Identification of common variants associated with human hippocampal and intracranial volumes

Jason L. Stein, Sarah E. Medland, Alejandro Arias Vasquez, Derrek P. Hibar, Rudy E. Senstad, Anderson M. Winkler, Roberto Toro, Katja Appel, Richard Bartecek, Ørjan Bergmann, Manon Bernard, Andrew A. Brown, Dara M. Cannon, M. Mallar Chakravarty, Andrea Christoforou, Martin Domin, Oliver Grimm, Marisa Hollinshead, Avram J. Holmes, Georg HomuthJouke Jan Hottenga, Camilla Langan, Lorna M. Lopez, Narelle K. Hansell, Kristy S. Hwang, Sungeun Kim, Gonzalo Laje, Phil H. Lee, Xinmin Liu, Eva Loth, Anbarasu Lourdusamy, Morten Mattingsdal, Sebastian Mohnke, Susana Muñoz Maniega, Kwangsik Nho, Allison C. Nugent, Carol O'brien, Martina Papmeyer, Benno Pütz, Adaikalavan Ramasamy, Jerod Rasmussen, Mark Rijpkema, Shannon L. Risacher, J. Cooper Roddey, Emma J. Rose, Mina Ryten, Li Shen, Emma Sprooten, Eric Strengman, Alexander Teumer, Daniah Trabzuni, Jessica Turner, Kristel Van Eijk, Theo G.M. Van Erp, Marie Jose Van Tol, Katharina Wittfeld, Christiane Wolf, Saskia Woudstra, Andre Aleman, Saud Alhusaini, Laura Almasy, Elisabeth B. Binder, David G. Brohawn, Rita M. Cantor, Melanie A. Carless, Aiden Corvin, Michael Czisch, Joanne E. Curran, Gail Davies, Marcio A.A. De Almeida, Norman Delanty, Chantal Depondt, Ravi Duggirala, Thomas D. Dyer, Susanne Erk, Jesen Fagerness, Peter T. Fox, Nelson B. Freimer, Michael Gill, Harald H.H. Göring, Donald J. Hagler, David Hoehn, Florian Holsboer, Martine Hoogman, Norbert Hosten, Neda Jahanshad, Matthew P. Johnson, Dalia Kasperaviciute, Jack W. Kent, Peter Kochunov, Jack L. Lancaster, Stephen M. Lawrie, David C. Liewald, René Mandl, Mar Matarin, Manuel Mattheisen, Eva Meisenzahl, Ingrid Melle, Eric K. Moses, Thomas W. Mühleisen, Matthias Nauck, Markus M. Nöthen, Rene L. Olvera, Massimo Pandolfo, G. Bruce Pike, Ralf Puls, Ivar Reinvang, Miguel E. Rentería, Marcella Rietschel, Joshua L. Roffman, Natalie A. Royle, Dan Rujescu, Jonathan Savitz, Hugo G. Schnack, Knut Schnell, Nina Seiferth, Colin Smith, Vidar M. Steen, Maria C.Valdés Hernández, Martijn Van Den Heuvel, Nic J. Van Der Wee, Neeltje E.M. Van Haren, Joris A. Veltman, Henry Völzke, Robert Walker, Lars T. Westlye, Christopher D. Whelan, Ingrid Agartz, Dorret I. Boomsma, Gianpiero L. Cavalleri, Anders M. Dale, Srdjan Djurovic, Wayne C. Drevets, Peter Hagoort, Jeremy Hall, Andreas Heinz, Clifford R. Jack, Tatiana Foroud, Stephanie Le Hellard, Fabio Macciardi, Grant W. Montgomery, Jean Baptiste Poline, David J. Porteous, Sanjay M. Sisodiya, John M. Starr, Jessika Sussmann, Arthur W. Toga, Dick J. Veltman, Henrik Walter, Michael W. Weiner, Joshua C. Bis, M. Arfan Ikram, Albert V. Smith, Vilmundur Gudnason, Christophe Tzourio, Meike W. Vernooij, Lenore J. Launer, Charles Decarli, Sudha Seshadri, Ole A. Andreassen, Liana G. Apostolova, Mark E. Bastin, John Blangero, Han G. Brunner, Randy L. Buckner, Sven Cichon, Giovanni Coppola, Greig I. De Zubicaray, Ian J. Deary, Gary Donohoe, Eco J.C. De Geus, Thomas Espeseth, Guillén Fernéndez, David C. Glahn, Hans J. Grabe, John Hardy, Hilleke E. Hulshoff Pol, Mark Jenkinson, René S. Kahn, Colm Mcdonald, Andrew M. Mcintosh, Francis J. Mcmahon, Katie L. Mcmahon, Andreas Meyer-Lindenberg, Derek W. Morris, Bertram Müller-Myhsok, Thomas E. Nichols, Roel A. Ophoff, Tomas Paus, Zdenka Pausova, Brenda W. Penninx, Steven G. Potkin, Philipp G. Sämann, Andrew J. Saykin, Gunter Schumann, Jordan W. Smoller, Joanna M. Wardlaw, Michael E. Weale, Nicholas G. Martin, Barbara Franke, Margaret J. Wright, Paul M. Thompson

Research output: Contribution to journalArticle

410 Scopus citations

Abstract

Identifying genetic variants influencing human brain structures may reveal new biological mechanisms underlying cognition and neuropsychiatric illness. The volume of the hippocampus is a biomarker of incipient Alzheimer's disease and is reduced in schizophrenia, major depression and mesial temporal lobe epilepsy. Whereas many brain imaging phenotypes are highly heritable, identifying and replicating genetic influences has been difficult, as small effects and the high costs of magnetic resonance imaging (MRI) have led to underpowered studies. Here we report genome-wide association meta-analyses and replication for mean bilateral hippocampal, total brain and intracranial volumes from a large multinational consortium. The intergenic variant rs7294919 was associated with hippocampal volume (12q24.22; N = 21,151; P = 6.70 × 10 -16) and the expression levels of the positional candidate gene TESC in brain tissue. Additionally, rs10784502, located within HMGA2, was associated with intracranial volume (12q14.3; N = 15,782; P = 1.12 × 10 -12). We also identified a suggestive association with total brain volume at rs10494373 within DDR2 (1q23.3; N = 6,500; P = 5.81 × 10 -7).

Original languageEnglish (US)
Pages (from-to)552-561
Number of pages10
JournalNature genetics
Volume44
Issue number5
DOIs
StatePublished - May 2012

ASJC Scopus subject areas

  • Genetics

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    Stein, J. L., Medland, S. E., Vasquez, A. A., Hibar, D. P., Senstad, R. E., Winkler, A. M., Toro, R., Appel, K., Bartecek, R., Bergmann, Ø., Bernard, M., Brown, A. A., Cannon, D. M., Chakravarty, M. M., Christoforou, A., Domin, M., Grimm, O., Hollinshead, M., Holmes, A. J., ... Thompson, P. M. (2012). Identification of common variants associated with human hippocampal and intracranial volumes. Nature genetics, 44(5), 552-561. https://doi.org/10.1038/ng.2250