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3 results on '"genetics [Chromosomes, Human]"'

1. Genome-Wide Association Study of Vascular Dementia

Author

Fernando Rivadeneira, M. Arfan Ikram, Jens Wiltfang, Frank Hentschel, Monique M.B. Breteler, Frank Jessen, Reinhard Heun, Peter J. Koudstaal, Oliver Peters, Eckart Rüther, Heike Kölsch, Albert Hofman, Johannes Kornhuber, Elisabeth M. C. Schrijvers, Wolfgang Maier, Martin Dichgans, Cornelia M. van Duijn, André G. Uitterlinden, Steffi G. Riedel-Heller, Hendrik van den Bussche, Britta Schürmann, Neurology, Epidemiology, Internal Medicine, and Radiology & Nuclear Medicine

Subjects
Male, Oncology, Pathology, Medizin, Genome-wide association study, Cohort Studies, Rotterdam Study, Germany, genetics [Chromosomes, Human, X], Chromosomes, Human, Netherlands, education.field_of_study, Middle Aged, Receptors, Androgen, Female, Alzheimer's disease, Cardiology and Cardiovascular Medicine, Cohort study, medicine.medical_specialty, epidemiology [Dementia, Vascular], Genotype, Population, epidemiology [Germany], genetics [Receptors, Androgen], genetics [Chromosomes, Human], Polymorphism, Single Nucleotide, Sex Factors, Internal medicine, medicine, Humans, Dementia, ddc:610, education, Vascular dementia, Alleles, Aged, genetics [Dementia, Vascular], Advanced and Specialized Nursing, Chromosomes, Human, X, genetics [DNA], business.industry, Dementia, Vascular, DNA, epidemiology [Netherlands], medicine.disease, Minor allele frequency, Neurology (clinical), business, Follow-Up Studies, Genome-Wide Association Study
Abstract

Background and Purpose— Most studies investigating the genetics of dementia have focused on Alzheimer disease, but little is known about the genetics of vascular dementia. The aim of our study was to identify new loci associated with vascular dementia. Methods— We performed a genome-wide association study in the Rotterdam Study, a large prospective population-based cohort study in the Netherlands. We sought to replicate genome-wide significant loci in 2 independent replication samples. Results— In the discovery analysis of 5700 dementia-free individuals, 67 patients developed incident vascular dementia over a mean follow-up time of 9.3±3.2 years. We showed genome-wide significance for rs12007229, which is located on the X chromosome near the androgen receptor gene (OR, 3.7; 95% CI, 2.3–5.8, per copy of the minor allele; P =1.3×10 −8 ). This association was further confirmed in 2 independent populations (probability value of combined replication samples=0.024). Conclusions— Our study shows a novel genetic locus for vascular dementia on the X chromosome. Further replication of this finding is required.

