Genetic architecture of subcortical brain structures in 38,851 individuals.
Journal: Nature genetics
Volume: 51
Issue: 11
Year of Publication: 2020
Affiliated Institutions: Glenn Biggs Institute for Alzheimer's and Neurodegenerative Diseases, UT Health San Antonio, San Antonio, TX, USA. satizabal@uthscsa.edu. Department of Epidemiology, Erasmus MC, Rotterdam, the Netherlands. Imaging Genetics Center, USC Mark and Mary Stevens Neuroimaging and Informatics Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA. Cell Circuits Program, Broad Institute, Cambridge, MA, USA. Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany. University of Bordeaux, Inserm, Bordeaux Population Health Research Center, Team VINTAGE, UMR , Bordeaux, France. Department of Biostatistics, University of Michigan, Ann Arbor, MI, USA. Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA. The Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX, USA. Department of Psychology, Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK. Clinical Division of Neurogeriatrics, Department of Neurology, Medical University of Graz, Graz, Austria. Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany. Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, USA. GeneSTAR Research Program, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Department of Neurology, Baylor College of Medicine, Houston, TX, USA. Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA. Department of Genetics, Harvard Medical School, Boston, MA, USA. Singapore Eye Research Institute, Singapore National Eye Centre, Singapore, Singapore. Division of Intramural Research, Population Sciences Branch, National Heart, Lung and Blood Institute, Framingham, MA, USA. MRC-SGDP Centre, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK. Department of Cognitive Neuroscience, Radboud University Medical Center, Nijmegen, the Netherlands. CoE NORMENT, Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway. Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia. Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, IN, USA. Max Planck Institute of Psychiatry, Munich, Germany. Mathematics and Statistics, Murdoch University, Perth, Western Australia, Australia. Lieber Institute for Brain Development, Baltimore, MD, USA. Department of Psychology, Yale University, New Haven, CT, USA. Department of Biological Psychology, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands. Medical University of Lodz, Lodz, Poland. Department of Integrative Medical Biology, Umeå University, Umeå, Sweden. Central Institute of Mental Health, Medical Faculty Mannheim, University Heidelberg, Mannheim, Germany. Department of Psychiatry, UMC Brain Center, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands. The Royal College of Surgeons in Ireland, Dublin, Ireland. Department of Psychiatry, Amsterdam Neuroscience, VU University Medical Center, Amsterdam, the Netherlands. Division of Psychiatry, Royal Edinburgh Hospital, University of Edinburgh, Edinburgh, UK. Department of Medical Sciences, Molecular Medicine and Science for Life Laboratory, Uppsala University, Uppsala, Sweden. Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA. Department of Psychiatry, University Hospital Marqués de Valdecilla, School of Medicine, University of Cantabria-IDIVAL, Santander, Spain. Section for Experimental Psychopathology and Neuroimaging, Department of General Psychiatry, Heidelberg University, Heidelberg, Germany. Department of Neuroscience, Faculty of Medicine, Norwegian University of Science and Technology, Trondheim, Norway. Centre for Academic Mental Health, Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK. Department of Radiology, University of Calgary, Calgary, Alberta, Canada. Department of Psychiatry and Mental Health, University of Cape Town, Cape Town, South Africa. