, the Netherlands (J.W.J.)

    J. Wouter Jukema Department of Cardiology (J.W.J.), Leiden University Medical Center, the Netherlands. Einthoven Laboratory for Experimental Vascular Medicine, LUMC, Leiden, the Netherlands (J.W.J.)

67. Martin Dichgans

    German Center for Neurodegenerative Diseases · LMU Klinikum · Munich Cluster for Systems Neurology · Institut für Schlaganfall- und Demenzforschung · Ludwig-Maximilians-Universität München

    Affiliation as printed

    German Center for Neurodegenerative Diseases, Munich, Germany (M.D.)

    Institute for Stroke and Dementia Research (ISD), University Hospital, Ludwig-Maximilians-Universität LMU Munich, Germany (R.M., M.D.)

    Munich Cluster for Systems Neurology (SyNergy), Germany (M.D.)

68. Ralph L. Sacco

    University of Miami

    Affiliation as printed

    Department of Neurology, Miller School of Medicine (R.L.S.), University of Miami, FL

    Department of Public Health Sciences, Miller School of Medicine (R.L.S.), University of Miami, FL

    Evelyn F. McKnight Brain Institute, Department of Neurology (R.L.S.), University of Miami, FL

    Ralph L. Sacco Department of Public Health Sciences, Miller School of Medicine (R.L.S.), University of Miami, FL. Department of Neurology, Miller School of Medicine (R.L.S.), University of Miami, FL. Evelyn F. McKnight Brain Institute, Department of Neurology (R.L.S.), University of Miami, FL

69. Clinton B. Wright

    National Institutes of Health · National Institute of Neurological Disorders and Stroke

    Affiliation as printed

    National Institute of Neurological Disorders and Stroke (C.B.W.), National Institutes of Health, Bethesda, MD

    Clinton B. Wright National Institute of Neurological Disorders and Stroke (C.B.W.), National Institutes of Health, Bethesda, MD

70. William S. Kremen

    University of California San Diego

    Affiliation as printed

    Center for Behavior Genetics of Aging (W.S.K.), University of California, San Diego, La Jolla, CA

    Department of Psychiatry (W.S.K.), University of California, San Diego, La Jolla, CA

    William S. Kremen Center for Behavior Genetics of Aging (W.S.K.), University of California, San Diego, La Jolla, CA. Department of Psychiatry (W.S.K.), University of California, San Diego, La Jolla, CA

71. Lewis C. Becker

    Johns Hopkins University · Johns Hopkins Medicine

    Affiliation as printed

    GeneSTAR Research Program (L.R.Y., B.G.K., L.C.B., P.A.N.), Johns Hopkins University School of Medicine, Baltimore, MD

    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

72. Paul M. Thompson

    University of Southern California

    Affiliation as printed

    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.)

    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.)

73. Thomas H. Mosley

    University of Mississippi Medical Center

    Affiliation as printed

    Department of Geriatric Medicine, Memory Impairment and Neurodegenerative Dementia (MIND) Center, University of Mississippi Medical Center, Jackson (T.H.M.)

    Thomas H. Mosley Department of Geriatric Medicine, Memory Impairment and Neurodegenerative Dementia (MIND) Center, University of Mississippi Medical Center, Jackson (T.H.M.)

74. Joanna Marguerite Wardlaw

    University of Edinburgh

    Affiliation as printed

    Centre for Clinical Brain Sciences, Edinburgh Imaging, Centre for Cognitive Ageing, University of Edinburgh, United Kingdom (M.E.B., J.M.W.)

    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.)

    Joanna M. Wardlaw 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.). Centre for Clinical Brain Sciences, Edinburgh Imaging, Centre for Cognitive Ageing, University of Edinburgh, United Kingdom (M.E.B., J.M.W.)

75. M. Arfan Ikram

    Erasmus MC

    Affiliation as printed

    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.)

    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.)

76. Hieab H.H. Adams

    Erasmus MC · Erasmus University Rotterdam

    Affiliation as printed

    Department of Clinical Genetics, Erasmus MC, Rotterdam, the Netherlands (H.H.H.A.)

    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.)

    Department of Radiology and Nuclear Medicine (G.V.R., M.W.V., H.H.H.A.)

