Genetic architecture of subcortical brain structures in 38,851 individuals.
Nature genetics
Authors:
Claudia L Satizabal, Hieab H H Adams, Derrek P Hibar, Charles C White, Maria J Knol, Jason L Stein, Markus Scholz, Muralidharan Sargurupremraj, Neda Jahanshad, Gennady V Roshchupkin, Albert V Smith, Joshua C Bis, Xueqiu Jian, Michelle Luciano, Edith Hofer, Alexander Teumer, Sven J van der Lee, Jingyun Yang, Lisa R Yanek, Tom V Lee, Shuo Li, Yanhui Hu, Jia Yu Koh, John D Eicher, Sylvane Desrivières, Alejandro Arias-Vasquez, Ganesh Chauhan, Lavinia Athanasiu, Miguel E Rentería, Sungeun Kim, David Hoehn, Nicola J Armstrong, Qiang Chen, Avram J Holmes, Anouk den Braber, Iwona Kloszewska, Micael Andersson, Thomas Espeseth, Oliver Grimm, Lucija Abramovic, Saud Alhusaini, Yuri Milaneschi, Martina Papmeyer, Tomas Axelsson, Stefan Ehrlich, Roberto Roiz-Santiañez, 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, Marco P Boks, Mar Matarin, Brenda W J H Penninx, Vince D Calhoun, M Mallar Chakravarty, Andre F Marquand, Christine Macare, Shahrzad Kharabian Masouleh, Jaap Oosterlaan, 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, Eco J C de Geus, 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, Dick J Veltman, 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, Paul M Thompson, Sudha Seshadri, M Arfan Ikram
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.