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

Nicola J Armstrong¹, Karen A Mather^{2

3}, Muralidharan Sargurupremraj⁴, Maria J Knol⁵, Rainer Malik⁶, Claudia L Satizabal^{7

8

9}, Lisa R Yanek¹⁰, Wei Wen², Vilmundur G Gudnason^{11

12}, Nicole D Dueker¹³, Lloyd T Elliott^{14

15}, Edith Hofer^{16

17}, Joshua Bis¹⁸, Neda Jahanshad¹⁹, Shuo Li²⁰, Mark A Logue^{21

20

22}, Michelle Luciano²³, Markus Scholz²⁴, Albert V Smith¹², Stella Trompet^{25

26}, Dina Vojinovic⁵, Rui Xia²⁷, Fidel Alfaro-Almagro¹⁵, David Ames^{28

29}, Najaf Amin⁵, Philippe Amouyel^{30

31}, Alexa S Beiser^{8

9

20}, Henry Brodaty^{2

32}, Ian J Deary²³, Christine Fennema-Notestine^{33

34}, Piyush G Gampawar³⁵, Rebecca Gottesman³⁶, Ludovica Griffanti¹⁵, Clifford R Jack Jr³⁷, Mark Jenkinson¹⁵, Jiyang Jiang², Brian G Kral¹⁰, John B Kwok^{38

39}, Leonie Lampe⁴⁰, David C M Liewald²³, Pauline Maillard⁴¹, Jonathan Marchini⁴², Mark E Bastin^{23

43}, Bernard Mazoyer⁴⁴, Lukas Pirpamer⁴⁵, José Rafael Romero^{8

9}, Gennady V Roshchupkin^{5

46}, Peter R Schofield^{38

3}, Matthias L Schroeter^{47

48

49}, David J Stott⁵⁰, Anbupalam Thalamuthu^{2

3}, Julian Trollor^{2

51}, Christophe Tzourio^{4

52}, Jeroen van der Grond⁵³, Meike W Vernooij^{5

46}, Veronica A Witte^{54

40}, Margaret J Wright^{55

56}, Qiong Yang²⁰, Zoe Morris⁵⁷, Siggi Siggurdsson^{7

8

9}, Bruce Psaty¹⁸, Arno Villringer^{48

49}, Helena Schmidt³⁵, Asta K Haberg^{58

59}, Cornelia M van Duijn^{5

60}, J Wouter Jukema^{61

62}, Martin Dichgans^{6

63

64}, Ralph L Sacco^{65

66

67}, Clinton B Wright⁶⁸, William S Kremen^{69

70}, Lewis C Becker¹⁰, Paul M Thompson¹⁹, Thomas H Mosley⁷¹, Joanna M Wardlaw^{23

43}, M Arfan Ikram⁵, Hieab H H Adams^{5

46

72}, Sudha Seshadri¹¹, Perminder S Sachdev^{2

73}, Stephen M Smith¹⁵, Lenore Launer⁷⁴, William Longstreth¹⁸, Charles DeCarli⁷⁵, Reinhold Schmidt¹⁶, Myriam Fornage^{27

