Novel genetic loci underlying human intracranial volume identified through genome-wide association

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Jeroen van der Grond, Aad van der Lugt, Marjolein M. J. van Donkelaar, Kristel R. van Eijk, D. van der Meer, Marcel van der Brug, Nic J. A. van der Wee, Cornelia M. van Duijn, Neeltje E. M. van Haren, Marie-Jose van Tol, Hieab H. Hhh AdamsORCID, Derrek P. Hibar, Vincent Chouraki, Jason L. Stein, Paul A. Nyquist, Miguel E. Rentería, Stella Trompet, Alejandro Arias-Vasquez, Sudha Seshadri, Sylvane DesrivièresORCID, Sven J. Van der LeeORCID, Ashley H. Beecham, Neda Jahanshad, Katharina Wittfeld, Lucija Abramovic, Saud Alhusaini, Najaf Amin, Micael Andersson, Konstantinos Arfanakis, Benjamin S. Aribisala, Nicola J. ArmstrongORCID, Manon Bernard, Lavinia Athanasiu, Tomas Axelsson, Joshua C. Bis, Laura M. E. Blanken, Susan H. Blanton, Marc Mar Bohlken, Janita Bralten, Adam M. Brickman, Owen Carmichael, Sj Van Der Lee, Mm Mallar Chakravarty, Ganesh Chauhan, Qiang Chen, Gabriel Cuellar-Partida, Sven J. van der Lee, Anouk Den Braber, M. Bernard, Nhat Trung Doan, Stefan Ehrlich, Irina Filippi, Tian Ge, Alex BeiserORCID, Sudheer Giddaluru, Aaron L. Goldman, Rebecca F. Gottesman, Corina U. Greven, Bernard Bernard, Oliver Grimm, Michael E. Griswold, Tulio Guadalupe, Johanna Hass, Mar BoksORCID, Unn K. Haukvik, Saima Hilal, Edith Hofer, David Hoehn, Avram J. Holmes, Christophe R. K. Ching, Martine Hoogman, Deborah Janowitz, Tianye Jia, Dalia Kasperaviciute, Sungeun Kim, Bernd Kraemer, Phil H. LeeORCID, Li Liao, Jiemin Liao, David C. M. LiewaldORCID, Lorna M. Lopez, Mar Marquand, Michelle Luciano, Christine Macare, Andre Marquand, Mar Matarin, Edith Ho, Karen A. Mather, Manuel MattheisenORCID, Bernard MazoyerORCID, David R. McKay, David Ho, Rebekah McWhirter, Yuri Milaneschi, Nazanin Mirza-Schreiber, Avram J. Ho, Ryan L. Muetzel, Susana Muñoz Maniega, Kwangsik Nho, Allison C. Nugent, Mar Martin, Loes M. Olde LoohuisORCID, Jaap Oosterlaan, Martina Papmeyer, Irene Pappa, Mar KleinORCID, Lukas Pirpamer, Sara Pudas, Benno Pütz, Kumar B. Rajan, Adaikalavan Ramasamy, Jennifer S. Richards, Shannon L. Risacher, Nanda Rommelse, Susana Munoz Maniega, Emma J. Rose, Natalie A. Royle, Tatjana Rundek, Philipp G. Sämann, Claudia L. SatizabalORCID, Andrew J. Schork, Loes M. Olde Loohuis, Li ShenORCID, Theo G. M. Van Erp, Jean Shin, Elena Shumskaya, Albert V. SmithORCID, Emma Sprooten, Lachlan T. Strike, Martina Martin, Russell J. (R18461) Thomson, Diana Tordesillas-Gutierrez, Robert Roiz-SantiañezORCID, Daniah TrabzuniORCID, Dhananjay Vaidya, Li Schmaal, Dennis Van der Meer, Alex TeumerORCID, Robert Toro, Marjolein M. J. Van Donkelaar, Kristel R. van Eijk, Daan Van Rooij, Esther Walton, Lars T. WestlyeORCID, Daan van Rooij, Christophe D. Whelan, Beverly G. Windham, Anderson M. WinklerORCID, Girma Woldehawariat, Christiane Wolf, Thomas W. Wolfers, Bing Xu, J. Van Der GrondORCID, Lisa R. Yanek, Jingyun Yang, Alex Zijdenbos, Marcel P. Zwiers, Mmj Van Donkelaar, Ingrid Agartz, Neelum T. Aggarwal, Laura Almasy, David A. Ames, Kr Van Eijk, Philippe AmouyelORCID, Ole Andreas AndreassenORCID, Sampath Arepalli, Amelia Aa Assareh, Tgm Van ErpORCID, Sandra Barral, Mark E. Bastin, Diane M. Becker, James T. BeckerORCID, David A. Bennett, John B. Blangero, Hans van Bokhoven, Dorret I. Boomsma, Henry BrodatyORCID, Rachel M. Brouwer, Hans van Bokhoven, Han G. Brunner, Randy L. Buckner, Jan K. Buitelaar, Kazima B. Bulayeva, Wiepke Cahn, Vince D. CalhounORCID, Dara M. Cannon, Gianpiero L. Cavalleri, Eco J. de Geus, Ching-Yu Cheng, Christophe Chen, Sven Cichon, Mark R. Cookson, Aiden Corvin, Benedicto Crespo-Facorro, Philip L. de Jager, Joanne E. Curran, Michael Czisch, Anders M. Dale, Gareth E. Davies, Greig I. de Zubicaray, Philip L. De Jager, Eco J. C. de Geus, Greig I. de Zubicaray, Norman Delanty, Chantal Depondt, Anita L. DeStefano, Allissa Dillman, Ejc J. C. De Geus, Srdjan Djurovic, Gary Donohoe, Wayne C. Drevets, Ravi Duggirala, Thomas D. DyerORCID, Susanne Erk, Gi De Zubicaray, Thomas E. Espeseth, Denis A. Evans, Iryna O. Fedko, Guillén Fernández, Luigi Ferrucci, Simon E. FisherORCID, Al Destefano, Debra A. Fleischman, Ian Ford, Tatiana M. Foroud, Peter T. Fox, Clyde Francks, Masaki Fukunaga, Harald Hhh Goring, J. Raphael Gibbs, David C. Glahn, Randy L. Gollub, Harald H. H. Göring, Hans J. Grabe, Robert C. Green, Oliver Gruber, Vilmundur Gudnason, Pg G. Samann, Sebastian Guelfi, Narelle K. Hansell, John Hardy, Catharina A. Hartman, Ryota HashimotoORCID, Hilleke E. Hulshoff Pol, Katrin Hegenscheid, Andreas Heinz, Stephanie Le Hellard, Dena G. Hernandez, Dirk J. Heslenfeld, Beng-Choon HoORCID, B.