Published
2012

2. Identification of common variants influencing risk of the tauopathy Progressive Supranuclear Palsy

Author

Marla Gearing, Jean Paul G. Vonsattel, Anna Karydas, Manuela Apfelbacher, Herbert Budka, Bernie Devlin, Alessandro Padovani, Wallace W. Tourtellotte, Andrew J. Lees, Karin Srulijes, Li-San Wang, Klaus Seppi, Gianni Pezzoli, Yvette Bordelon, Claudia Trenkwalder, Ryan J. Uitti, Peter Paul De Deyn, Nicole A. Finch, Roger L. Albin, Ranjan Duara, Gerard D. Schellenberg, Alberto Rábano, Kelly E. Lyons, Rosa Rademakers, Douglas Galasko, Giorgio Sacilotto, Dennis W. Dickson, Günter U. Höglinger, Silvana Tesei, John Hardy, Carlo Colosimo, Eliezer Masliah, Pia Winter, Joseph Jankovic, William W. Seeley, Claudio Mariani, David E. Riley, Matthew J. Farrer, Angelo Antonini, Jens Carsten Möller, Alex Rajput, Hans A. Kretzschmar, Nenad Bogdanovic, Nadine M. Melhem, Ulrich Müller, Steven E. Arnold, Wolfgang H. Oertel, Jorge L. Juncos, Rachel G. Gross, Daniela Berg, Rajesh Pahwa, Deborah A. Hall, Alexandra Durr, Chris Zarow, Lili-Naz Hazrati, Virginia M.-Y. Lee, Justo Garcãa De Yebenes, Donatella Ottaviani, John C. van Swieten, Tamas Revesz, John Q. Trojanowski, Zbigniew K. Wszolek, Sigrun Roeber, Werner Poewe, Matthias Höllerhage, Neill R. Graff-Radford, Laura B. Cantwell, Elena Alonso, Irene Litvan, Claire Troakes, Patrick M. A. Sleiman, Peter St George-Hyslop, Isabelle Leber, Lawrence I. Golbe, Chang En Yu, Allissa Dillman, Anna Zecchinelli, Stephen G. Reich, Stefano Goldwurm, Salvatore Spina, Eduardo Tolosa, Vivianna M. Van Deerlin, Charles L. White, Agnita J.W. Boon, Andrew B. Singleton, Huw R. Morris, Mi Ryung Han, Dena G. Hernandez, Carles Gaig, Matthew P. Frosch, Sebastiaan Engelborghs, Juan C. Troncoso, Roberto Cilia, Catriona McLean, Thomas Gasser, Robyn Flook, Barbara Borroni, Rohan de Silva, Murray Grossman, Martin N. Rossor, Bruce L. Miller, Sean S. O'Sullivan, Hakon Hakonarson, Walter Maetzler, Thomas D. Bird, David G. Standaert, Gesine Respondek, Marcel P. van der Brug, Sherry Beecher, Howard I. Hurtig, Gregor K. Wenning, J. Raphael Gibbs, Alexis Brice, Stuart Pickering-Brown, Jonathan D. Rohrer, Christopher Morris, Jana Vandrovcova, Giovanni Fabbrini, Jesús Avila, Owen A. Ross, Margherita Canesi, Lambertus Klei, Andrew P. Lieberman, Bernardino Ghetti, Laura Silveira-Moriyama, Peter Heutink, Pau Pastor, Nicoletta Meucci, Evan T. Geller, Luke A. Massey, Wang Zheng Chiu, Laura Donker Kaat, Maria Stamelou, Brit Mollenhauer, Mark R. Cookson, Thomas G. Beach, Novartis, Federal Ministry of Education and Research (Germany), Helmholtz Association, European Commission, Human genetics, NCA - Neurodegeneration, Neurology, Foundation for the National Institutes of Health, National Institute of Mental Health (US), German Genomics Initiative, German Research Foundation, Medical Research Council (UK), NIHR Biomedical Research Centre (UK), Harvard Brain Tissue Resource Center, Telethon Italia, Canadian Institutes of Health Research, Mayo Clinic, Nafarroako Gobernua, Fondazione Grigioni per il Morbo di Parkinson, De Deyn, Peter Paul, Engelborghs, Sebastiaan, and PSP Genetics Study Group

Subjects
pathology [Tauopathies], Genome-wide association study, Neurodegenerative, Medical and Health Sciences, Cohort Studies, 0302 clinical medicine, Degenerative disease, Risk Factors, Corticobasal degeneration, GWAS, 2.1 Biological and endogenous factors, Supranuclear Palsy, Chromosomes, Human, EIF2AK3, Aetiology, Genetics, Pediatric, 0303 health sciences, genetics [Supranuclear Palsy, Progressive], Single Nucleotide, Biological Sciences, Prognosis, 3. Good health, Frontotemporal Dementia (FTD), Tauopathies, Neurological, genetics [Polymorphism, Single Nucleotide], Tauopathy, Brain diseases, Supranuclear Palsy, Progressive, Palsy, Human, pathology [Supranuclear Palsy, Progressive], Single-nucleotide polymorphism, MAPT protein, human, tau Proteins, Neuropathology, Progressive Supranuclear Palsy, Biology, genetics [Chromosomes, Human], Polymorphism, Single Nucleotide, Chromosomes, Article, Progressive supranuclear palsy, PSP Genetics Study Group, 03 medical and health sciences, Rare Diseases, Progressive, ddc:570, medicine, Acquired Cognitive Impairment, Humans, Genetic Predisposition to Disease, Polymorphism, 030304 developmental biology, Cerebral Palsy, Prevention, Human Genome, genetics [Tauopathies], Neurosciences, Genetic Variation, Perinatal Period - Conditions Originating in Perinatal Period, medicine.disease, eye diseases, Brain Disorders, genetics [tau Proteins], Genetic Loci, Case-Control Studies, Dementia, Human medicine, 030217 neurology & neurosurgery, Developmental Biology, Genome-Wide Association Study
Abstract

