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Genetic architecture of subcortical brain structures in 38,851 individuals

  • Bernd Kraemer
  • , Asta K. Håberg
  • , Hannah J. Jones
  • , G. Bruce Pike
  • , Dan J. Stein
  • , Allison Stevens
  • , Janita Bralten
  • , Meike W. Vernooij
  • , Tamara B. Harris
  • , Irina Filippi
  • , A. Veronica Witte
  • , Tulio Guadalupe
  • , Katharina Wittfeld
  • , Thomas H. Mosley
  • , James T. Becker
  • , Nhat Trung Doan
  • , Saskia P. Hagenaars
  • , Yasaman Saba
  • , Gabriel Cuellar-Partida
  • , Najaf Amin
  • Saima Hilal, Kwangsik Nho, Nazanin Mirza-Schreiber, Konstantinos Arfanakis, Diane M. Becker, David Ames, Aaron L. Goldman, Phil H. Lee, Dorret I. Boomsma, Simon Lovestone, Sudheer Giddaluru, Stephanie le Hellard, Manuel Mattheisen, Marc M. Bohlken, Dalia Kasperaviciute, Lianne Schmaal, Stephen M. Lawrie, Ingrid Agartz, Esther Walton, Diana Tordesillas-Gutierrez, Gareth E. Davies, Jean Shin, Jonathan C. Ipser, Louis N. Vinke, Martine Hoogman, Tianye Jia, Ralph Burkhardt, Marieke Klein, Fabrice Crivello, Deborah Janowitz, Owen Carmichael, Unn K. Haukvik, Benjamin S. Aribisala, Helena Schmidt, Lachlan T. Strike, Ching-Yu Cheng, Shannon L. Risacher, Benno Pütz, Debra A. Fleischman, Amelia A. Assareh, Venkata S. Mattay, Randy L. Buckner, Patrizia Mecocci, Anders M. Dale, Sven Cichon, Mar Matarin, Vince D. Calhoun, M. Mallar Chakravarty, Andre F. Marquand, Christine Macare, Shahrzad Kharabian Masouleh, Philippe Amouyel, Katrin Hegenscheid, Jerome I. Rotter, Andrew J. Schork, David C. M. Liewald, Greig I. de Zubicaray, Tien Yin Wong, Li Shen, Philipp G. Sämann, Henry Brodaty, Joshua L. Roffman, Magda Tsolaki, Susanne Erk, Kristel R. van Eijk, Gianpiero L. Cavalleri, Nic J. A. van der Wee, Andrew M. McIntosh, Randy L. Gollub, Kazima B. Bulayeva, Manon Bernard, Jennifer S. Richards, Jayandra J. Himali, Markus Loeffler, Nanda Rommelse, Wolfgang Hoffmann, Lars T. Westlye, Maria C. Valdés Hernández, Narelle K. Hansell, Theo G. M. van Erp, Christiane Wolf, John B. J. Kwok, Bruno Vellas, Andreas Heinz, Loes M. Olde Loohuis, Norman Delanty, Beng-Choon Ho, Christopher R. K. Ching, Elena Shumskaya, Baljeet Singh, Albert Hofman, Dennis van der Meer, Georg Homuth, Bruce M. Psaty, Mark E. Bastin, Grant W. Montgomery, Tatiana M. Foroud, Simone Reppermund, Jouke-Jan Hottenga, Andrew Simmons, Andreas Meyer-Lindenberg, Wiepke Cahn, Christopher D. Whelan, Marjolein M. J. van Donkelaar, Qiong Yang, Norbert Hosten, Robert C. Green, Anbupalam Thalamuthu, Sebastian Mohnke, Hilleke E. Hulshoff Pol, Honghuang Lin, Clifford R. Jack, Peter R. Schofield, Thomas W. Mühleisen, Pauline Maillard, Steven G. Potkin, Wei Wen, Evan Fletcher, Arthur W. Toga, Oliver Gruber, Matthew Huentelman, George Davey Smith, Lenore J. Launer, Lars Nyberg, Erik G. Jönsson, Benedicto Crespo-Facorro, Nastassja Koen, Douglas N. Greve, André G. Uitterlinden, Daniel R. Weinberger, Vidar M. Steen, Iryna O. Fedko, Nynke A. Groenewold, Wiro J. Niessen, Roberto Toro, Christophe Tzourio, William T. Longstreth, M. Kamran Ikram, Jordan W. Smoller, Marie-Jose van Tol, Jessika E. Sussmann, Tomas Paus, Hervé Lemaître, Matthias L. Schroeter, Bernard