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. 2012 Apr 15;44(5):552-61.
doi: 10.1038/ng.2250.

Identification of common variants associated with human hippocampal and intracranial volumes

Jason L Stein  1 , 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 Homuth, Jouke-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 Jr, 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 Jr, Tatiana M 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; Alzheimer's Disease Neuroimaging Initiative; EPIGEN Consortium; IMAGEN Consortium; Saguenay Youth Study Group; Joshua C Bis, M Arfan Ikram, Albert V Smith, Vilmundur Gudnason, Christophe Tzourio, Meike W Vernooij, Lenore J Launer, Charles DeCarli, Sudha Seshadri; Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium; 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 Fernández, 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; Enhancing Neuro Imaging Genetics through Meta-Analysis Consortium
Collaborators, Affiliations

Identification of common variants associated with human hippocampal and intracranial volumes

Jason L Stein et al. Nat Genet. .

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)).

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Figures

Figure 1
Figure 1
Association results and meta-analysis of effects in individual and combined analyses. (a) The strongest association with hippocampal volume was found for rs7294919. Fixed-effects meta-analysis P values are shown after controlling for intracranial volume using all subjects in the discovery sample. (b) The strongest association with intracranial volume was found for rs10784502. Fixed-effects meta-analysis P values are shown in healthy subjects only. (c,d) The effect within each sample contributing to the meta-analysis is shown in forest plots for hippocampal volume (c) and intracranial volume (d). Association data using intracranial volume as a phenotype were not available for the EPIGEN sample. Head size was not controlled for in the CHARGE Consortium association analyses.
Figure 2
Figure 2
Association of rs7294919 with hippocampal volume stratified by disease and covariates. Effects are consistent in the discovery sample regardless of whether individuals with disease (N = 7,795) or only healthy subjects (N = 5,775) were included. The effect is also consistent whether accounting for intracranial volume (ICV), total brain volume (TBV) or without a measure of head size (Other).
Figure 3
Figure 3
Regulatory effects of hippocampal-associated variant and expression of TESC within the hippocampus. (a–d) The locus most associated with hippocampal volume was also associated with mRNA expression of the TESC gene in brain in three independent samples, the UCL epilepsy cohort (a), the SNPExpress database (b), where a proxy SNP was used, and the UK Brain Expression Database (d), where differences in TESC expression of the directly genotyped hippocampal variant (rs7294919) were strongest in the temporal cortex (TCTX) (red box) but also found in the average expression of all cortex (AvgCTX) and average expression of all brain structures tested (AvgALL). Symbol color represents genotype in a and d. These regional gradients in expression support the hypothesis that the SNP may associate with hippocampal but not total brain volume. No effects were detected in PBMCs from the SNPExpress database (c). CRBL, cerebellar cortex; FCTX, frontal cortex; HIPP, hippocampus; MEDU, medulla (specifically the inferior olivary nucleus); OCTX, occipital cortex; PUTM, putamen; SNIG, substantia nigra; THAL, thalamus; WHMT, intralobular white matter. (e) TESC is differentially expressed within the fetal human brain (P = 1.33 × 10−12), with the highest expression in striatum (STRIAT) and hippocampus (HIPP). Box plots represent median and 25th to 75th percentiles. Upper and lower lines show minimum and maximum values, respectively. CBLM, cerebellum; DLPFC, dorsolateral prefrontal neocortex; MPFC, medial prefrontal neocortex; MS, motor-somatosensory neocortex; OCC, occipital visual neocortex; OFC, orbital prefrontal neocortex; PAS, parietal association neocortex; TAC, temporal association neocortex; TAU, temporal auditory neocortex; THAL, mediodorsal thalamus; VLPFC, ventrolateral prefrontal neocortex. (f) TESC has moderate to high gene expression throughout the adult human hippocampus (shown in green), as visualized in the Allen Institute Human Brain Atlas using Brain Explorer 2 software. An inferior view of the brain is shown in two subjects; the anterior portion of the brain is at the top. The colors of spheres within the hippocampus indicate the Z-scores of TESC expression normalized within each subject across brain structures. Heat maps show that expression of TESC is higher in the hippocampus (HiF) and striatum (Str) than in other brain structures.
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