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 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 A 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; Ravindranath Duggirala; Thomas D. Dyer; Susanne Erk; Jesen Fagerness; Peter T. Fox; Nelson B. Freimer; Michael Gill; Harald HH Goring; 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 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; 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 C 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

doi:10.1038/ng.2250

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 A 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, Ravindranath Duggirala, Thomas D. Dyer, Susanne Erk, Jesen Fagerness, Peter T. Fox, Nelson B. Freimer, Michael Gill, Harald HH Goring, 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 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, 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 C 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 journal › Article › peer-review

513 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 language	English (US)
Pages (from-to)	552-561
Number of pages	10
Journal	Nature Genetics
Volume	44
Issue number	5
DOIs	https://doi.org/10.1038/ng.2250
State	Published - May 2012

ASJC Scopus subject areas

Genetics

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10.1038/ng.2250

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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

Stein, JL, Medland, SE, Vasquez, AA, Hibar, DP, Senstad, RE, Winkler, AM, Toro, R, Appel, K, Bartecek, R, Bergmann, Ø, Bernard, M, Brown, AA, Cannon, DM, Chakravarty, MM, Christoforou, A, Domin, M, Grimm, O, Hollinshead, M, Holmes, AJ, Homuth, G, Hottenga, JJ, Langan, C, Lopez, LM, Hansell, NK, Hwang, KS, Kim, S, Laje, G, Lee, PH, Liu, X, Loth, E, Lourdusamy, A, Mattingsdal, M, Mohnke, S, Maniega, SM, Nho, K, Nugent, AC, O'brien, C, Papmeyer, M, Pütz, B, Ramasamy, A, Rasmussen, J, Rijpkema, M, Risacher, SL, Roddey, JC, Rose, EJ, Ryten, M, Shen, L, Sprooten, E, Strengman, E, Teumer, A, Trabzuni, D, Turner, J, Van Eijk, K, Van Erp, TGM, Van Tol, MJ, Wittfeld, K, Wolf, C, Woudstra, S, Aleman, A, Alhusaini, S, Almasy, LA, Binder, EB, Brohawn, DG, Cantor, RM, Carless, MA, Corvin, A, Czisch, M, Curran, JE, Davies, G, De Almeida, MAA, Delanty, N, Depondt, C, Duggirala, R, Dyer, TD, Erk, S, Fagerness, J, Fox, PT, Freimer, NB, Gill, M, Goring, HHH, Hagler, DJ, Hoehn, D, Holsboer, F, Hoogman, M, Hosten, N, Jahanshad, N, Johnson, MP, Kasperaviciute, D, Kent, JW, Kochunov, P, Lancaster, JL, Lawrie, SM, Liewald, DC, Mandl, R, Matarin, M, Mattheisen, M, Meisenzahl, E, Melle, I, Moses, EK, Mühleisen, TW, Nauck, M, Nöthen, MM, Olvera, RL, Pandolfo, M, Pike, GB, Puls, R, Reinvang, I, Rentería, ME, Rietschel, M, Roffman, JL, Royle, NA, Rujescu, D, Savitz, J, Schnack, HG, Schnell, K, Seiferth, N, Smith, C, Steen, VM, Hernández, MCV, Van Den Heuvel, M, Van Der Wee, NJ, Van Haren, NEM, Veltman, JA, Völzke, H, Walker, R, Westlye, LT, Whelan, CD, Agartz, I, Boomsma, DI, Cavalleri, GL, Dale, AM, Djurovic, S, Drevets, WC, Hagoort, P, Hall, J, Heinz, A, Jack, CR, Foroud, TM, Le Hellard, S, Macciardi, F, Montgomery, GW, Poline, JB, Porteous, DJ, Sisodiya, SM, Starr, JM, Sussmann, J, Toga, AW, Veltman, DJ, Walter, H, Weiner, MW, Bis, JC, Ikram, MA, Smith, AV, Gudnason, V, Tzourio, C, Vernooij, MW, Launer, LJ, Decarli, C, Seshadri, S, Andreassen, OA, Apostolova, LG, Bastin, ME, Blangero, JC, Brunner, HG, Buckner, RL, Cichon, S, Coppola, G, De Zubicaray, GI, Deary, IJ, Donohoe, G, De Geus, EJC, Espeseth, T, Fernéndez, G, Glahn, DC, Grabe, HJ, Hardy, J, Hulshoff Pol, HE, Jenkinson, M, Kahn, RS, Mcdonald, C, Mcintosh, AM, Mcmahon, FJ, Mcmahon, KL, Meyer-Lindenberg, A, Morris, DW, Müller-Myhsok, B, Nichols, TE, Ophoff, RA, Paus, T, Pausova, Z, Penninx, BW, Potkin, SG, Sämann, PG, Saykin, AJ, Schumann, G, Smoller, JW, Wardlaw, JM, Weale, ME, Martin, NG, Franke, B, Wright, MJ & Thompson, PM 2012, 'Identification of common variants associated with human hippocampal and intracranial volumes', Nature Genetics, vol. 44, no. 5, pp. 552-561. https://doi.org/10.1038/ng.2250