    Hieab H.H. Adams 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.). Department of Radiology and Nuclear Medicine (G.V.R., M.W.V., H.H.H.A.) Department of Clinical Genetics, Erasmus MC, Rotterdam, the Netherlands (H.H.H.A.)

77. Sudha S. Seshadri

    Icelandic Heart Association

    Affiliation as printed

    Icelandic Heart Association, Kopavogur (V.G.G., S.S.)

    Sudha Seshadri Icelandic Heart Association, Kopavogur (V.G.G., S.S.)

78. Perminder Singh Sachdev

    UNSW Sydney · Prince of Wales Hospital · Centre for Healthy Brain Ageing

    Affiliation as printed

    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

    Neuropsychiatric Institute, Prince of Wales Hospital, Sydney, Australia (P.S.S.)

    Perminder S. Sachdev 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. Neuropsychiatric Institute, Prince of Wales Hospital, Sydney, Australia (P.S.S.)

79. Stephen M. Smith

    University of Oxford · Wellcome Centre for Integrative Neuroimaging

    Affiliation as printed

    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

    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

80. Lenore J. Launer

    National Institutes of Health · National Institute on Aging

    Affiliation as printed

    Laboratory of Epidemiology and Population Sciences, National Institute on Aging, Intramural Research Program (L.L.), National Institutes of Health, Bethesda, MD

    Lenore Launer Laboratory of Epidemiology and Population Sciences, National Institute on Aging, Intramural Research Program (L.L.), National Institutes of Health, Bethesda, MD

81. William T. Longstreth Jr.

    University of Washington

    Affiliation as printed

    Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA (J.B., B.P., W.L.)

    William Longstreth Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA (J.B., B.P., W.L.)

82. Charles S DeCarli

    University of California, Davis

    Affiliation as printed

    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.)

    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.)

83. Reinhold Schmidt

    Medical University of Graz

    Affiliation as printed

    Clinical Division of Neurogeriatrics, Department of Neurology, Medical University of Graz, Austria (E.H., R.S.)

    Reinhold Schmidt Clinical Division of Neurogeriatrics, Department of Neurology, Medical University of Graz, Austria (E.H., R.S.)

84. Myriam Fornage

    Brown Foundation Institute of Molecular Medicine for the Prevention of Human Diseases · The University of Texas Health Science Center at Houston

    Affiliation as printed

    Brown Foundation Institute of Molecular Medicine, McGovern Medical School, University of Texas Health Science Center at Houston, TX (R.X., M.F.)

    Human Genetics Center, School of Public Health UT, Houston, TX (M.F.)

    Myriam Fornage Brown Foundation Institute of Molecular Medicine, McGovern Medical School, University of Texas Health Science Center at Houston, TX (R.X., M.F.). Human Genetics Center, School of Public Health UT, Houston, TX (M.F.)

85. Stéphanie Debette

    Inserm · Centre Hospitalier Universitaire de Bordeaux · Bordeaux Population Health

    Affiliation as printed

    Department of Neurology, CHU de Bordeaux (University Hospital), Bordeaux, France (S.D.)

    University Bordeaux, Inserm, Bordeaux Population Health Research Center, France (M.S., C.T., S.D.)

    Stephanie Debette University Bordeaux, Inserm, Bordeaux Population Health Research Center, France (M.S., C.T., S.D.). Department of Neurology, CHU de Bordeaux (University Hospital), Bordeaux, France (S.D.)

86. Paul Nyquist

    National Institutes of Health · Johns Hopkins University · Johns Hopkins Medicine · Johns Hopkins Hospital

    Affiliation as printed

    Critical Care Medicine Department (P.A.N.), National Institutes of Health, Bethesda, MD

    Departments of Neurology, Critical Care Medicine, Neurosurgery (P.A.N.), Johns Hopkins University School of Medicine, Baltimore, MD

    GeneSTAR Research Program (L.R.Y., B.G.K., L.C.B., P.A.N.), Johns Hopkins University School of Medicine, Baltimore, MD

    Critical Care Medicine Department (P.A.N.), National Institutes of Health, Bethesda, MD.; Departments of Neurology, Critical Care Medicine, Neurosurgery (P.A.N.), Johns Hopkins University School of Medicine, Baltimore, MD.; GeneSTAR Research Program (L.R.Y., B.G.K., L.C.B., P.A.N.), Johns Hopkins University School of Medicine, Baltimore, MD