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Common genetic variants influence human subcortical brain structures

  • Derrek P. Hibar
  • , Jason L. Stein
  • , Miguel E. Renteria
  • , Alejandro Arias-Vasquez
  • , Sylvane Desrivières
  • , Neda Jahanshad
  • , Roberto Toro
  • , Katharina Wittfeld
  • , Lucija Abramovic
  • , Micael Andersson
  • , Benjamin S. Aribisala
  • , Nicola J. Armstrong
  • , Manon Bernard
  • , Marc M. Bohlken
  • , Marco P. Boks
  • , Janita Bralten
  • , Andrew A. Brown
  • , M. Mallar Chakravarty
  • , Qiang Chen
  • , Christopher R.K. Ching
  • Gabriel Cuellar-Partida, Anouk Den Braber, Sudheer Giddaluru, Aaron L. Goldman, Oliver Grimm, Tulio Guadalupe, Johanna Hass, Girma Woldehawariat, Avram J. Holmes, Martine Hoogman, Deborah Janowitz, Tianye Jia, Sungeun Kim, Marieke Klein, Bernd Kraemer, Phil H. Lee, Loes M. Olde Loohuis, Michelle Luciano, Christine MacAre, Karen A. Mather, Manuel Mattheisen, Yuri Milaneschi, Kwangsik Nho, Martina Papmeyer, Adaikalavan Ramasamy, Shannon L. Risacher, Roberto Roiz-Santiañez, Emma J. Rose, Alireza Salami, Philipp G. Sämann, Lianne Schmaal, Andrew J. Schork, Jean Shin, Lachlan T. Strike, Alexander Teumer, Marjolein M.J. Van Donkelaar, Kristel R. Van Eijk, Raymond K. Walters, Lars T. Westlye, Christopher D. Whelan, Anderson M. Winkler, Marcel P. Zwiers, Saud Alhusaini, Lavinia Athanasiu, Stefan Ehrlich, Marina M.H. Hakobjan, Cecilie B. Hartberg, Unn K. Haukvik, Angelien J.G.A.M. Heister, David Hoehn, Dalia Kasperaviciute, David C.M. Liewald, Lorna M. Lopez, Remco R.R. Makkinje, Mar Matarin, Marlies A.M. Naber, D. Reese McKay, Margaret Needham, Allison C. Nugent, Benno Pütz, Natalie A. Royle, Li Shen, Emma Sprooten, Daniah Trabzuni, Saskia S.L. Van Der Marel, Kimm J.E. Van Hulzen, Esther Walton, Christiane Wolf, Laura Almasy, David Ames, Sampath Arepalli, Amelia A. Assareh, Mark E. Bastin, Henry Brodaty, Kazima B. Bulayeva, Melanie A. Carless, Sven Cichon, Aiden Corvin, Joanne E. Curran, Michael Czisch, Greig I. De Zubicaray, Allissa Dillman, Ravi Duggirala, Thomas D. Dyer, Susanne Erk, Iryna O. Fedko, Luigi Ferrucci, Tatiana M. Foroud, Peter T. Fox, Masaki Fukunaga, J. Raphael Gibbs, Harald H.H. Göring, Robert C. Green, Sebastian Guelfi, Narelle K. Hansell, Catharina A. Hartman, Katrin Hegenscheid, Andreas Heinz, Dena G. Hernandez, Dirk J. Heslenfeld, Pieter J. Hoekstra, Florian Holsboer, Georg Homuth, Jouke Jan Hottenga, Masashi Ikeda, Clifford R. Jack, Mark Jenkinson, Robert Johnson, Ryota Kanai, Maria Keil, Jack W. Kent, Peter Kochunov, John B. Kwok, Stephen M. Lawrie, Xinmin Liu, Dan L. Longo, Katie L. McMahon, Eva Meisenzahl, Ingrid Melle, Sebastian Mohnke, Grant W. Montgomery, Jeanette C. Mostert, Thomas W. Mühleisen, Michael A. Nalls, Thomas E. Nichols, Lars G. Nilsson, Markus M. Nöthen, Kazutaka Ohi, Rene L. Olvera, Rocio Perez-Iglesias, G. Bruce Pike, Steven G. Potkin, Ivar Reinvang, Simone Reppermund, Marcella Rietschel, Nina Romanczuk-Seiferth, Glenn D. Rosen, Dan Rujescu, Knut Schnell, Peter R. Schofield, Colin Smith, Vidar M. Steen, Jessika E. Sussmann, Anbupalam Thalamuthu, Arthur W. Toga, Bryan J. Traynor, Juan Troncoso, Jessica A. Turner, Maria C. Valdés Hernández, Dennis Van 'T Ent, Marcel Van Der Brug, Nic J.A. Van Der Wee, Marie Jose Van Tol, Dick J. Veltman, Thomas H. Wassink, Eric Westman, Ronald H. Zielke, Alan B. Zonderman, David G. Ashbrook, Reinmar Hager, Lu Lu, Francis J. McMahon, Derek W. Morris, Robert W. Williams, Han G. Brunner, Randy L. Buckner, Jan K. Buitelaar, Wiepke Cahn, Vince D. Calhoun, Gianpiero L. Cavalleri, Benedicto Crespo-Facorro, Anders M. Dale, Gareth E. Davies, Norman Delanty, Chantal Depondt, Srdjan Djurovic, Wayne C. Drevets, Thomas Espeseth, Randy L. Gollub, Beng Choon Ho, Wolfgang Hoffmann, Norbert Hosten, René S. Kahn, Stephanie Le Hellard, Andreas