@article{418e7648a4f14f7fbbafe0cc5ff1904f,

title = "Identification of common variants associated with human hippocampal and intracranial volumes",

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).",

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

note = "Funding Information: ImaGene: ImaGene wishes to acknowledge J. Lee and J. Lane for processing the blood samples, The Easton Consortium for Alzheimer{\textquoteright}s Disease Drug Discovery and Biomarker Development and the Alzheimer{\textquoteright}s Disease Research Center (ADRC) funded by the NIA at the University of California, Los Angeles (AG16570). Funding Information: IMAGEN: IMAGEN is funded by the European Commission Framework Programme 6 (FP6) Integrated Project IMAGEN (PL037286), the European Commission Framework Programme 7 (FP7) Project Alzheimer{\textquoteright}s Disease, Alcoholism, Memory, Schizophrenia (ADAMS), the FP7 Innovative Medicine Initiative Project European Autism Interventions (AIMS), the UK Department of Health National Institute of Health Research (NIHR)–Biomedical Research Centre Mental Health program and the MRC programme grant Developmental Pathways into Adolescent Substance Abuse (93558). Funding Information: SHIP-TREND: The authors from SHIP are grateful to M. Stanke for the opportunity to use his Server Cluster for SNP Imputation. This cohort is part of the Community Medicine Research net (CMR) of the University of Greifswald, which is funded by the German Federal Ministry of Education and Research and the German Ministry of Cultural Affairs, as well as by the Social Ministry of the Federal State of Mecklenburg–West Pomerania. CMR encompasses several research projects that share data from the populationbased Study of Health in Pomerania (SHIP; see URLs). The work is also supported by the German Research Foundation (DFG; GR 1912/51) and the Greifswald Approach to Individualized Medicine (GANI_MED) network funded by the Federal Ministry of Education and Research (grant 03IS2061A). Genomewide data and MRI scans were supported by the Federal Ministry of Education and Research (grant 03ZIK012) and a joint grant from Siemens Healthcare, Erlangen, Germany, and the Federal State of Mecklenburg–West Pomerania. The University of Greifswald is a member of the Center of Knowledge Interchange program of the Siemens AG. Funding Information: Innogenetics, Johnson & Johnson, Eli Lilly & Company, Medpace, Merck and Cocpany, Novartis AG, Pfizer, F. Hoffman–La Roche, ScheringPlough and Synarc, as well as from nonprofit partners at the Alzheimer{\textquoteright}s Association and the Alzheimer{\textquoteright}s Drug Discovery Foundation, with participation from the US Food and Drug Administration (FDA). Private sector contributions to ADNI are facilitated by the Foundation for the NIH (see URLs). The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer{\textquoteright}s Disease Cooperative Study at the University of California, San Diego. ADNI data are disseminated by the Laboratory of Neuro Imaging at the University of California, Los Angeles. This research was also supported by NIH grants (P30 AG010129 and K01 AG030514) and by the Dana Foundation. ADNI was launched in 2003 by the NIA, the NIBIB, the FDA, private pharmaceutical companies and nonprofit organizations as a 5year publicprivate partnership. The primary goal of ADNI has been to test whether serial MRI), positron emission tomography (PET), other biological markers and clinical and neuropsychological assessments can be combined to measure the progression of mild cognitive impairment (MCI) and early Alzheimer{\textquoteright}s disease. Determination of sensitive and specific markers of very early Alzheimer{\textquoteright}s disease progression is intended to aid researchers and clinicians in developing new treatments and monitoring their effectiveness, as well as lessening the time and cost of clinical trials. The Principal Investigator of this initiative is M.W. Weiner. ADNI is the result of efforts of many coinvestigators from a broad range of academic institutions and private corporations, and subjects have been recruited from over 50 sites across the United States and Canada. The initial goal of ADNI was to recruit 800 adults ages 55 to 90 to participate in the research—approximately 200 cognitively normal older individuals to be followed for 3 years, 400 people with MCI to be followed for 3 years and 200 people with early Alzheimer{\textquoteright}s disease to be followed for 2 years. For uptodate information, please visit the ADNI website (see URLs). Funding Information: TCD: We wish to express our sincere thanks to all participants and to clinical staff who facilitated patients{\textquoteright} involvement. In particular, we