Year: 2017
Type: review
Study design: Observational Study
Abstract: The hippocampal formation is a brain structure integrally involved in episodic memory, spatial navigation, cognition and stress responsiveness. Structural abnormalities in hippocampal volume and shape are found in several common neuropsychiatric disorders. To identify the genetic underpinnings of hippocampal structure here we perform a genome-wide association study (GWAS) of 33,536 individuals and discover six independent loci significantly associated with hippocampal volume, four of them novel. Of the novel loci, three lie within genes ( ASTN2 , DPP4 and MAST4 ) and one is found 200 kb upstream of SHH . A hippocampal subfield analysis shows that a locus within the MSRB3 gene shows evidence of a localized effect along the dentate gyrus, subiculum, CA1 and fissure. Further, we show that genetic variants associated with decreased hippocampal volume are also associated with increased risk for Alzheimer’s disease ( r g =−0.155). Our findings suggest novel biological pathways through which human genetic variation influences hippocampal volume and risk for neuropsychiatric illness.
Source: Nature Communications
DOI: 10.1038/ncomms13624
Authors: Derrek P. Hibar, Hieab H. H. Adams, Neda Jahanshad, Ganesh Chauhan, Jason L. Stein, Edith Hofer, Miguel E. Renteria, Joshua C. Bis, Alejandro Arias-Vasquez, M. Kamran Ikram, Sylvane Desrivières, Meike W. Vernooij, Lucija Abramovic, Saud Alhusaini, Najaf Amin, Micael Andersson, Konstantinos Arfanakis, Benjamin S. Aribisala, Nicola J. Armstrong, Lavinia Athanasiu, Tomas Axelsson, Ashley H. Beecham, Alexa Beiser, Manon Bernard, Susan H. Blanton, Marc M. Bohlken, Marco P. Boks, Janita Bralten, Adam M. Brickman, Owen Carmichael, M. Mallar Chakravarty, Qiang Chen, Christopher R. K. Ching, Vincent Chouraki, Gabriel Cuellar-Partida, Fabrice Crivello, Anouk Den Braber, Nhat Trung Doan, Stefan Ehrlich, Sudheer Giddaluru, Aaron L. Goldman, Rebecca F. Gottesman, Oliver Grimm, Michael E. Griswold, Tulio Guadalupe, Boris A. Gutman, Johanna Hass, Unn K. Haukvik, David Hoehn, Avram J. Holmes, Martine Hoogman, Deborah Janowitz, Tianye Jia, Kjetil N. Jørgensen, Nazanin Karbalai, Dalia Kasperaviciute, Sungeun Kim, Marieke Klein, Bernd Kraemer, Phil H. Lee, David C. M. Liewald, Lorna M. Lopez, Michelle Luciano, Christine Macare, Andre F. Marquand, Mar Matarin, Karen A. Mather, Manuel Mattheisen, David R. McKay, Yuri Milaneschi, Susana Muñoz Maniega, Kwangsik Nho, Allison C. Nugent, Paul Nyquist, Loes M. Olde Loohuis, Jaap Oosterlaan, Martina Papmeyer, Lukas Pirpamer, Benno Pütz, Adaikalavan Ramasamy, Jennifer S. Richards, Shannon L. Risacher, Roberto Roiz-Santiañez, Nanda Rommelse, Stefan Ropele, Emma J. Rose, Natalie A. Royle, Tatjana Rundek, Philipp G. Sämann, Arvin Saremi, Claudia L. Satizabal, Lianne Schmaal, Andrew J. Schork, Li Shen, Jean Shin, Elena Shumskaya, Albert V. Smith, Emma Sprooten, Lachlan T. Strike, Alexander Teumer, Diana Tordesillas-Gutierrez, Roberto Toro, Daniah Trabzuni, Stella Trompet, Dhananjay Vaidya, Jeroen Van der Grond, Sven J. Van der Lee, Dennis Van der Meer, Marjolein M. J. Van Donkelaar, Kristel R. Van Eijk, Theo G. M. Van Erp, Daan Van Rooij, Esther Walton, Lars T. Westlye, Christopher D. Whelan, Beverly G. Windham, Anderson M. Winkler, Katharina Wittfeld, Girma Woldehawariat, Christiane Wolf, Thomas Wolfers, Lisa R. Yanek, Jingyun Yang, Alex Zijdenbos, Marcel P. Zwiers, Ingrid Agartz, Laura Almasy, David Ames, Philippe Amouyel, Ole A. Andreassen, Sampath Arepalli, Amelia A. Assareh, Sandra Barral, Mark E. Bastin, Diane