Meyer-Lindenberg, Bertram Müller-Myhsok, Matthias Nauck, Lars Nyberg, Massimo Pandolfo, Brenda W.J.H. Penninx, Joshua L. Roffman, Sanjay M. Sisodiya, Jordan W. Smoller, Hans Van Bokhoven, Neeltje E.M. Van Haren, Henry Völzke, Henrik Walter, Michael W. Weiner, Wei Wen, Tonya White, Ingrid Agartz, Ole A. Andreassen, John Blangero, Dorret I. Boomsma, Rachel M. Brouwer, Dara M. Cannon, Mark R. Cookson, Eco J.C. De Geus, Ian J. Deary, Gary Donohoe, Guillén Fernández, Simon E. Fisher, Clyde Francks, David C. Glahn, Hans J. Grabe, Oliver Gruber, John Hardy, Ryota Hashimoto, Hilleke E. Hulshoff Pol, Erik G. Jönsson, Iwona Kloszewska, Simon Lovestone, Venkata S. Mattay, Patrizia Mecocci, Colm McDonald, Andrew M. McIntosh, Roel A. Ophoff, Tomas Paus, Zdenka Pausova, Mina Ryten, Perminder S. Sachdev, Andrew J. Saykin, Andy Simmons, Andrew Singleton, Hilkka Soininen, Joanna M. Wardlaw, Michael E. Weale, Daniel R. Weinberger, Hieab H.H. Adams, Lenore J. Launer, Stephan Seiler, Reinhold Schmidt, Ganesh Chauhan, Claudia L. Satizabal, James T. Becker, Lisa Yanek, Sven J. Van Der Lee, Maritza Ebling, Bruce Fischl, W. T. Longstreth, Douglas Greve, Helena Schmidt, Paul Nyquist, Louis N. Vinke, Cornelia M. Van Duijn, Luting Xue, Bernard Mazoyer, Joshua C. Bis, Vilmundur Gudnason, Sudha Seshadri, M. Arfan Ikram, Nicholas G. Martin, Margaret J. Wright, Gunter Schumann, Barbara Franke, Paul M. Thompson*, Sarah E. Medland
*Corresponding author for this work
  • Imaging Genetics Center
  • University of Southern California
  • Neurogenetics Program
  • University of California at Los Angeles
  • Queensland Institute of Medical Research
  • Department of Human Genetics
  • Radboud University Nijmegen
  • Department of Psychiatry
  • Department of Cognitive Neuroscience
  • King's College London
  • Institut Pasteur Paris
  • CNRS
  • Université Paris Descartes
  • German Center for Neurodegenerative Diseases
  • Department of Psychiatry
  • University of Greifswald
  • Department of Psychiatry
  • Utrecht University
  • Umeå University
  • Brain Research Imaging Centre
  • University of Edinburgh
  • Lagos State University
  • Scottish Imaging Network
  • University of New South Wales
  • The University of Sydney
  • University of Toronto
  • NORMENT-KG Jebsen Centre
  • University of Oslo
  • NORMENT - KG Jebsen Centre
  • Cerebral Imaging Centre
  • Douglas Mental Health University Institute
  • Department of Psychiatry and Biomedical Engineering
  • McGill University
  • Lieber Institute for Brain Development
  • Interdepartmental Neuroscience Graduate Program
  • Department of Biological Psychology
  • VU University Medical Center
  • Department of Clinical Science
  • University of Bergen
  • Dr Einar Martens Research Group for Biological Psychiatry
  • Heidelberg University 
  • Language and Genetics Department
  • Max Planck Institute for Psycholinguistics
  • Department of Child and Adolescent Psychiatry
  • Technische Universität Dresden
  • Experimental Therapeutics and Pathophysiology Branch
  • National Institutes of Health
  • Department of Psychology
  • Yale University
  • Department of Psychiatry
  • Massachusetts General Hospital
  • Center for Neuroimaging
  • Indiana University Bloomington
  • Indiana Alzheimer Disease Center
  • Department of Psychiatry and Psychotherapy
  • University of Göttingen
  • Psychiatric and Neurodevelopmental Genetics Unit
  • Broad Institute
  • Harvard University
  • Centre for Cognitive Ageing and Cognitive Epidemiology
  • Department of Biomedicine
  • Aarhus University
  • Lundbeck Foundation Initiative for Integrative Psychiatric Research
  • H. Lundbeck A/S
  • iSEQ
  • Department of Psychiatry
  • Division of Psychiatry
  • Department of Medical and Molecular Genetics
  • Department of Molecular Neuroscience
  • University College London