76}, Stephanie Debette^{4

77}, Paul A Nyquist^{10

78

79}

Affiliations

¹ Mathematics and Statistics, Murdoch University, Perth, Australia (N.J.A.).
² 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.
³ Neuroscience Research Australia, Sydney, Australia (K.A.M., P.R.S., A.T.).
⁴ University Bordeaux, Inserm, Bordeaux Population Health Research Center, France (M.S., C.T., S.D.).
⁵ 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.).
⁶ Institute for Stroke and Dementia Research (ISD), University Hospital, Ludwig-Maximilians-Universität LMU Munich, Germany (R.M., M.D.).
⁷ Glenn Biggs Institute for Alzheimer's & Neurodegenerative Diseases, UT Health San Antonio, San Antonio, TX (C.L.S., S.S.).
⁸ The Framingham Heart Study, MA (C.L.S., A.S.B., J.R.R., S.S.).
⁹ Department of Neurology (C.L.S., A.S.B., J.R.R., S.S.), Boston University School of Medicine, MA.
¹⁰ GeneSTAR Research Program (L.R.Y., B.G.K., L.C.B., P.A.N.), Johns Hopkins University School of Medicine, Baltimore, MD.
¹¹ Icelandic Heart Association, Kopavogur (V.G.G., S.S.).
¹² University of Iceland, Reykjavik, Iceland (V.G.G., A.V.S.).
¹³ Dr. John T. Macdonald Foundation Department of Human Genetics (R.L.S.), University of Miami, FL.
¹⁴ Department of Statistics and Actuarial Science, Simon Fraser University, Burnaby, BC, Canada (L.T.E.).
¹⁵ 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.
¹⁶ Clinical Division of Neurogeriatrics, Department of Neurology, Medical University of Graz, Austria (E.H., R.S.).
¹⁷ Institute for Medical Informatics, Statistics and Documentation, Medical University of Graz, Austria (E.H.).
¹⁸ Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA (J.B., B.P., W.L.).
¹⁹ 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.).
²⁰ Department of Biostatistics, Boston University School of Public Health, Boston, MA (S.L., M.A.L., A.S.B., Q.Y.).
²¹ Department of Psychiatry and Biomedical Genetics Section (M.A.L.), Boston University School of Medicine, MA.
²² National Center for PTSD: Behavioral Science Division, VA Boston Healthcare System, Boston, MA (M.A.L.).
²³ 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.).
²⁴ Institute for Medical Informatics, Statistics and Epidemiology (M.S.).
²⁵ Department of Internal Medicine, Section of Gerontology and Geriatrics (S.T.), Leiden University Medical Center, the Netherlands.
²⁶ Department of Cardiology (S.T.), Leiden University Medical Center, the Netherlands.
²⁷ Brown Foundation Institute of Molecular Medicine, McGovern Medical School, University of Texas Health Science Center at Houston, TX (R.X., M.F.).
²⁸ National Ageing Research Institute, Parkville, Victoria, Australia (D.A.).
²⁹ Academic Unit for Psychiatry of Old Age, University of Melbourne, St George's Hospital, Kew, Australia (D.A.).
³⁰ Lille University, Inserm, Institut Pasteur de Lille, RID-AGE - Risk Factors and Molecular Determinants of Aging-Related Diseases and Labex Distalz, France (P.A.).
³¹ Lille University, Inserm, CHU Lille, Institut Pasteur de Lille, RID-AGE (P.A.).
³² Dementia Centre for Research Collaboration (H.B.), University of New South Wales, Sydney, Australia.
³³ Department of Psychiatry (C.F.-N.), University of California, San Diego, La Jolla, CA.
³⁴ Center for Behavior Genetics of Aging (C.F.-N.), University of California, San Diego, La Jolla, CA.
³⁵ Gottfried Schatz Research Center (for Cell Signaling, Metabolism and Aging), Medical University of Graz, Austria (P.G.G., H.S.).
³⁶ Department of Neurology, Cerebrovascular and stroke Division (R.G.), Johns Hopkins University School of Medicine, Baltimore, MD.
³⁷ Department of Radiology, Mayo Clinic, Rochester, MN (C.R.J.J.).
³⁸ School of Medical Sciences (J.B.K., P.R.S.), University of New South Wales, Sydney, Australia.
³⁹ Brain and Mind Centre - The University of Sydney, Camperdown, NSW, Australia (J.B.K.).
⁴⁰ Department of Neurology, Max-Planck-Institute for Human Cognitive and Brain Sciences, Leipzig, Germany (L.L., V.A.W.).