-C. Ho, Pieter J. Hoekstra, Wolfgang Hoffmann, Albert Hofman, Florian Holsboer, Georg Homuth, Eg Jonsson, Norbert Hosten, Jouke-Jan Hottenga, Hilleke E. Hulshoff Pol, Masashi Ikeda, Mk Kamran Ikram, Clifford R. Jack, Mark Jenkinson, Clifford R. Jack Jr, Robert Johnson, Erik G. Jönsson, Jw Wouter Jukema, René S. Kahn, Ryota Kanai, Iwona Kloszewska, Oliver Martin, David S. Knopman, Peter Kochunov, John B. Kwok, Stephen M. Lawrie, Hervé Lemaître, Xinmin Liu, Dan L. Longo, Wt T. Longstreth, W. T. Longstreth Jr, Oscar L. Lopez, Simon Lovestone, Oliver P. Martinez, Jean-Luc Martinot, Jean-Luc Martin, Venkata S. Mattay, Colm McDonald, Andrew M. McIntoshORCID, Katie L. McMahonORCID, Andrew Mcintosh, Francis J. McMahon, Patrizia Mecocci, Ingrid Melle, Andreas Meyer-LindenbergORCID, Sebastian Mohnke, Grant W. Montgomery, Markus Mm Nothen, Derek W. MorrisORCID, Thomas H. Mosley, Thomas W. MühleisenORCID, Bertram Müller-Myhsok, Michael A. Nalls, Matthias Nauck, Thomas E. NicholsORCID, 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, Gb Bruce PikeORCID, Steven G. Potkin, Bruce M. Psaty, Marcel Rietschel, Simone Reppermund, Joshua L. Roffman, Nina Romanczuk-Seiferth, Maria C. Valdes Hernandez, Jerome I. Rotter, Mina Ryten, Ralph L. Sacco, Perminder S. SachdevORCID, Andrew J. SaykinORCID, Reinhold Schmidt, Marcel van der Brug, Peter R. SchofieldORCID, Sigurdur Sigurdsson, Andy Simmons, Andrew Singleton, Sanjay M. Sisodiya, Aad van der Lugt, Colin Smith, Jordan W. Smoller, Hilkka Soininen, Velandai Srikanth, Vidar M. Steen, David J. Stott, Nic J. van der Wee, Jessika E. Sussmann, Anbupalam Thalamuthu, Henning TiemeierORCID, Arthur W. Toga, Bryan J. Traynor, Juan Troncoso, Cornelia M. van Duijn, Jessica A. TurnerORCID, Christophe TzourioORCID, A. Van Der Lugt, Andre G. Uitterlinden, Neeltje E. van Haren, Maria C. Valdés Hernández, Nja Van Der Wee, Dennis Van′t Ent, Marie-Jose van Tol, Cm Van Duijn, Dennis Van ′t Ent, Nem Van Haren, Badri N. Vardarajan, Dennis Van T. Ent, Dick J. Veltman, Meike W. Vernooij, Henry Völzke, Henrik Walter, Joanna M. WardlawORCID, Wei Weinberger, Thomas H. Wassink, Michael E. WealeORCID, Daniel R. Weinberger, Michael Wei Weiner, Wei Wen, Eric Westman, Tonya White, C. Decarli, Tien Y. Wong, Clinton B. Wright, Hr Ronald Zielke, Alan B. Zonderman, Ian J. Deary, Charles DeCarli, Nicholas G. Martin, Helena Schmidt, Anton J. M. de Craen, N. G. Martin, Margaret J. Wright, Anton J. de Craen, Ng Martin, Ajm De Craen, Lenore J. Launer, Gunter Schumann, Myriam Fornage, Barbara FrankeORCID, Stéphanie Debette, Sarah E. Medland, M. Arfan IkramORCID, Paul M. Thompson

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Abstract
Intracranial volume reflects the maximally attained brain size during development, and remains stable with loss of tissue in late life. It is highly heritable, but the underlying genes remain largely undetermined. In a genome-wide association study of 32,438 adults, we discovered five previously unknown loci for intracranial volume and confirmed two known signals. Four of the loci were also associated with adult human stature, but these remained associated with intracranial volume after adjusting for height. We found a high genetic correlation with child head circumference (genetic = 0.748), which indicates a similar genetic background and allowed us to identify four additional loci through meta-analysis (N combined = 37,345). Variants for intracranial volume were also related to childhood and adult cognitive function, and Parkinson's disease, and were enriched near genes involved in growth pathways, including PI3K-AKT signaling. These findings identify the biological underpinnings of intracranial volume and their link to physiological and pathological traits. 2016 Nature America, Inc., part of Springer Nature. All rights reserved.