M. Becker, James T. Becker, David A. Bennett, John Blangero, Hans van Bokhoven, Dorret I. Boomsma, Henry Brodaty, Rachel M. Brouwer, Han G. Brunner, Randy L. Buckner, Jan K. Buitelaar, Kazima B. Bulayeva, Wiepke Cahn, Vince D. Calhoun, Dara M. Cannon, Gianpiero L. Cavalleri, Ching-Yu Cheng, Sven Cichon, Mark R. Cookson, Aiden Corvin, Benedicto Crespo-Facorro, Joanne E. Curran, Michael Czisch, Anders M. Dale, Gareth E. Davies, Anton J. M. De Craen, Eco J. C. De Geus, Philip L. De Jager, Greig I. De Zubicaray, Ian J. Deary, Stéphanie Debette, Charles DeCarli, Norman Delanty, Chantal Depondt, Anita DeStefano, Allissa Dillman, Srdjan Djurovic, Gary Donohoe, Wayne C. Drevets, Ravi Duggirala, Thomas D. Dyer, Christian Enzinger, Susanne Erk, Thomas Espeseth, Iryna O. Fedko, Guillén Fernández, Luigi Ferrucci, Simon E. Fisher, Debra A. Fleischman, Ian Ford, Myriam Fornage, Tatiana M. Foroud, Peter T. Fox, Clyde Francks, Masaki Fukunaga, J. Raphael Gibbs, David C. Glahn, Randy L. Gollub, Harald H. H. Göring, Robert C. Green, Oliver Gruber, Vilmundur Gudnason, Sebastian Guelfi, Asta K. Håberg, Narelle K. Hansell, John Hardy, Catharina A. Hartman, Ryota Hashimoto, Katrin Hegenscheid, Andreas Heinz, Stephanie Le Hellard, Dena G. Hernandez, Dirk J. Heslenfeld, Beng-Choon Ho, Pieter J. Hoekstra, Wolfgang Hoffmann, Albert Hofman, Florian Holsboer, Georg Homuth, Norbert Hosten, Jouke-Jan Hottenga, Matthew Huentelman, Hilleke E. Hulshoff Pol, Masashi Ikeda, Clifford R. Jack Jr, Mark Jenkinson, Robert Johnson, Erik G. Jönsson, J. Wouter Jukema, René S. Kahn, Ryota Kanai, Iwona Kloszewska, David S. Knopman, Peter Kochunov, John B. Kwok, Stephen M. Lawrie, Hervé Lemaître, Xinmin Liu, Dan L. Longo, Oscar L. Lopez, Simon Lovestone, Oliver Martinez, Jean-Luc Martinot, Venkata S. Mattay, Colm McDonald, Andrew M. McIntosh, Francis J. McMahon, Katie L. McMahon, Patrizia Mecocci, Ingrid Melle, Andreas Meyer-Lindenberg, Sebastian Mohnke, Grant W. Montgomery, Derek W. Morris, Thomas H. Mosley, Thomas W. Mühleisen, Bertram Müller-Myhsok, Michael A. Nalls, Matthias Nauck, Thomas E. Nichols, Wiro J. Niessen, Markus M. Nöthen, Lars Nyberg, Kazutaka Ohi, Rene L. Olvera, Roel A. Ophoff, Massimo Pandolfo, Tomas Paus, Zdenka Pausova, Brenda W. J. H. Penninx, G. Bruce Pike, Steven G. Potkin, Bruce M. Psaty, Simone Reppermund, Marcella Rietschel, Joshua L. Roffman, Nina Romanczuk-Seiferth, Jerome I. Rotter, Mina Ryten, Ralph L. Sacco, Perminder S. Sachdev, Andrew J. Saykin, Reinhold Schmidt, Helena Schmidt, Peter R. Schofield, Sigurdur Sigursson, Andrew Simmons, Andrew Singleton, Sanjay M. Sisodiya, Colin Smith, Jordan W. Smoller, Hilkka Soininen, Vidar M. Steen, David J. Stott, Jessika E. Sussmann, Anbupalam Thalamuthu, Arthur W. Toga, Bryan J. Traynor, Juan Troncoso, Magda Tsolaki, Christophe Tzourio, Andre G. Uitterlinden, Maria C. Valdés Hernández, Marcel Van der Brug, Aad van der Lugt, Nic J. A. van der Wee, Neeltje E. M. Van Haren, Dennis van ’t Ent, Marie-Jose Van Tol, Badri N. Vardarajan, Bruno Vellas, Dick J. Veltman, Henry Völzke, Henrik Walter, Joanna M. Wardlaw, Thomas H. Wassink, Michael E. Weale, Daniel R. Weinberger, Michael W. Weiner, Wei Wen, Eric Westman, Tonya White, Tien Y. Wong, Clinton B. Wright, Ronald H. Zielke, Alan B. Zonderman, Nicholas G. Martin, Cornelia M. Van Duijn, Margaret J. Wright, W. T. Longstreth, Gunter Schumann, Hans J. Grabe, Barbara Franke, Lenore J. Launer, Sarah E. Medland, Sudha Seshadri, Paul M. Thompson, M. Arfan Ikram
