Multiethnic genome-wide association study of cerebral white matter hyperintensities on MRI.

Benjamin F J Verhaaren (1) , Stéphanie Debette (2) , Joshua C Bis (3) , Jennifer A Smith (4) , M Kamran Ikram (1, 5) , Hieab H Adams (6) , Ashley H Beecham (7) , Kumar B Rajan (8) , Lorna M Lopez (9) , Sandra Barral (9) , Mark A van Buchem (10) , Jeroen van Der Grond (11) , Albert V Smith (12, 13) , Katrin Hegenscheid (14) , Neelum T Aggarwal (8) , Mariza de Andrade (15) , Elizabeth J Atkinson (16) , Marian Beekman (17) , Alexa S Beiser (18, 19) , Susan H Blanton (20) , Eric Boerwinkle (21) , Adam M Brickman (22) , R Nick Bryan (23) , Ganesh Chauhan (24) , Christopher P L H Chen (25) , Vincent Chouraki (26) , Anton J M de Craen (27) , Fabrice Crivello (28) , Ian J Deary (29) , Joris Deelen (30) , Philip L de Jager (31, 32, 33) , Carole Dufouil (2) , Mitchell S V Elkind (34) , Denis A Evans (35) , Paul Freudenberger (36) , Rebecca F Gottesman (37) , Vilmundur Guðnason (38, 39) , Mohamad Habes (23, 40) , Susan R Heckbert (41, 42) , Gerardo Heiss (43) , Saima Hilal (44) , Edith Hofer (45, 46) , Albert Hofman (1, 5) , Carla A Ibrahim-Verbaas (1) , David S Knopman (47) , Cora E Lewis (48) , Jiemin Liao (49) , David C M Liewald (9) , Michelle Luciano (50) , Aad van Der Lugt (1) , Oliver O Martinez (51) , Richard Mayeux (52) , Bernard Mazoyer (28) , Mike Nalls (53) , Matthias Nauck (54) , Wiro J Niessen (1, 55) , Ben A Oostra (1) , Bruce M Psaty (56, 57, 41, 42, 58) , Kenneth M Rice (59) , Jerome I Rotter (60) , Bettina von Sarnowski (61) , Helena Schmidt (62) , Pamela J Schreiner (63) , Maaike Schuur (1) , Stephen S Sidney (64) , Sigurdur Sigurdsson (65, 66) , P Eline Slagboom (30) , David J M Stott (67) , John C van Swieten (1) , Alexander Teumer (68) , Anna Maria Töglhofer (69) , Matthew Traylor (70) , Stella Trompet (71) , Stephen T Turner (72) , Christophe Tzourio (2) , Hae-Won Uh (73) , André G Uitterlinden (1, 5) , Meike W Vernooij (1) , Jing J Wang (74, 19) , Tien y Wong (75, 44) , Joanna M Wardlaw (9) , B Gwen Windham (76) , Katharina Wittfeld (14, 77) , Christiane Wolf (78, 79) , Clinton B Wright (80) , Qiong Yang (81) , Wei Zhao (82) , Alex Zijdenbos (83) , J Wouter Jukema (71) , Ralph L Sacco (84, 85) , Sharon L R Kardia (4) , Philippe Amouyel (86) , Thomas H Mosley (87) , W T Longstreth (3) , Charles C Decarli (88) , Cornelia M van Duijn (1, 5, 89) , Reinhold Schmidt (90) , Lenore J Launer (91) , Hans J Grabe (92) , Sudha S Seshadri (18) , M Arfan Ikram (1, 5) , Myriam Fornage (21, 93)