Progressive supranuclear palsy (PSP) is a movement disorder with prominent tau neuropathology. Brain diseases with abnormal tau deposits are called tauopathies, the most common being Alzheimer’s disease. Environmental causes of tauopathies include repetitive head trauma associated with some sports. To identify common genetic variation contributing to risk for tauopathies, we carried out a genome-wide association study of 1,114 PSP cases and 3,247 controls (Stage 1) followed up by a second stage where 1,051 cases and 3,560 controls were genotyped for Stage 1 SNPs that yielded P ≤ 10−3. We found significant novel signals (P < 5 × 10−8) associated with PSP risk at STX6, EIF2AK3, and MOBP. We confirmed two independent variants in MAPT affecting risk for PSP, one of which influences MAPT brain expression. The genes implicated encode proteins for vesicle-membrane fusion at the Golgi-endosomal interface, for the endoplasmic reticulum unfolded protein response, and for a myelin structural component., T.G. serves as an editorial board member of Movement Disorders and Parkinsonism and Related Disorders and is funded by Novartis Pharma, the Federal Ministry of Education and Research (BMBF) (NGFN-Plus and ERA-Net NEURON), the Helmholtz Association (HelMA, Helmholtz Alliance for Health in an Ageing Society) and the European Community (MeFoPa, Medndelian Forms of Parkinsonism). T.G. received speakers honoraria from Novartis, Merck-Serono, Schwarz Pharma, Boehringer Ingelheim and Valeant Pharma and royalties for his consulting activities from Cefalon Pharma and Merck-Serono. T.G. holds a patent concerning the LRRK2 gene and neurodegenerative disorders. J.H. is consulting for Merck Serono and Eisai. I.Litvan is the founder of the Litvan Neurological Research Foundation, whose mission is to increase awareness, determine the cause/s and search for a cure for neurodegenerative disorders presenting with either parkinsonian or dementia symptoms (501c3).