Institutions: University of Southern California, University of California, Los Angeles, Erasmus MC, Université de Bordeaux, Inserm, Bordeaux Population Health, University of North Carolina at Chapel Hill, Medical University of Graz, QIMR Berghofer Medical Research Institute, University of Washington, Radboud University Nijmegen, Radboud University Medical Center, Donders Institute for Brain, Cognition and Behaviour, National Institutes of Health, National University of Singapore, Singapore National Eye Center, Singapore Eye Research Institute, Duke-NUS Medical School, National University Health System, King's College London, University Medical Center Utrecht, Montreal Neurological Institute and Hospital, Royal College of Surgeons in Ireland, McGill University, Sahlgrenska University Hospital, Umeå University, Rush University Medical Center, Illinois Institute of Technology, Lagos State University, University of Edinburgh, Murdoch University, UNSW Sydney, Assistance Publique Hôpitaux de Marseille, Centre for Healthy Brain Ageing, Oslo University Hospital, University of Oslo, Uppsala University, Science for Life Laboratory, University of Miami, Boston University, Framingham Heart Study, University of Toronto, Hospital for Sick Children, Columbia University Irving Medical Center, Pennington Biomedical Research Center, University of California, Davis, Douglas Mental Health University Institute, Lieber Institute for Brain Development, Institut Pasteur de Lille, Centre Hospitalier Universitaire de Lille, Approches épidémiologiques et moléculaires intégratives visant à améliorer la compréhension des maladies chroniques liées au vieillissement, Université Lille Nord de France, Centre National de la Recherche Scientifique, Commissariat à l'Énergie Atomique et aux Énergies Alternatives, Institut des Maladies Neurodégénératives, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMC Location Vrije Universiteit Amsterdam, Massachusetts General Hospital, Athinoula A. Martinos Center for Biomedical Imaging, MetaGenoPolis, Technische Universität Dresden, Haukeland University Hospital, University of Bergen, Iowa State University, Ames National Laboratory, Johns Hopkins University, Johns Hopkins Medicine, Heidelberg University, Central Institute of Mental Health, Medizinische Fakultät Mannheim, University of Mississippi Medical Center, Max Planck Institute for Psycholinguistics, Georgia Institute of Technology, Diakonhjemmet Hospital, Max Planck Institute of Psychiatry, University Hospital Heidelberg, Yale University, Universitätsmedizin Greifswald, Beijing Normal University, Aalborg University, UCL Queen Square Institute of Neurology, University College London, Epilepsy Society, Imperial College London, Indiana University Indianapolis, Indiana University School of Medicine, Centre Hospitalier Régional et Universitaire de Nancy, University of Göttingen, Broad Institute, Harvard University, Stanley Center for Psychiatric Research, MedStar Health Research Institute, Donders Centre for Cognitive Neuroimaging, University of Bonn, Aarhus University, Lundbeck Foundation, Life & Brain (Germany), Amsterdam Public Health, GGZ inGeest, University College Dublin, National Institute of Mental Health, Johns Hopkins Hospital, University of Bern, Royal Edinburgh Hospital, University of Oxford, Jenner Institute, Universidad de Cantabria, Instituto de Salud Carlos III, Centro de Investigación Biomédica en Red de Salud Mental, Marqués de Valdecilla University Hospital, Instituto de Investigación Marqués de Valdecilla, Centro de Investigación Biomédica en Red, Trinity College Dublin, Institut Parisien de Chimie Moléculaire, Université Pierre-et-Marie-Curie, The University of