  • Department of Psychiatry
  • Hospital Universitario Marques de Valdecilla
  • San Juan de Dios Sanitary Park
  • Department of Psychiatry
  • Trinity College Dublin
  • Neurodevelopment and Substance Abuse (C-TRANS)
  • Center for Translational Research on Adversity
  • Stockholm University
  • Max Planck Institute of Psychiatry
  • University of California at San Diego
  • School of Psychology
  • University of Queensland
  • Centre for Advanced Imaging
  • Institute for Community Medicine
  • Analytic and Translational Genetics Unit
  • Department of Psychology
  • University of Oxford
  • Department of Psychiatry
  • Department of Neurology and Neurosurgery
  • Department of Molecular and Cellular Therapeutics
  • Royal College of Surgeons in Ireland
  • Athinoula A.Martinos Center for Biomedical Imaging
  • Department of Research and Development
  • Diakonhjemmet Hospital
  • UCL Institute of Neurology
  • Epilepsy Society
  • Imperial College London
  • Department of Clinical and Experimental Epilepsy
  • Olin Neuropsychiatric Research Center
  • Institute of Living
  • Department of Genetics
  • King Faisal Specialist Hospital and Research Centre
  • Southwest Foundation for Biomedical Research
  • University of Texas Health Science Center at San Antonio
  • Royal Melbourne Hospital
  • Academic Unit for Psychiatry of Old Age
  • University of Melbourne
  • Laboratory of Neurogenetics
  • Russian Academy of Sciences
  • University of Basel
  • University of Bonn
  • Institute of Neuroscience and Medicine (INM-1)
  • Jülich Research Centre
  • Department of Genomics
  • Department of Psychiatry and Psychotherapy
  • Charité – Universitätsmedizin Berlin
  • Clinical Research Branch
  • Medical and Molecular Genetics
  • Department of Veterans Affairs
  • Biofunctional Imaging
  • The University of Osaka
  • Division of Genetics
  • Brigham and Women’s Hospital
  • Interdisciplinary Center Psychopathology and Emotion regulation (ICPE)
  • University of Groningen
  • Institute of Diagnostic Radiology and Neuroradiology
  • Department of Clinical Neuropsychology
  • Vrije Universiteit Amsterdam
  • Interfaculty Institute for Genetics and Functional Genomics
  • Department of Psychiatry
  • Fujita Health University
  • Department of Radiology
  • Mayo Clinic Rochester, MN
  • University of Maryland, Baltimore
  • School of Psychology
  • University of Sussex
  • Department of Psychiatry
  • Neuroscience Research Australia
  • Columbia University
  • Lymphocyte Cell Biology Unit
  • Department of Psychiatry
  • Ludwig Maximilian University of Munich
  • Department of Statistics and WMG
  • University of Warwick
  • Department of Psychiatry
  • Institute of Psychiatry
  • Department of Neurology
  • University of Calgary
  • Department of Clinical Neurosciences
  • Psychiatry and Human Behavior
  • University of California at Irvine
  • Beth Israel Deaconess Medical Center
  • Section for Experimental Psychopathology and Neuroimaging
  • Department of Neuropathology
  • Laboratory of Neuro Imaging
  • Johns Hopkins University
  • Department of Psychology and Neuroscience Institute
  • Georgia State University
  • Genentech Incorporated
  • Department of Psychiatry
  • Leiden University
  • Neuroimaging Centre
  • Department of Psychiatry
  • University of Iowa
  • Karolinska Institutet
  • Behavioral Epidemiology Section
  • Faculty of Life Sciences
  • University of Manchester
  • Center for Integrative and Translational Genomics
  • University of Tennessee Health Science Center
  • Department of Genetics
  • Jiangsu Province Key Laboratory for Inflammation and Molecular Drug Target
  • Nantong University
  • Cognitive Genetics and Cognitive Therapy Group
  • University of Galway
  • Department of Clinical Genetics
  • Maastricht University
  • Department of Psychology