Published
2011

3. Multiethnic Genome-Wide Association Study of Cerebral White Matter Hyperintensities on MRI

Author

Susan H. Blanton, Ashley Beecham, Pamela J. Schreiner, Ralph L. Sacco, Stéphanie Debette, Ben A. Oostra, Marian Beekman, M. Arfan Ikram, Edith Hofer, Anna Maria Töglhofer, Alexander Teumer, Ganesh Chauhan, Clinton B. Wright, Meike W. Vernooij, Wiro J. Niessen, Aad van der Lugt, Cornelia M. van Duijn, Christophe Tzourio, Matthias Nauck, Bernard Mazoyer, Bettina von Sarnowski, Alexa S. Beiser, Susan R. Heckbert, André G. Uitterlinden, Alex P. Zijdenbos, David S. Knopman, Paul Freudenberger, Myriam Fornage, Maaike Schuur, Stephen Turner, Matthew Traylor, Qiong Yang, Fabrice Crivello, P. Eline Slagboom, Ian J. Deary, Sharon L.R. Kardia, Cora E. Lewis, Stella Trompet, Mike A. Nalls, Jennifer A. Smith, Katrin Hegenscheid, Hans J. Grabe, Lenore J. Launer, Reinhold Schmidt, Albert V. Smith, M. Kamran Ikram, Kumar B. Rajan, Mariza de Andrade, Sudha Seshadri, Lorna M. Lopez, Philip L. De Jager, Albert Hofman, Joshua C. Bis, Gerardo Heiss, Neelum T. Aggarwal, Elizabeth J. Atkinson, Carla A. Ibrahim-Verbaas, David C. Liewald, Anton J. M. de Craen, Jing Wang, David J. Stott, Sandra Barral, Adam M. Brickman, Mohamad Habes, Eric Boerwinkle, Katharina Wittfeld, Jerome I. Rotter, Saima Hilal, R. Nick Bryan, Charles C. DeCarli, Mark A. van Buchem, Mitchell S.V. Elkind, Rebecca F. Gottesman, Christiane Wolf, Vincent Chouraki, Jeroen van der Grond, Jiemin Liao, Joris Deelen, Stephen Sidney, Kenneth Rice, Vilmundur Guðnason, Hieab H.H. Adams, Benjamin F.J. Verhaaren, Tien Yin Wong, Oliver Martinez, Denis A. Evans, Helena Schmidt, W. T. Longstreth, J. Wouter Jukema, Richard Mayeux, Joanna M. Wardlaw, Thomas H. Mosley, Michelle Luciano, Sigurdur Sigurdsson, Carole Dufouil, Christopher Chen, Philippe Amouyel, Wei Zhao, John C. van Swieten, Bruce M. Psaty, Hae-Won Uh, B. Gwen Windham, Erasmus University Medical Center [Rotterdam] (Erasmus MC), INSERM U897, University of Bordeaux, France, University of Washington [Seattle], University of Michigan [Ann Arbor], University of Michigan System, Netherlands Consortium for Healthy Ageing, Leiden, The Netherlands, Institut Gilbert-Laustriat : Biomolécules, Biotechnologie, Innovation Thérapeutique, Université Louis Pasteur - Strasbourg I-Centre National de la Recherche Scientifique (CNRS), John P. Hussman Institute for Human Genomics, University of Miami Leonard M. Miller School of Medicine (UMMSM), Rush University Medical Center [Chicago], University of Edinburgh, Department of Radiology, Leiden University Medical Center, Leiden, The Netherlands, Depts of Radiology, Leiden University Medical Center (LUMC), Universiteit Leiden-Universiteit Leiden, Department of Materials Science and Metallurgy [Cambridge University] (DMSM), University of Cambridge [UK] (CAM), JRC Institute for Transuranium Elements [Karlsruhe] (ITU ), European Commission - Joint Research Centre [Karlsruhe] (JRC), Greifswald University Hospital, Division of Biomedical Statistics and Informatics, Mayo Clinic, Division of Biomedical Statistics and Informatics, Mayo Clinic, Laboratoire Interuniversitaire des Systèmes Atmosphériques (LISA (UMR_7583)), Institut national des sciences de l'Univers (INSU - CNRS)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Centre National de la Recherche Scientifique (CNRS), Boston University School of Medicine (BUSM), Boston University [Boston] (BU), Genetics, The University of Texas Health Science Center at Houston (UTHealth), Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University [New York], Perelman School of Medicine, University of Pennsylvania, INSERM Research Center for Epidemiology and Biostatistics (U897) Team Neuroepidemiology, Bordeaux, France College of Health Sciences, University of Bordeaux, Bordeaux, France, Systèmes et Applications des Technologies de l'Information et de l'Energie (SATIE), École normale supérieure - Cachan (ENS Cachan)-Université Paris-Sud - Paris 11 (UP11)-Institut Français des Sciences et Technologies des Transports, de l'Aménagement et des Réseaux (IFSTTAR)-École normale supérieure - Rennes (ENS Rennes)-Université de Cergy Pontoise (UCP), Université Paris-Seine-Université Paris-Seine-Conservatoire National des Arts et Métiers [CNAM] (CNAM), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-Centre National de la Recherche Scientifique (CNRS), Université Lille Nord de France (COMUE), Department of neurology, Groupe d'Imagerie Neurofonctionnelle (GIN - UMR 5296), Service NEUROSPIN (NEUROSPIN), Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), Dept of Psychology, Molecular Epidemiology, Harvard Medical School [Boston] (HMS), Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, USA, Broad Institute of MIT and Harvard (BROAD INSTITUTE), Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston]-Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], Program in Translational NeuroPsychiatric Genomics, Brigham and Women's Hospital [Boston], Columbia Mailman School of Public Health, Laboratoire pharmaceutique Lilly France [Neuilly-sur-Seine], Institute of Molecular Biology & Biochemistry, Johns Hopkins University School of Medicine [Baltimore], Faculty of Medicine, University of Iceland [Reykjavik], The Icelandic Heart Association, Kopavogur, Iceland, Institutes for Community Medicine, Department of Epidemiology, University of Washington, Group Health Research Institute, Group Health Cooperative, University of North Carolina [Chapel Hill] (UNC), University of North Carolina System (UNC), National University of Singapore (NUS), Université Grenoble Alpes - UFR Sciences de l'Homme et de la Société (UGA UFR SHS), Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Université Grenoble Alpes - UFR Langage, lettres et arts du spectacle, information et communication - Dpt Sciences de l'information et de la communication (UGA UFR LLASIC SIC), Mayo Clinic [Rochester], Academic Unit of