Melbourne, Orygen, University of California San Diego, Wuhan University, University of Iceland, Icelandic Heart Association, University of Plymouth, Icahn School of Medicine at Mount Sinai, The University of Queensland, Institut Pasteur, Gènes, synapses et cognition, King Faisal Specialist Hospital & Research Centre, Leiden University Medical Center, University Medical Center Groningen, University of Groningen, University of Twente, University of California, Irvine, Georgia State University, Epigénétique et Destin Cellulaire, Université Paris Diderot, German Center for Neurodegenerative Diseases, Wellcome Centre for Integrative Neuroimaging, University of Würzburg, The University of Texas Rio Grande Valley, Karolinska Institutet, University of Pennsylvania, The Royal Melbourne Hospital, Children's Hospital of Philadelphia, National Ageing Research Institute, Université de Lille, National Institute on Aging, Texas Biomedical Research Institute, The University of Texas Health Science Center at Houston, University of Pittsburgh, Dementia Collaborative Research Centres, Maastricht University Medical Centre, Maastricht University, Russian Academy of Sciences, Vavilov Institute of General Genetics, Mind Research Network, University of New Mexico, Dagestan State University, Northwestern Polytechnical University, Ollscoil na Gaillimhe – University of Galway, Forschungszentrum Jülich, University of Basel, University Hospital of Basel, Utrecht University, University of York, Avera Institute for Human Genetics, Brigham and Women's Hospital, Queensland University of Technology, Centre Hospitalier Universitaire de Bordeaux, Beaumont Hospital, Université Libre de Bruxelles, Erasmus Hospital, Janssen Research & Development (United States), Institut des Sciences du Mouvement Etienne-Jules Marey, Stiftung Charité, Charité – Universitätsmedizin Berlin, École des hautes études en sciences sociales, Mayo Clinic, University of Glasgow, Rensselaer Polytechnic Institute, Okayama University, The University of Texas at San Antonio Health Science Center, University of New Haven, University of Colorado Boulder, University of Colorado System, National Institute for Physiological Sciences, Norwegian University of Science and Technology, St Olav's University Hospital, The University of Osaka, Molecular Research Center for Children's Mental Development, Vietnam National University Ho Chi Minh City, Ho Chi Minh City University of Science, University of Iowa, Universität Greifswald, HolsboerMaschmeyer NeuroChemie (Germany), Translational Genomics Research Institute, Fujita Health University, University of Florida, University of Gothenburg, University of Maryland, Baltimore, University of Sussex, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Medical University of Lodz, Araya Inc. (Japan), Université de Cergy-Pontoise, Neuroscience Research Australia, Université Paris-Sud, Université Paris-Saclay, Neuroimaging and Psychiatry, Université Paris Descartes, Unité de Nutrition Humaine, Institut National de Recherche pour l'Agriculture, l'Alimentation et l'Environnement, United States Department of Health and Human Services, Department of Health and Human Services, Australian National University, University of Perugia, University Medical Centre Mannheim, Munich Cluster for Systems Neurology, University of Liverpool, University of Warwick, German Centre for Cardiovascular Research, Delft University of Technology, University of Nottingham, Rotman Research Institute, Child Mind Institute, University of Calgary, Kaiser Permanente Washington Health Research Institute, Cedars-Sinai Medical