1 Erasmus MC - Erasmus University Medical Center [Rotterdam]
2 Epidémiologie et Biostatistique [Bordeaux]
3 University of Washington [Seattle]
4 University of Michigan [Ann Arbor]
5 Netherlands Consortium for Healthy Ageing, Leiden, The Netherlands
6 Institut Gilbert-Laustriat : Biomolécules, Biotechnologie, Innovation Thérapeutique
7 John P. Hussman Institute for Human Genomics
8 Rush University Medical Center [Chicago]
9 Edin. - University of Edinburgh
10 Department of Radiology, Leiden University Medical Center, Leiden, The Netherlands
11 Depts of Radiology
12 DMSM - Department of Materials Science and Metallurgy [Cambridge University]
13 ITU - JRC Institute for Transuranium Elements [Karlsruhe]
14 Greifswald University Hospital
15 Division of Biomedical Statistics and Informatics
16 Division of Biomedical Statistics and Informatics, Mayo Clinic
17 LISA (UMR_7583) - Laboratoire Interuniversitaire des Systèmes Atmosphériques
18 BUSM - Boston University School of Medicine
19 BU - Boston University [Boston]
20 Genetics
21 UTHealth - The University of Texas Health Science Center at Houston
22 Taub Institute for Research on Alzheimer's Disease and the Aging Brain
23 Perelman School of Medicine
24 INSERM Research Center for Epidemiology and Biostatistics (U897) Team Neuroepidemiology, Bordeaux, France College of Health Sciences, University of Bordeaux, Bordeaux, France
25 SATIE - Systèmes et Applications des Technologies de l'Information et de l'Energie
26 Université Lille Nord de France (COMUE)
27 Department of neurology
28 GIN - UMR 5296 - Groupe d'Imagerie Neurofonctionnelle
29 Dept of Psychology
30 Molecular Epidemiology
31 HMS - Harvard Medical School [Boston]
32 Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, USA
33 Program in Translational NeuroPsychiatric Genomics,
34 Columbia Mailman School of Public Health
35 Laboratoire pharmaceutique Lilly France [Neuilly-sur-Seine]
36 Institute of Molecular Biology & Biochemistry
37 Johns Hopkins University School of Medicine [Baltimore]
38 Faculty of Medicine
39 The Icelandic Heart Association, Kopavogur, Iceland
40 Institutes for Community Medicine
41 Department of Epidemiology, University of Washington
42 Group Health Research Institute, Group Health Cooperative
43 UNC - University of North Carolina [Chapel Hill]
44 NUS - National University of Singapore
45 UGA UFR SHS - Université Grenoble Alpes - UFR Sciences de l'Homme et de la Société
46 UGA UFR LLASIC SIC - Université Grenoble Alpes - UFR Langage, lettres et arts du spectacle, information et communication - Dpt Sciences de l'information et de la communication
47 Mayo Clinic [Rochester]
48 Academic Unit of Inflammation and Tumour Targeting, Dept. of Oncology
49 East China University of Science and Technology
50 Medstar Research Institute
51 IPBS - Institut de pharmacologie et de biologie structurale
52 Bioinformatics
53 NIH - National Institutes of Health [Bethesda, MD, USA]
54 Institute of Clinical Chemistry and Laboratory Medicine
55 TU Delft - Delft University of Technology
56 Cardiovascular Health Research Unit, University of Washington
57 Department of Medicine, University of Washington
58 Department of Health Services, University of Washington
59 Department of Biostatistics, University of Washington
60 Cedars-Sinai Medical Center
61 Dept of Neurology, Univ Medicine of Greifswald, Germany
62 Department of Physics [Stockholm]
63 UMN - University of Minnesota [Twin Cities]
64 Kaiser Permanente
65 Broad Institute [Cambridge]
66 Department of Medical Biochemistry and Microbiology
67 Institute of Cardiovascular and Medical Sciences [Glasgow]
68 King‘s College London
69 Medical University of Graz
70 Research Centre for Stroke & Dementia, St George 's Univ of London
71 Interuniversity Cardiology Institute Netherlands
72 SAC, Bush Estate
73 School Medicine
74 Framingham Heart Study
75 Singapore Eye Research Institute, Singapore National Eye Centre
76 UiO - University of Oslo
77 DZNE - German Research Center for Neurodegenerative Diseases - Deutsches Zentrum für Neurodegenerative Erkrankungen
78 Ninewells Hospital and Medical School, Biomedical Research Centre
79 Dundee Technopole
80 AOSS - Department of Atmospheric, Oceanic, and Space Sciences [Ann Arbor]
81 University of Miami [Coral Gables]
82 CIML - Centre d'Immunologie de Marseille - Luminy
83 Biospective [Montréal]
84 Dept of Epidemiology & Public Health Sciences
85 UMMSM - University of Miami Leonard M. Miller School of Medicine
86 RID-AGE - Facteurs de Risque et Déterminants Moléculaires des Maladies liées au Vieillissement - U 1167
87 UMMC - University of Mississippi Medical Center
88 Department of Neurology and Center for Neuroscience, University of California at Davis, Sacramento
89 Center for Medical Systems Biology, Netherlands Genomics Initiative, Leiden University Medical Center, Leiden, The Netherlands
90 AIT - Austrian Institute of Technology [Vienna]
91 Donders Institute for Brain, Cognition and Behaviour
92 Department of Psychiatry and Psychotherapy
93 Human Genetics Center

The burden of cerebral white matter hyperintensities (WMH) is associated with an increased risk of stroke, dementia, and death. WMH are highly heritable, but their genetic underpinnings are incompletely characterized. To identify novel genetic variants influencing WMH burden, we conducted a meta-analysis of multiethnic genome-wide association studies. We included 21 079 middle-aged to elderly individuals from 29 population-based cohorts, who were free of dementia and stroke and were of European (n=17 936), African (n=1943), Hispanic (n=795), and Asian (n=405) descent. WMH burden was quantified on MRI either by a validated automated segmentation method or a validated visual grading scale. Genotype data in each study were imputed to the 1000 Genomes reference. Within each ethnic group, we investigated the relationship between each single-nucleotide polymorphism and WMH burden using a linear regression model adjusted for age, sex, intracranial volume, and principal components of ancestry. A meta-analysis was conducted for each ethnicity separately and for the combined sample. In the European descent samples, we confirmed a previously known locus on chr17q25 (P=2.7×10(-19)) and identified novel loci on chr10q24 (P=1.6×10(-9)) and chr2p21 (P=4.4×10(-8)). In the multiethnic meta-analysis, we identified 2 additional loci, on chr1q22 (P=2.0×10(-8)) and chr2p16 (P=1.5×10(-8)). The novel loci contained genes that have been implicated in Alzheimer disease (chr2p21 and chr10q24), intracerebral hemorrhage (chr1q22), neuroinflammatory diseases (chr2p21), and glioma (chr10q24 and chr2p16). We identified 4 novel genetic loci that implicate inflammatory and glial proliferative pathways in the development of WMH in addition to previously proposed ischemic mechanisms.

Mots clés: polymorphisms; leukoencephalopathies; cerebral small vessel diseases; cerebrovascular disorders; genome-wide association study; hypertension; single nucleotide

Domaines: Neurosciences

Benjamin F J Verhaaren, Stéphanie Debette, Joshua C Bis, Jennifer A Smith, M Kamran Ikram, et al.. Multiethnic genome-wide association study of cerebral white matter hyperintensities on MRI.. Circulation: Cardiovascular Genetics, 2015, 8 (2), pp.398-409. ⟨10.1161/CIRCGENETICS.114.000858⟩. ⟨hal-01198723⟩