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Identification of common variants associated with human hippocampal and intracranial volumes

Author(s): J. L. Stein, S. E. Medland, A. A. Vasquez, D. P. Hibar, R. E. Senstad, A. M. Winkler, R. Toro, K. Appel, R. Bartecek, O. Bergmann, M. Bernard, A. A. Brown, D. M. Cannon, M. M. Chakravarty, A. Christoforou, M. Domin, O. Grimm, M. Hollinshead, A. J. Holmes, G. Homuth, J. J. Hottenga, C. Langan, L. M. Lopez, N. K. Hansell, K. S. Hwang, S. Kim, G. Laje, P. H. Lee, X. Liu, E. Loth, A. Lourdusamy, M. Mattingsdal, S. Mohnke, S. M. Maniega, K. Nho, A. C. Nugent, C. O'Brien, M. Papmeyer, B. Putz, A. Ramasamy, J. Rasmussen, M. Rijpkema, S. L. Risacher, J. C. Roddey, E. J. Rose, M. Ryten, L. Shen, E. Sprooten, E. Strengman, A. Teumer, D. Trabzuni, J. Turner, K. van Eijk, T. G. van Erp, M. J. van Tol, K. Wittfeld, C. Wolf, S. Woudstra, A. Aleman, S. Alhusaini, L. Almasy, E. B. Binder, D. G. Brohawn, R. M. Cantor, M. A. Carless, A. Corvin, M. Czisch, J. E. Curran, G. Davies, M. A. de Almeida, N. Delanty, C. Depondt, R. Duggirala, T. D. Dyer, S. Erk, J. Fagerness, P. T. Fox, N. B. Freimer, M. Gill, H. H. Goring, D. J. Hagler, D. Hoehn, F. Holsboer, M. Hoogman, N. Hosten, N. Jahanshad, M. P. Johnson, D. Kasperaviciute, J. W., Jr. Kent, P. Kochunov, J. L. Lancaster, S. M. Lawrie, D. C. Liewald, R. Mandl, M. Matarin, M. Mattheisen, E. Meisenzahl, I. Melle, E. K. Moses, T. W. Muhleisen, M. Nauck, M. M. Nothen, R. L. Olvera, M. Pandolfo, G. B. Pike, R. Puls, I. Reinvang, M. E. Renteria, M. Rietschel, J. L. Roffman, N. A. Royle, D. Rujescu, J. Savitz, H. G. Schnack, K. Schnell, N. Seiferth, C. Smith, V. M. Steen, M. C. Valdes Hernandez, M. Van den Heuvel, N. J. van der Wee, N. E. Van Haren, J. A. Veltman, H. Volzke, R. Walker, L. T. Westlye, C. D. Whelan, I. Agartz, D. I. Boomsma, G. L. Cavalleri, A. M. Dale, S. Djurovic, W. C. Drevets, P. Hagoort, J. Hall, A. Heinz, C. R., Jr. Jack, T. M. Foroud, S. Le Hellard, F. Macciardi, G. W. Montgomery, J. B. Poline, D. J. Porteous, S. M. Sisodiya, J. M. Starr, J. Sussmann, A. W. Toga, D. J. Veltman, H. Walter, M. W. Weiner, J. C. Bis, M. A. Ikram, A. V. Smith, V. Gudnason, C. Tzourio, M. W. Vernooij, L. J. Launer, C. DeCarli, S. Seshadri, O. A. Andreassen, L. G. Apostolova, M. E. Bastin, J. Blangero, H. G. Brunner, R. L. Buckner, S. Cichon, G. Coppola, G. I. de Zubicaray, I. J. Deary, G. Donohoe, E. J. de Geus, T. Espeseth, G. Fernandez, D. C. Glahn, H. J. Grabe, J. Hardy, H. E. Hulshoff Pol, M. Jenkinson, R. S. Kahn, C. McDonald, A. M. McIntosh, F. J. McMahon, K. L. McMahon, A. Meyer-Lindenberg, D. W. Morris, B. Muller-Myhsok, T. E. Nichols, R. A. Ophoff, T. Paus, Z. Pausova, B. W. Penninx, S. G. Potkin, P. G. Samann, A. J. Saykin, G. Schumann, J. W. Smoller, J. M. Wardlaw, M. E. Weale, N. G. Martin, B. Franke, M. J. Wright, P. M. Thompson

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 x 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 x 10(-12)). We also identified a suggestive association with total brain volume at rs10494373 within DDR2 (1q23.3; N = 6,500; P = 5.81 x 10(-7)).

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ISBN: 1546-1718 (Electronic) 1061-4036 (Linking)
Publication Year: 2012
Periodical: Nat Genet
Periodical Number: 5
Volume: 44
Pages: 552-61
Author Address: Laboratory of Neuro Imaging, David Geffen School of Medicine, University of California, Los Angeles, California, USA.