Center, The Lundquist Institute, Harbor–UCLA Medical Center, Politecnico di Milano, Munich University of Applied Sciences, Prince of Wales Hospital, University of Eastern Finland, Kuopio University Hospital, Aristotle University of Thessaloniki, G. Papanikolaou General Hospital, Genentech, Leiden University, Laboratoire Epidémiologie et Analyses en Santé Publique : Risques, Maladies Chroniques et Handicaps, Université de Toulouse, San Francisco VA Medical Center, University of California, San Francisco, University of Pretoria, Erasmus MC - Sophia Children’s Hospital, University of Missouri, University of Applied Sciences Stralsund
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $6,990
Funders: McKnight Foundation, Brigham and Women's Hospital, Massachusetts General Hospital, Yale University, University of Southern California, University of Miami, University of Pennsylvania, Harvard University, School of Medicine, Boston University, Alzheimer's Disease Neuroimaging Initiative, Aarhus Universitet, University of Washington, Johns Hopkins University, University of Pittsburgh, Universität Basel, Georgia State University, Harvard T.H. Chan School of Public Health, McGill University, Rush University, University of Bern, Norges Teknisk-Naturvitenskapelige Universitet, National University of Ireland, Wellcome Trust, Deutsches Zentrum für Herz-Kreislaufforschung, University of Texas Health Science Center at Houston, Neuroscience Research Australia, Royal College of Surgeons in Ireland, QIMR Berghofer Medical Research Institute, Broad Institute, University of Texas Rio Grande Valley, Duke-NUS Medical School, Child Mind Institute, International Max Planck Research School for Environmental, Cellular and Molecular Microbiology, National Institute for Health and Care Research, Parkinson's UK, University of Warwick, Imperial College London, King's College London, University College London, University of Oxford, University of Sussex, University of Glasgow, National University of Singapore, Singapore Eye Research Institute, University of Galway, Trinity College Dublin, Institut National de la Santé et de la Recherche Médicale, Rijksuniversiteit Groningen, University of New South Wales, University of Melbourne, Queensland University of Technology, Murdoch University, Technische Universiteit Delft, Radboud Universiteit, Vrije Universiteit Amsterdam, King Faisal Specialist Hospital and Research Centre, Technische Universität Dresden, GGZ inGeest, Lundbeckfonden, University of Toronto, Universitair Medisch Centrum Utrecht, Karolinska Institutet, Maastricht Universitair Medisch Centrum, Centre National de la Recherche Scientifique, Umeå Universitet, Universitetet i Bergen, Leids Universitair Medisch Centrum, Universitair Medisch Centrum Groningen, Deutsches Zentrum für Neurodegenerative Erkrankungen, Universitetet i Oslo, Háskóli Íslands, Uniwersytet Łódzki, Hospital for Sick Children, Radboud Universitair Medisch Centrum, Université de Bordeaux, Universidad de Cantabria, Centre d'Imagerie BioMédicale, Vifor Pharma, Centro de Investigación Biomédica en Red de Salud Mental, Uppsala Universitet, Diakonhjemmet, Fujita Health University, Rheinische Friedrich-Wilhelms-Universität Bonn, Science for Life Laboratory, Haukeland Universitetssjukehus, Università degli Studi di Perugia, National University Health System, Hjartavernd, Centre for Cognitive Ageing and Cognitive Epidemiology, Epilepsy Society, Instituto de Investigación Marqués de Valdecilla, Amsterdam Neuroscience, Avera Institute for Human Genetics, Max Planck Instituut voor Psycholinguïstiek, National