Mazoyer, Ole A. Andreassen, Florian Holsboer, Chantal Depondt, Jessica A. Turner, Zdenka Pausova, Gunter Schumann, Daan van Rooij, Srdjan Djurovic, Ian J. Deary, Katie L. McMahon, Bertram Müller-Myhsok, Rachel M. Brouwer, Hilkka Soininen, Massimo Pandolfo, Thomas H. Wassink, Joshua W. Cheung, Thomas Wolfers, Jean-Luc Martinot, Marcel P. Zwiers, Matthias Nauck, Ingrid Melle, Nicholas G. Martin, Ryota Kanai, Eric Westman, René S. Kahn, Sanjay M. Sisodiya, Tonya White, Arvin Saremi, Hans van Bokhoven, Han G. Brunner, Henry Völzke, Margaret J. Wright, Dennis van ‘t Ent, Markus M. Nöthen, Roel A. Ophoff, Jan K. Buitelaar, Guillén Fernández, Perminder S. Sachdev, Marcella Rietschel, Neeltje E. M. van Haren, Simon E. Fisher, Alexa S. Beiser, Clyde Francks, Andrew J. Saykin, Karen A. Mather, Nina Romanczuk-Seiferth, Catharina A. Hartman, Anita L. DeStefano, Dirk J. Heslenfeld, Michael W. Weiner, Henrik Walter, Pieter J. Hoekstra, Paul A. Nyquist, Barbara Franke, David A. Bennett, Hans J. Grabe, Andrew D. Johnson, Christopher Chen, Cornelia M. van Duijn, Oscar L. Lopez, Myriam Fornage, Joanna M. Wardlaw, Reinhold Schmidt, Charles DeCarli, Philip L. de Jager, Arno Villringer, Stéphanie Debette, Vilmundur Gudnason, Sarah E. Medland, Joshua M. Shulman, CHARGE, Marco P. Boks
  • University of Texas Health Science Center at San Antonio
  • National Institutes of Health
  • Boston University
  • Erasmus University Rotterdam
  • University of Southern California
  • Broad Institute
  • Columbia University
  • University of North Carolina at Chapel Hill
  • Leipzig University
  • Université de Bordeaux
  • University of Michigan, Ann Arbor
  • University of Iceland
  • Icelandic Heart Association
  • University of Washington
  • University of Texas Health Science Center at Houston
  • University of Edinburgh
  • Medical University of Graz
  • University of Medicine Greifswald
  • Rush University
  • Johns Hopkins University School of Medicine
  • Baylor College of Medicine
  • Harvard University
  • Singapore National Eye Center
  • King's College London
  • Radboud University Nijmegen
  • Indian Institute of Science Bangalore
  • University of Oslo
  • Queensland Institute of Medical Research
  • Indiana University-Purdue University Indianapolis
  • Max Planck Institute of Psychiatry
  • Murdoch University
  • Lieber Institute for Brain Development
  • Yale University
  • Brigham and Women’s Hospital
  • Medical University of Łódź
  • Umeå University
  • Universitätsmedizin Mannheim
  • Utrecht University
  • Royal College of Surgeons in Ireland
  • Bern University Hospital ‘Inselspital’
  • Uppsala University
  • Technische Universität Dresden
  • Hospital Universitario Marques de Valdecilla
  • CIBERSAM (Centro Investigación Biomédica en Red Salud Mental)
  • Erasmus University Medical Center

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Abstract

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.
Original languageEnglish
Pages (from-to)1624-1636
Number of pages13
JournalNature genetics
Volume51
Issue number11
Early online date1 Nov 2019
DOIs
Publication statusPublished - Nov 2019

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