⁴¹ Imaging of Dementia and Aging (IDeA) Laboratory, Department of Neurology, University of California-Davis, Davis, CA (P.M.).
⁴² Statistical Genetics and Methods at Regeneron Pharmaceuticals, Inc, New York, NY (J.M.).
⁴³ Centre for Clinical Brain Sciences, Edinburgh Imaging, Centre for Cognitive Ageing, University of Edinburgh, United Kingdom (M.E.B., J.M.W.).
⁴⁴ Institut des Maladies Neurodégénératives, University of Bordeaux, France (B.M.).
⁴⁵ Clinical Division of Neurogeriatrics, Department of Neurology, Medical University of Graz, Austria (L.P.).
⁴⁶ Department of Radiology and Nuclear Medicine (G.V.R., M.W.V., H.H.H.A.).
⁴⁷ LIFE Research Center for Civilization Disease, Leipzig, Germany (M.S.).
⁴⁸ Department of Neurology, Max-Planck-Institute for Human Cognitive and Brain Sciences, Leipzig, Germany (M.L.S., A.V.).
⁴⁹ Day Clinic for Cognitive Neurology, University Hospital Leipzig, Germany (M.L.S., A.V.).
⁵⁰ Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, United Kingdom (D.J.S.).
⁵¹ Department of Developmental Disability Neuropsychiatry, School of Psychiatry (J.T.), University of New South Wales, Sydney, Australia.
⁵² CHU de Bordeaux, Public Health Department, Medical information Department, Bordeaux, France (C.T.).
⁵³ Department of Radiology (J.v.d.G.), Leiden University Medical Center, the Netherlands.
⁵⁴ Collaborative Research Center 1052 Obesity Mechanisms, Faculty of Medicine, University of Leipzig, Germany (V.A.W).
⁵⁵ Queensland Brain Institute (M.J.W.), The University of Queensland, St Lucia, QLD, Australia.
⁵⁶ Centre for Advanced Imaging (M.J.W.), The University of Queensland, St Lucia, QLD, Australia.
⁵⁷ Neuroradiology Department, Department of Clinical Neurosciences, Western General Hospital, Edinburgh, United Kingdom (Z.M.).
⁵⁸ Department of Neuromedicine and Movement Science (A.K.H.), Norwegian University of Science and Technology, Trondheim, Norway.
⁵⁹ Department of Radiology and Nuclear Medicine (A.K.H.), Norwegian University of Science and Technology, Trondheim, Norway.
⁶⁰ Nuffield Department of Population Health (C.M.v.D.), University of Oxford, United Kingdom.
⁶¹ Department of Cardiology (J.W.J.), Leiden University Medical Center, the Netherlands.
⁶² Einthoven Laboratory for Experimental Vascular Medicine, LUMC, Leiden, the Netherlands (J.W.J.).
⁶³ German Center for Neurodegenerative Diseases, Munich, Germany (M.D.).
⁶⁴ Munich Cluster for Systems Neurology (SyNergy), Germany (M.D.).
⁶⁵ Department of Public Health Sciences, Miller School of Medicine (R.L.S.), University of Miami, FL.
⁶⁶ Department of Neurology, Miller School of Medicine (R.L.S.), University of Miami, FL.
⁶⁷ Evelyn F. McKnight Brain Institute, Department of Neurology (R.L.S.), University of Miami, FL.
⁶⁸ National Institute of Neurological Disorders and Stroke (C.B.W.), National Institutes of Health, Bethesda, MD.
⁶⁹ Center for Behavior Genetics of Aging (W.S.K.), University of California, San Diego, La Jolla, CA.
⁷⁰ Department of Psychiatry (W.S.K.), University of California, San Diego, La Jolla, CA.
⁷¹ Department of Geriatric Medicine, Memory Impairment and Neurodegenerative Dementia (MIND) Center, University of Mississippi Medical Center, Jackson (T.H.M.).
⁷² Department of Clinical Genetics, Erasmus MC, Rotterdam, the Netherlands (H.H.H.A.).
⁷³ Neuropsychiatric Institute, Prince of Wales Hospital, Sydney, Australia (P.S.S.).
⁷⁴ Laboratory of Epidemiology and Population Sciences, National Institute on Aging, Intramural Research Program (L.L.), National Institutes of Health, Bethesda, MD.
⁷⁵ 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.).
⁷⁶ Human Genetics Center, School of Public Health UT, Houston, TX (M.F.).
⁷⁷ Department of Neurology, CHU de Bordeaux (University Hospital), Bordeaux, France (S.D.).
⁷⁸ Departments of Neurology, Critical Care Medicine, Neurosurgery (P.A.N.), Johns Hopkins University School of Medicine, Baltimore, MD.
⁷⁹ Critical Care Medicine Department (P.A.N.), National Institutes of Health, Bethesda, MD.