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Charlestown, MA, USA. Department of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands. Laboratory of Epidemiology and Population Sciences, National Institute on Aging, Intramural Research Program, National Institutes of Health, Bethesda, MD, USA. INSERM, Research Unit 'Neuroimaging and Psychiatry', Paris Saclay University and Paris Descartes University-DIGITEO Labs, Gif sur Yvette, France. Department of Neurology, Max Planck Institute for Human Cognitive and Brain Sciences, Leipzig, Germany. International Max Planck Research School for Language Sciences, Nijmegen, the Netherlands. Department of Psychiatry, University Medicine Greifswald, Greifswald, Germany. Department of Medicine, University of Mississippi Medical Center, Jackson, MS, USA. Department of Psychology, University of Pittsburgh, Pittsburgh, PA, USA. CoE NORMENT, Institute of Clinical Medicine, University of Oslo, Oslo, Norway. Research Unit-Genetic Epidemiology, Gottfried Schatz Research Centre for Cell Signaling, Metabolism and Aging, Molecular Biology and Biochemistry, Medical University of Graz, Graz, Austria. QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia. Department of Pharmacology, National University of Singapore, Singapore, Singapore. Academic Unit for Psychiatry of Old Age, University of Melbourne, Melbourne, Victoria, Australia. Department of Psychiatry, University of Oxford, Oxford, UK. NORMENT, Department of Clinical Science, University of Bergen, Bergen, Norway. Centre for integrated Sequencing, Aarhus University, Aarhus, Denmark. UCL Queen Square Institute of Neurology, London, UK. Centre for Youth Mental Health, The University of Melbourne, Melbourne, Victoria, Australia. Division of Psychological and Social Medicine and Developmental Neurosciences, Faculty of Medicine, TU Dresden, Dresden, Germany. Centro Investigación Biomédica en Red Salud Mental, Santander, Spain. Avera Institute for Human Genetics, Sioux Falls, SD, USA. Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada. Center for Systems Neuroscience, Boston University, Boston, MA, USA. LIFE: The Leipzig Research Center for Civilization Diseases, University of Leipzig, Leipzig, Germany. Neurodegeneratives Diseases Institute, CNRS UMR , Université de Bordeaux, Bordeaux, France. Pennington Biomedical Research Center, Baton Rouge, LA, USA. Brain Research Imaging Centre, University of Edinburgh, Edinburgh, UK. Center for Neuroimaging, Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, IN, USA. Centre for Healthy Brain Ageing, School of Psychiatry, University of New South Wales, Sydney, New South Wales, Australia. Section of Gerontology and Geriatrics, Department of Medicine, University of Perugia, Perugia, Italy. Center for Multimodal Imaging and Genetics, University of California, San Diego, San Diego, CA, USA. Division of Medical Genetics, Department of Biomedicine, University of Basel, Basel, Switzerland. Department of ECE, University of New Mexico, Albuquerque, NM, USA. Cerebral Imaging Centre, Douglas Mental Health University Institute, Montreal, Québec, Canada. Donders Institute for Brain, Cognition and Behaviour, Radboud University, Nijmegen, the Netherlands. Clinical Neuropsychology Section, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands. LabEx DISTALZ-U, RID-AGE-Risk Factors and Molecular Determinants of Aging-Related Diseases, University of Lille, Lille, France. Institute of Diagnostic Radiology and Neuroradiology, University Medicine Greifswald, Greifswald, Germany. Institute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute and Pediatrics at Harbor-UCLA Medical Center, Torrance, CA, USA. Institute of Biological Psychiatry, Mental Health Center Sct. Hans, Roskilde, Denmark. Faculty of Health, Queensland University of Technology, Brisbane, Queensland, Australia. Department of Biostatistics, Epidemiology and Informatics, University of Pennsylvania, Philadelphia, PA, USA. st Department of Neurology, AHEPA University Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece. Division of Mind and Brain Research, D, Corporate member of Freie Universität Berliepartment of Psychiatry and Psychotherapy, Charité-Universitätsmedizin Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Berlin, Germany. Brain Center Rudolf Magnus, Human Neurogenetics Unit, UMC Utrecht, Utrecht, the Netherlands. Department of Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland, Dublin, Ireland. Department