Institutes of Health, University of California, Los Angeles, University of California, San Diego, Perelman School of Medicine, University of Pennsylvania, Leonard M. Miller School of Medicine, School of Medicine, Indiana University, Stanley Center for Psychiatric Research, Broad Institute, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Medical Research Council, Brain Research Imaging Centre, University of Edinburgh, Queensland Brain Institute, Erasmus Universitair Medisch Centrum Rotterdam, National Institute on Aging, National Heart, Lung, and Blood Institute, National Institute of Mental Health, National Institute of Neurological Disorders and Stroke, National Institute of Biomedical Imaging and Bioengineering, U.S. National Library of Medicine, National Center for Advancing Translational Sciences, National Institute for Physiological Sciences
Awards: Epidemiologic Study of Neural Reserve and Neurobiology of Aging, 1/3-A Neurobehavioral Family Study of Schizophrenia, UC Davis Alzheimer's Disease Core Center, Centre for Cognitive Ageing & Cognitive Epidemiology, G1595590610, CHARGE: Identifying Risk & Protective SNV for AD in ADSP Case-control Sample, 1/2 Genetics of Brain Structure and Function, Brain imaging and cognitive ageing in the Lothian Birth Cohort 1936: III, G214445032, Rare variants and NHLBI traits in deeply phenotyped cohorts, G232264632, Using genetic variability in whole transcriptome expression in cells and tissues to understand the pathogenesis of Parkinson's and Alzheimer's disease, CHS research resources for the cardiovascular health of older adults, Integration of Bio-, Medical, and Imaging Informatics for Complex Diseases, Neuroimaging genetics to study social cognitive deficits in ASD and schizophrenia, G3706078857, G4261184745, ARIC Neurocognitive Study (ARIC-NCS) Renewal UNC 4 of 5, Alzheimer's disease risk analyzed using population imaging genomics, MRC Brain Banks: Joint Application to Underpin Neuroscience Research, G4869640648, Risk Factors, Pathology, and Clinical Expressions of AD, ARIC Neurocognitive Study (ARIC-NCS) Renewal 4 of 5, Rush Alzheimer's Disease Core Center, G5364873420, Integrating Neuroimaging, Multi-omics, and Clinical Data in Complex Disease, G583528397, Genetics of Brain Structure and Function: Genome-Wide Association, CHARGE consortium: omics discovery for CVD and aging phenotypes, Vascular Cognitive and Motor Decline: Impact of aPL, ENIGMA Center for Worldwide Medicine, Imaging & Genomics, Genetic Influences on Human Cortical Development, Stratifying Resilience and Depression Longitudinally (STRADL), Using transcriptomics to transform the diagnosis and understanding of inherited adult neurological disorders, Transforming statistical methodology for neuroimaging meta-analysis., ARIC Neurocognitive Study (ARIC-NCS) Renewal 2 of 5, ARIC Neurocognitive Study (ARIC-NCS), G6951299480, Alzheimer Disease Research Center, Johns Hopkins Alzheimer's Disease Research Center, Training Grant in Neurobehavioral Genetics, G7899427922, Growth factors, neuroinflammation, exercise, and brain integrity, Risk Factors, Pathology, and Clinical Expressions of AD, Dimensional Neurogenetic Markers of Limbic System Integrity & Psychiatric Illness, G86511330, Epidemiology of Dementia in the Framingham Study, ARIC Neurocognitive Study (ARIC-NCS) Renewal 2023-2028, Training Grant in Neurobehavioral Genetics, Yale Clinical and Translational Science Award, Precursors of Stroke Incidence and Prognosis, Genomic Studies of Bipolar Disorder in a Large Cohort from The Netherlands, G986231656
OpenAlex ID: W2574432813