PMID: 32517579
PMCID: PMC7365038
DOI: 10.1161/STROKEAHA.119.027544

Meta-Analysis

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

Nicola J Armstrong et al. Stroke. 2020 Jul.

. 2020 Jul;51(7):2111-2121.

doi: 10.1161/STROKEAHA.119.027544. Epub 2020 Jun 10.

Authors

Affiliations

¹ Mathematics and Statistics, Murdoch University, Perth, Australia (N.J.A.).
² 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.
³ Neuroscience Research Australia, Sydney, Australia (K.A.M., P.R.S., A.T.).
⁴ University Bordeaux, Inserm, Bordeaux Population Health Research Center, France (M.S., C.T., S.D.).
⁵ 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.).
⁶ Institute for Stroke and Dementia Research (ISD), University Hospital, Ludwig-Maximilians-Universität LMU Munich, Germany (R.M., M.D.).
⁷ Glenn Biggs Institute for Alzheimer's & Neurodegenerative Diseases, UT Health San Antonio, San Antonio, TX (C.L.S., S.S.).
⁸ The Framingham Heart Study, MA (C.L.S., A.S.B., J.R.R., S.S.).
⁹ Department of Neurology (C.L.S., A.S.B., J.R.R., S.S.), Boston University School of Medicine, MA.
¹⁰ GeneSTAR Research Program (L.R.Y., B.G.K., L.C.B., P.A.N.), Johns Hopkins University School of Medicine, Baltimore, MD.
¹¹ Icelandic Heart Association, Kopavogur (V.G.G., S.S.).
¹² University of Iceland, Reykjavik, Iceland (V.G.G., A.V.S.).
¹³ Dr. John T. Macdonald Foundation Department of Human Genetics (R.L.S.), University of Miami, FL.
¹⁴ Department of Statistics and Actuarial Science, Simon Fraser University, Burnaby, BC, Canada (L.T.E.).
¹⁵ 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.
¹⁶ Clinical Division of Neurogeriatrics, Department of Neurology, Medical University of Graz, Austria (E.H., R.S.).
¹⁷ Institute for Medical Informatics, Statistics and Documentation, Medical University of Graz, Austria (E.H.).
¹⁸ Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA (J.B., B.P., W.L.).
¹⁹ 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.).
²⁰ Department of Biostatistics, Boston University School of Public Health, Boston, MA (S.L., M.A.L., A.S.B., Q.Y.).
²¹ Department of Psychiatry and Biomedical Genetics Section (M.A.L.), Boston University School of Medicine, MA.
²² National Center for PTSD: Behavioral Science Division, VA Boston Healthcare System, Boston, MA (M.A.L.).
²³ 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.).
²⁴ Institute for Medical Informatics, Statistics and Epidemiology (M.S.).
²⁵ Department of Internal Medicine, Section of Gerontology and Geriatrics (S.T.), Leiden University Medical Center, the Netherlands.
²⁶ Department of Cardiology (S.T.), Leiden University Medical Center, the Netherlands.
²⁷ Brown Foundation Institute of Molecular Medicine, McGovern Medical School, University of Texas Health Science Center at Houston, TX (R.X., M.F.).
²⁸ National Ageing Research Institute, Parkville, Victoria, Australia (D.A.).
²⁹ Academic Unit for Psychiatry of Old Age, University of Melbourne, St George's Hospital, Kew, Australia (D.A.).
³⁰ Lille University, Inserm, Institut Pasteur de Lille, RID-AGE - Risk Factors and Molecular Determinants of Aging-Related Diseases and Labex Distalz, France (P.A.).
³¹ Lille University, Inserm, CHU Lille, Institut Pasteur de Lille, RID-AGE (P.A.).
³² Dementia Centre for Research Collaboration (H.B.), University of New South Wales, Sydney, Australia.
³³ Department of Psychiatry (C.F.-N.), University of California, San Diego, La Jolla, CA.
³⁴ Center for Behavior Genetics of Aging (C.F.-N.), University of California, San Diego, La Jolla, CA.
³⁵ Gottfried Schatz Research Center (for Cell Signaling, Metabolism and Aging), Medical University of Graz, Austria (P.G.G., H.S.).
³⁶ Department of Neurology, Cerebrovascular and stroke Division (R.G.), Johns Hopkins University School of Medicine, Baltimore, MD.
³⁷ Department of Radiology, Mayo Clinic, Rochester, MN (C.R.J.J.).
³⁸ School of Medical Sciences (J.B.K., P.R.S.), University of New South Wales, Sydney, Australia.
³⁹ Brain and Mind Centre - The University of Sydney, Camperdown, NSW, Australia (J.B.K.).