of Psychiatry, Leiden University Medical Center, Leiden, the Netherlands. Department of Evolution and Genetics, Dagestan State University, Makhachkala, Russia. The Framingham Heart Study, Framingham, MA, USA. Department of Psychiatry, Radboud University Medical Center, Nijmegen, the Netherlands. German Center for Neurodegenerative Diseases, Greifswald, Germany. Clinical Translational Neuroscience Laboratory, Department of Psychiatry and Human Behavior, University of California, Irvine, Irvine, CA, USA. Department of Psychiatry, Psychosomatics and Psychotherapy, University of Wuerzburg, Wuerzburg, Germany. Brain and Mind Centre, University of Sydney, Sydney, New South Wales, Australia. Department of Internal Medicine, INSERM U , University of Toulouse, Toulouse, France. Department of Psychiatry and Psychotherapy, Charité Universitätsmedizin Berlin, Berlin, Germany. Center for Neurobehavioral Genetics, University of California, Los Angeles, Los Angeles, CA, USA. Department of Psychiatry, Carver College of Medicine, University of Iowa, Iowa City, IA, USA. Imaging of Dementia and Aging Laboratory, Department of Neurology, University of California, Davis, Davis, CA, USA. Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, Germany. Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia. Indiana Alzheimer Disease Center, Indiana University School of Medicine, Indianapolis, IN, USA. Biomedical Research Unit for Dementia, King's College London, London, UK. Harvard Medical School, Boston, MA, USA. Department of Radiology, Mayo Clinic, Rochester, MN, USA. Neuroscience Research Australia, Sydney, New South Wales, Australia. Institute for Neuroscience and Medicine: Structural and Functional Organisation of the Brain (INM-), Research Centre Jülich, Jülich, Germany. Department of Psychiatry and Human Behavior, University of California, Irvine, Irvine, CA, USA. Laboratory of Neuro Imaging, USC Mark and Mary Stevens Neuroimaging and Informatics Institute, Keck School of Medicine of the University of Southern California, Los Angeles, CA, USA. Neurogenomics Division, Translational Genomics Research Institute, Phoenix, AZ, USA. MRC Integrative Epidemiology Unit, Bristol Medical School, University of Bristol, Bristol, UK. Department of Medicine, University Hospital Marqués de Valdecilla, School of Medicine, University of Cantabria-IDIVAL, Santander, Spain. Department of Radiology and Nuclear Medicine, Erasmus MC, Rotterdam, the Netherlands. Institut Pasteur, Paris, France. Department of Neurology, CHU de Bordeaux, Bordeaux, France. Department of Epidemiology, University of Washington, Seattle, WA, USA. Cognitive Neuroscience Center, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands. Bloorview Research Institute, Holland Bloorview Kids Rehabilitation Hospital, Toronto, Ontario, Canada. Department of Neurology, Hopital Erasme, Universite Libre de Bruxelles, Brussels, Belgium. The Mind Research Network and LBERI, Albuquerque, NM, USA. Institute of Clinical Medicine-Neurology, University of Eastern Finland, Kuopio, Finland. Institute of Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, Greifswald, Germany. Department of Neuroinformatics, Araya, Tokyo, Japan. Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden. Queensland Brain Institute, University of Queensland, Brisbane, Queensland, Australia. Institute of Human Genetics, University of Bonn, Bonn, Germany. University Medical Center Groningen, Department of Psychiatry, University of Groningen, Groningen, the Netherlands. Department of Psychology, VU University Amsterdam, Amsterdam, the Netherlands. Center for Imaging of Neurodegenerative Disease, San Francisco VA Medical Center, University of California, San Francisco, San Francisco, CA, USA. Department of Neurology, University of Pittsburgh, Pittsburgh, PA, USA. Department of Neurology, Center for Neuroscience, University of California, Davis, Sacramento, CA, USA. Department of Neurology, Boston University School of Medicine, Boston, MA, USA. Faculty of Medicine, University of Iceland, Reykjavík, Iceland. Department of Epidemiology, Erasmus MC, Rotterdam, the Netherlands. m.a.ikram@erasmusmc.nl.