  • Karakter Child and Adolescent Psychiatry
  • The Mind Research Network
  • University of New Mexico
  • Center for Translational Imaging and Personalized Medicine
  • Avera Health
  • Neurology Division
  • Department of Neurology
  • Université libre de Bruxelles
  • Department of Medical Genetics
  • Johnson & Johnson
  • Munich Cluster for Systems Neurology (SyNergy)
  • Institute of Translational Medicine
  • University of Liverpool
  • Institute of Clinical Chemistry and Laboratory Medicine
  • Center for Imaging of Neurodegenerative Disease
  • University of California at San Francisco
  • Department of Child and Adolescent Psychiatry
  • Erasmus University Rotterdam
  • Department of Radiology
  • Clinical Neuroimaging Laboratory
  • Department of Psychiatry and Psychotherapy
  • HELIOS Hospital
  • Medical University of Łódź
  • NIHR Dementia Biomedical Research Unit
  • Department of Neurology
  • Section of Gerontology and Geriatrics
  • University of Perugia
  • Laboratory of Neuro Imaging
  • Departments of Psychology and Psychiatry
  • Departments of Physiology and Nutritional Sciences
  • Neuropsychiatric Institute
  • Prince of Wales Hospital
  • Department of Neuroimaging
  • Biomedical Research Centre for Mental Health
  • NIHR Maudsley Biomedical Research Centre
  • Institute of Clinical Medicine—Neurology
  • University of Eastern Finland
  • Department of Psychiatry
  • Department of Epidemiology
  • Laboratory of Epidemiology and Population Sciences
  • Clinical Division of Neurogeriatrics
  • Medical University of Graz
  • Université de Bordeaux
  • Department of Neurology
  • Boston University
  • National Heart Lung and Blood Institute’s and Boston University’s Framingham Heart Study
  • University of Pittsburgh
  • Department of Psychology
  • General Internal Medicine
  • Department of Radiology
  • Massachusetts Institute of Technology
  • University of Washington
  • Department of Biostatistics
  • Cardiovascular Health Research Unit
  • University of Iceland
  • Department of Psychiatry

Research output: Contribution to journalArticlepeer-review

Abstract

The highly complex structure of the human brain is strongly shaped by genetic influences. Subcortical brain regions form circuits with cortical areas to coordinate movement, learning, memory and motivation, and altered circuits can lead to abnormal behaviour and disease. To investigate how common genetic variants affect the structure of these brain regions, here we conduct genome-wide association studies of the volumes of seven subcortical regions and the intracranial volume derived from magnetic resonance images of 30,717 individuals from 50 cohorts. We identify five novel genetic variants influencing the volumes of the putamen and caudate nucleus. We also find stronger evidence for three loci with previously established influences on hippocampal volume and intracranial volume. These variants show specific volumetric effects on brain structures rather than global effects across structures. The strongest effects were found for the putamen, where a novel intergenic locus with replicable influence on volume (rs945270; P = 1.08×10 -33; 0.52% variance explained) showed evidence of altering the expression of the KTN1 gene in both brain and blood tissue. Variants influencing putamen volume clustered near developmental genes that regulate apoptosis, axon guidance and vesicle transport. Identification of these genetic variants provides insight into the causes of variability in human brain development, and may help to determine mechanisms of neuropsychiatric dysfunction.

Original languageEnglish
Pages (from-to)224-229
Number of pages6
JournalNature
Volume520
Issue number7546
DOIs
Publication statusPublished - 21 Jan 2015
Externally publishedYes

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