⁴⁰ Department of Neurology, Max-Planck-Institute for Human Cognitive and Brain Sciences, Leipzig, Germany (L.L., V.A.W.).
⁴¹ Imaging of Dementia and Aging (IDeA) Laboratory, Department of Neurology, University of California-Davis, Davis, CA (P.M.).
⁴² Statistical Genetics and Methods at Regeneron Pharmaceuticals, Inc, New York, NY (J.M.).
⁴³ Centre for Clinical Brain Sciences, Edinburgh Imaging, Centre for Cognitive Ageing, University of Edinburgh, United Kingdom (M.E.B., J.M.W.).
⁴⁴ Institut des Maladies Neurodégénératives, University of Bordeaux, France (B.M.).
⁴⁵ Clinical Division of Neurogeriatrics, Department of Neurology, Medical University of Graz, Austria (L.P.).
⁴⁶ Department of Radiology and Nuclear Medicine (G.V.R., M.W.V., H.H.H.A.).
⁴⁷ LIFE Research Center for Civilization Disease, Leipzig, Germany (M.S.).
⁴⁸ Department of Neurology, Max-Planck-Institute for Human Cognitive and Brain Sciences, Leipzig, Germany (M.L.S., A.V.).
⁴⁹ Day Clinic for Cognitive Neurology, University Hospital Leipzig, Germany (M.L.S., A.V.).
⁵⁰ Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, United Kingdom (D.J.S.).
⁵¹ Department of Developmental Disability Neuropsychiatry, School of Psychiatry (J.T.), University of New South Wales, Sydney, Australia.
⁵² CHU de Bordeaux, Public Health Department, Medical information Department, Bordeaux, France (C.T.).
⁵³ Department of Radiology (J.v.d.G.), Leiden University Medical Center, the Netherlands.
⁵⁴ Collaborative Research Center 1052 Obesity Mechanisms, Faculty of Medicine, University of Leipzig, Germany (V.A.W).
⁵⁵ Queensland Brain Institute (M.J.W.), The University of Queensland, St Lucia, QLD, Australia.
⁵⁶ Centre for Advanced Imaging (M.J.W.), The University of Queensland, St Lucia, QLD, Australia.
⁵⁷ Neuroradiology Department, Department of Clinical Neurosciences, Western General Hospital, Edinburgh, United Kingdom (Z.M.).
⁵⁸ Department of Neuromedicine and Movement Science (A.K.H.), Norwegian University of Science and Technology, Trondheim, Norway.
⁵⁹ Department of Radiology and Nuclear Medicine (A.K.H.), Norwegian University of Science and Technology, Trondheim, Norway.
⁶⁰ Nuffield Department of Population Health (C.M.v.D.), University of Oxford, United Kingdom.
⁶¹ Department of Cardiology (J.W.J.), Leiden University Medical Center, the Netherlands.
⁶² Einthoven Laboratory for Experimental Vascular Medicine, LUMC, Leiden, the Netherlands (J.W.J.).
⁶³ German Center for Neurodegenerative Diseases, Munich, Germany (M.D.).
⁶⁴ Munich Cluster for Systems Neurology (SyNergy), Germany (M.D.).
⁶⁵ Department of Public Health Sciences, Miller School of Medicine (R.L.S.), University of Miami, FL.
⁶⁶ Department of Neurology, Miller School of Medicine (R.L.S.), University of Miami, FL.
⁶⁷ Evelyn F. McKnight Brain Institute, Department of Neurology (R.L.S.), University of Miami, FL.
⁶⁸ National Institute of Neurological Disorders and Stroke (C.B.W.), National Institutes of Health, Bethesda, MD.
⁶⁹ Center for Behavior Genetics of Aging (W.S.K.), University of California, San Diego, La Jolla, CA.
⁷⁰ Department of Psychiatry (W.S.K.), University of California, San Diego, La Jolla, CA.
⁷¹ Department of Geriatric Medicine, Memory Impairment and Neurodegenerative Dementia (MIND) Center, University of Mississippi Medical Center, Jackson (T.H.M.).
⁷² Department of Clinical Genetics, Erasmus MC, Rotterdam, the Netherlands (H.H.H.A.).
⁷³ Neuropsychiatric Institute, Prince of Wales Hospital, Sydney, Australia (P.S.S.).
⁷⁴ Laboratory of Epidemiology and Population Sciences, National Institute on Aging, Intramural Research Program (L.L.), National Institutes of Health, Bethesda, MD.
⁷⁵ 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.).
⁷⁶ Human Genetics Center, School of Public Health UT, Houston, TX (M.F.).
⁷⁷ Department of Neurology, CHU de Bordeaux (University Hospital), Bordeaux, France (S.D.).
⁷⁸ Departments of Neurology, Critical Care Medicine, Neurosurgery (P.A.N.), Johns Hopkins University School of Medicine, Baltimore, MD.
⁷⁹ Critical Care Medicine Department (P.A.N.), National Institutes of Health, Bethesda, MD.