Abstract summary
Subcortical brain structures are integral to motion, consciousness, emotions and learning. We identified common genetic variation related to the volumes of the nucleus accumbens, amygdala, brainstem, caudate nucleus, globus pallidus, putamen and thalamus, using genome-wide association analyses in almost 40,000 individuals from CHARGE, ENIGMA and UK Biobank. We show that variability in subcortical volumes is heritable, and identify 48 significantly associated loci (40 novel at the time of analysis). Annotation of these loci by utilizing gene expression, methylation and neuropathological data identified 199 genes putatively implicated in neurodevelopment, synaptic signaling, axonal transport, apoptosis, inflammation/infection and susceptibility to neurological disorders. This set of genes is significantly enriched for Drosophila orthologs associated with neurodevelopmental phenotypes, suggesting evolutionarily conserved mechanisms. Our findings uncover novel biology and potential drug targets underlying brain development and disease.Authors & Co-authors: Satizabal Claudia L CL Adams Hieab H H HHH Hibar Derrek P DP White Charles C CC Knol Maria J MJ Stein Jason L JL Scholz Markus M Sargurupremraj Muralidharan M Jahanshad Neda N Roshchupkin Gennady V GV Smith Albert V AV Bis Joshua C JC Jian Xueqiu X Luciano Michelle M Hofer Edith E Teumer Alexander A van der Lee Sven J SJ Yang Jingyun J Yanek Lisa R LR Lee Tom V TV Li Shuo S Hu Yanhui Y Koh Jia Yu JY Eicher John D JD Desrivières Sylvane S Arias-Vasquez Alejandro A Chauhan Ganesh G Athanasiu Lavinia L Rentería Miguel E ME Kim Sungeun S Hoehn David D Armstrong Nicola J NJ Chen Qiang Q Holmes Avram J AJ den Braber Anouk A Kloszewska Iwona I Andersson Micael M Espeseth Thomas T Grimm Oliver O Abramovic Lucija L Alhusaini Saud S Milaneschi Yuri Y Papmeyer Martina M Axelsson Tomas T Ehrlich Stefan S Roiz-Santiañez Roberto R Kraemer Bernd B Håberg Asta K AK Jones Hannah J HJ Pike G Bruce GB Stein Dan J DJ Stevens Allison A Bralten Janita J Vernooij Meike W MW Harris Tamara B TB Filippi Irina I Witte A Veronica AV Guadalupe Tulio T Wittfeld Katharina K Mosley Thomas H TH Becker James T JT Doan Nhat Trung NT Hagenaars Saskia P SP Saba Yasaman Y Cuellar-Partida Gabriel G Amin Najaf N Hilal Saima S Nho Kwangsik K Mirza-Schreiber Nazanin N Arfanakis Konstantinos K Becker Diane M DM Ames David D Goldman Aaron L AL Lee Phil H PH Boomsma Dorret I DI Lovestone Simon S Giddaluru Sudheer S Le Hellard Stephanie S Mattheisen Manuel M Bohlken Marc M MM Kasperaviciute Dalia D Schmaal Lianne L Lawrie Stephen M SM Agartz Ingrid I Walton Esther E Tordesillas-Gutierrez Diana D Davies Gareth E GE Shin Jean J Ipser Jonathan C JC Vinke Louis N LN Hoogman Martine M Jia Tianye T Burkhardt Ralph R Klein Marieke M Crivello Fabrice F Janowitz Deborah D Carmichael Owen O Haukvik Unn K UK Aribisala Benjamin S BS Schmidt Helena H Strike Lachlan T LT Cheng Ching-Yu CY Risacher Shannon L SL Pütz Benno B Fleischman Debra A DA Assareh Amelia A AA Mattay Venkata S VS Buckner Randy L RL Mecocci Patrizia P Dale Anders M AM Cichon Sven S Boks Marco P MP Matarin Mar M Penninx Brenda W J H BWJH Calhoun Vince D VD Chakravarty M Mallar MM Marquand Andre F AF Macare Christine C Kharabian Masouleh Shahrzad S Oosterlaan Jaap J Amouyel Philippe P Hegenscheid Katrin K Rotter Jerome I JI Schork Andrew J AJ Liewald David C M