Inflammation and Tumour Targeting, Dept. of Oncology, University of Sheffield Medical School, East China University of Science and Technology, Medstar Research Institute, Institut de pharmacologie et de biologie structurale (IPBS), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), Bioinformatics, GlaxoSmithKline, National Institutes of Health [Bethesda] (NIH), Institute of Clinical Chemistry and Laboratory Medicine, Universität Greifswald - University of Greifswald, Delft University of Technology (TU Delft), Cardiovascular Health Research Unit, University of Washington, Department of Medicine, University of Washington, Department of Health Services, University of Washington, Department of Biostatistics, University of Washington, Cedars-Sinai Medical Center, Dept of Neurology, Univ Medicine of Greifswald, Germany, Department of Physics [Stockholm], Stockholm University, University of Minnesota [Twin Cities] (UMN), University of Minnesota System, Kaiser Permanente, Broad Institute [Cambridge], Harvard University-Massachusetts Institute of Technology (MIT), Department of Medical Biochemistry and Microbiology, Uppsala University, Institute of Cardiovascular and Medical Sciences [Glasgow], University of Glasgow, King‘s College London, Institute of Molecular Biology and Biochemistry, Centre for Molecular Medicine, Medical University of Graz, Graz, Austria, Research Centre for Stroke & Dementia, St George 's Univ of London, Interuniversity Cardiology Institute Netherlands, SAC, Bush Estate, School Medicine, University of Pittsburgh (PITT), Pennsylvania Commonwealth System of Higher Education (PCSHE)-Pennsylvania Commonwealth System of Higher Education (PCSHE), Framingham Heart Study, Boston University [Boston] (BU)-National Heart, Lung, and Blood Institute [Bethesda] (NHLBI), Singapore Eye Research Institute, Singapore National Eye Centre, University of Oslo (UiO), German Research Center for Neurodegenerative Diseases - Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), Ninewells Hospital and Medical School, Biomedical Research Centre, University of Dundee, Dundee Technopole, CXR Biosciences Ltd, Department of Atmospheric, Oceanic, and Space Sciences [Ann Arbor] (AOSS), University of Michigan System-University of Michigan System, University of Miami [Coral Gables], Centre d'Immunologie de Marseille - Luminy (CIML), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Biospective [Montréal], Dept of Epidemiology & Public Health Sciences, Facteurs de Risque et Déterminants Moléculaires des Maladies liées au Vieillissement - U 1167 (RID-AGE), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), University of Mississippi Medical Center (UMMC), Department of Neurology and Center for Neuroscience, University of California at Davis, Sacramento, University of California [Davis] (UC Davis), University of California (UC)-University of California (UC), Center for Medical Systems Biology, Netherlands Genomics Initiative, Leiden University Medical Center, Leiden, The Netherlands, Austrian Institute of Technology [Vienna] (AIT), Donders Institute for Brain, Cognition and Behaviour, Radboud University [Nijmegen], Department of Psychiatry and Psychotherapy, HELIOS Klinikum Stralsund Hanseatic-Greifswald University Hospital, Human Genetics Center, University of Pennsylvania [Philadelphia], Université Paris-Seine-Université Paris-Seine-Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Centre National de la Recherche Scientifique (CNRS), Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS)-Service NEUROSPIN (NEUROSPIN), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Memory Aging & Cognition Centre, National Univ of Singapore, Singapore, East China University of Science and Technology, 130 Meilong Road, Shanghai 200237, China, Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Harvard University [Cambridge]-Massachusetts Institute of Technology (MIT), National Heart, Lung, and Blood Institute [Bethesda] (NHLBI)-Boston University [Boston] (BU), Dept of Ophthalmology, National Univ of Singapore & National Univ Health System, Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Université de Lille-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), University of California-University of California, Radboud university [Nijmegen], Epidemiology, Radiology & Nuclear Medicine, General Practice, Neurology, Medical Informatics, Clinical Genetics, Internal Medicine, Human genetics, NCA - neurodegeneration, Hal, GIN, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), and HESAM Université (HESAM)-HESAM Université (HESAM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Oncology, Male, single nucleotide, Pathology, Genome-wide association study, leukoencephalopathies, polymorphisms, single nucleotide, Chromosomes, Human, Genetics (clinical), Aged, 80 and over, education.field_of_study, Continental Population Groups, cerebrovascular disorders, Middle Aged, White Matter, 3. Good health, Stroke, genetics [Stroke], Female, cerebral small vessel diseases, Alzheimer's disease, Cardiology and Cardiovascular Medicine, medicine.medical_specialty, hypertension, Population, genetics [Chromosomes, Human], Article, Meta-Analysis as Topic, Internal medicine, Genetics, medicine, Dementia, Humans, ddc:610, 1000 Genomes Project, education, Genetic association, Aged, Intracerebral hemorrhage, genome-wide association study, Models, Genetic, business.industry, [SCCO.NEUR]Cognitive science/Neuroscience, [SCCO.NEUR] Cognitive science/Neuroscience, Racial Groups, medicine.disease, ethnology [Stroke], Hyperintensity, Genetic Loci, pathology [Stroke], business, polymorphisms, Genome-Wide Association Study
Abstract

Background— 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. Methods and Results— 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). Conclusions— 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.

Published
2015

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