PMID: 32517579
PMCID: PMC7365038
DOI: 10.1161/STROKEAHA.119.027544

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.

Keywords: brain; genome-wide association study; neuroimaging; risk factors; white matter.

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Figures

**Figure 1.**
(A) Phase II GWAS meta-analysis. Miami plot for PVWMH (upper panel) and DWMH (lower panel). Dashed line shows genome-wide significance threshold (p<5e-8). (B) Chr17 regional plot of genome-wide significant SNPs for DWMH. Colors of the SNPs indicate the level of LD with the top SNP (purple), rs35392904.

**Figure 2.**
(A) Overlap between genome-wide significant SNPs (p<5e-8) for DWMH and PVWMH. (B - C) Circos plots for chr17 for both phenotypes, showing two identified regions for PVWMH (B) but only one for DWMH (C). Outer ring shows SNPs <0.05 with the most significant SNPs located towards the outermost ring. SNPs in high LD with the independent significant SNPs in each locus are colored in red (r²>0.8)-blue (r²>0.2); no LD (grey). Genomic risk loci are colored in dark blue (2^nd layer). Genes are mapped by chromatin interaction (orange), eQTL (green) or both (red). (D) Overlap between significant genes identified by MAGMA for both phenotypes.

**Figure 3.**
Genetic correlations (r_g) between DWMH, PVWMH, Alzheimer’s disease (AD) and stroke phenotypes. Horizontal bars represent standard errors and the size of the square corresponds precision. SVD = small vessel disease stroke, All ICH = All intracranial hemorrhage, Deep ICH = deep intracranial hemorrhage, Lobar ICH = lobar intracranial hemorrhage

See this image and copyright information in PMC

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

Affiliations

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

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