DCM de Zubicaray Greig I GI Wong Tien Yin TY Shen Li L Sämann Philipp G PG Brodaty Henry H Roffman Joshua L JL de Geus Eco J C EJC Tsolaki Magda M Erk Susanne S van Eijk Kristel R KR Cavalleri Gianpiero L GL van der Wee Nic J A NJA McIntosh Andrew M AM Gollub Randy L RL Bulayeva Kazima B KB Bernard Manon M Richards Jennifer S JS Himali Jayandra J JJ Loeffler Markus M Rommelse Nanda N Hoffmann Wolfgang W Westlye Lars T LT Valdés Hernández Maria C MC Hansell Narelle K NK van Erp Theo G M TGM Wolf Christiane C Kwok John B J JBJ Vellas Bruno B Heinz Andreas A Olde Loohuis Loes M LM Delanty Norman N Ho Beng-Choon BC Ching Christopher R K CRK Shumskaya Elena E Singh Baljeet B Hofman Albert A van der Meer Dennis D Homuth Georg G Psaty Bruce M BM Bastin Mark E ME Montgomery Grant W GW Foroud Tatiana M TM Reppermund Simone S Hottenga Jouke-Jan JJ Simmons Andrew A Meyer-Lindenberg Andreas A Cahn Wiepke W Whelan Christopher D CD van Donkelaar Marjolein M J MMJ Yang Qiong Q Hosten Norbert N Green Robert C RC Thalamuthu Anbupalam A Mohnke Sebastian S Hulshoff Pol Hilleke E HE Lin Honghuang H Jack Clifford R CR Schofield Peter R PR Mühleisen Thomas W TW Maillard Pauline P Potkin Steven G SG Wen Wei W Fletcher Evan E Toga Arthur W AW Gruber Oliver O Huentelman Matthew M Davey Smith George G Launer Lenore J LJ Nyberg Lars L Jönsson Erik G EG Crespo-Facorro Benedicto B Koen Nastassja N Greve Douglas N DN Uitterlinden André G AG Weinberger Daniel R DR Steen Vidar M VM Fedko Iryna O IO Groenewold Nynke A NA Niessen Wiro J WJ Toro Roberto R Tzourio Christophe C Longstreth William T WT Ikram M Kamran MK Smoller Jordan W JW van Tol Marie-Jose MJ Sussmann Jessika E JE Paus Tomas T Lemaître Hervé H Schroeter Matthias L ML Mazoyer Bernard B Andreassen Ole A OA Holsboer Florian F Depondt Chantal C Veltman Dick J DJ Turner Jessica A JA Pausova Zdenka Z Schumann Gunter G van Rooij Daan D Djurovic Srdjan S Deary Ian J IJ McMahon Katie L KL Müller-Myhsok Bertram B Brouwer Rachel M RM Soininen Hilkka H Pandolfo Massimo M Wassink Thomas H TH Cheung Joshua W JW Wolfers Thomas T Martinot Jean-Luc JL Zwiers Marcel P MP Nauck Matthias M Melle Ingrid I Martin Nicholas G NG Kanai Ryota R Westman Eric E Kahn René S RS Sisodiya Sanjay M SM White Tonya T Saremi Arvin A van Bokhoven Hans H Brunner Han G HG Völzke Henry H Wright Margaret J MJ van 't Ent Dennis D Nöthen Markus M MM Ophoff Roel A RA Buitelaar Jan K JK Fernández Guillén G Sachdev Perminder S PS Rietschel Marcella M van Haren Neeltje E M NEM Fisher Simon E SE Beiser Alexa S AS Francks Clyde C Saykin Andrew J AJ Mather Karen A KA Romanczuk-Seiferth Nina N Hartman Catharina A CA DeStefano Anita L AL Heslenfeld Dirk J DJ Weiner Michael W MW Walter Henrik H Hoekstra Pieter J PJ Nyquist Paul A PA Franke Barbara B Bennett David A DA Grabe Hans J HJ Johnson Andrew D AD Chen Christopher C van Duijn Cornelia M CM Lopez Oscar L OL Fornage Myriam M Wardlaw Joanna M JM Schmidt Reinhold R DeCarli Charles C De Jager Philip L PL Villringer Arno A Debette Stéphanie S Gudnason Vilmundur V Medland Sarah E SE Shulman Joshua M JM Thompson Paul M PM Seshadri Sudha S Ikram M Arfan MA
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Citations : Marsden CD The mysterious motor function of the basal ganglia: the Robert Wartenberg Lecture. Neurology 32, 514–539 (1982).Authors : 289
Identifiers
Doi : 10.1038/s41588-019-0511-ySSN : 1546-1718