acknowledge colleagues from the Trinity College Institute of Neuroscience A. Bodke, J. McGrath, F. Newell, H. Garavan, and J. O{\textquoteright}Doherty for their support in sample collection. Collection and analysis of these samples were funded by the Wellcome Trust (072894/z/03/zGill) and the Science Foundation Ireland (08/IN.1/B1916_Corvin). Funding Information: NESDA-NTR: Funding was obtained from the NWO (MagW/ZonMW 90461090; 98510002; 90461193; 48004004; 40005717, Addiction31160008; 91109032; SPI 5646414192 and Geestkracht Program, 100001002), the Center for Medical Systems Biology (CMSB; NWO Genomics), NBIC/ BioAssist/RK/2008.024, BBMRINL, Biobanking and Biomolecular Resources Research Infrastructure, the VU University, the EMGO Institute for Health and Care Research and Neuroscience Campus Amsterdam, the European Science Foundation (EU/QLRT200101254), the European Community{\textquoteright}s FP7 (HEALTHF42007201413), the European Science Council (ERC) Genetics of Mental Illness (230374), Rutgers University Cell and DNA Repository (cooperative agreement NIMH U24 MH06845706), the US NIH (R01D004215701A) and the Genetic Association Information Network (a publicprivate partnership between the NIH and Pfizer, Affymetrix and Abbott Laboratories). Funding Information: fBIRN: fBIRN wishes to acknowledge D.B. Keator for leading fBIRN neuroinformatics development, B.A. Mueller for image calibration and quality assurance and A. Belger, V.D. Calhoun, G.G. Brown, J.M. Ford, G.H. Glover, R. Kikinis, K. Lim, J. Laurriello, J. Bustillo, G. McCarthy, D.S. O{\textquoteright}Leary, B. Rosen, A.W.T. and J.T. Voyvodic for their leadership contributions to fBIRN scanner and sequence calibration, tool development and data collection efforts. The fBIRN study was supported by the US NIH (U24 RR21992) for phenotypic data collection. Genotyping was performed with the support of the grant RBIN04SWHR to F.M. from the Italian Ministry of University and Research. Funding Information: NIMH-IRP: This study was supported by funding from the Intramural Research Program of the National Institute of Mental Health (NIMH) from the NIH and the US Department of Health and Human Services (K99 MH085098 to G.L., 1ZIA MH002810 to F.J.M. and 1ZIA MH002790 to W.C.D.). The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products or organizations imply endorsement by the US government. Funding Information: QTIM: We are extremely grateful to the twins for their participation, the radiographers at the Centre for Advanced Imaging at the University of Queensland for image acquisition and the many research assistants and support staff at the Queensland Institute of Medical Research for twin recruitment and daily management, and we especially thank K. Johnson for MRI scanning and processing, A. Henders for DNA processing and preparation and S. Gordon for quality control and management of the genotypes. Phenotyping was funded by the US National Institute of Child Health and Human Development (R01 HD050735) and the Australian National Health and Medical Research Council (NHMRC) Funding Information: MPIP: The MPIP Munich Morphometry Sample comprises images acquired as part of the Munich Antidepressant Response Signature Study and the Recurrent Unipolar Depression (RUD) CaseControl Study performed at the MPIP and control subjects acquired at the Department of Psychiatry at the LudwigMaximiliansUniversity. We wish to acknowledge A. Olynyik and radiographers R. Schirmer, E. Schreiter and R. Borschke for image acquisition and data preparation. We thank D.P. Auer for local study management in the initial phase of the RUD study. We are grateful to GlaxoSmithKline for providing the genotypes of the RUD CaseControl Sample. We thank the staff of the Center of Applied Genotyping (CAGT) for generating the genotypes of the MARS cohort. The study is supported by a grant from the ExzellenzStiftung of the Max Planck Society. This work has also been funded by the BMBF in the framework of the National Genome Research Network (NGFN) (FKZ 01GS0481). Funding Information: SHIP: The Study of Health in Pomerania (SHIP) is supported by the German Federal Ministry of Education and Research (grants 01ZZ9603, 01ZZ0103 and 01ZZ0403) and the German Research Foundation (DFG; GR 1912/51). Genomewide data and MRI scans were supported by the Federal Ministry of Education and Research (grant 03ZIK012) and a joint grant from Siemens Healthcare, Erlangen, Germany, and the Federal State of Mecklenburg–West Pomerania. The University of Greifswald is a member of the Center of Knowledge Interchange program of the Siemens AG. We thank all staff members and participants of the SHIP study, as well as all of the genotyping staff for generating the SHIP SNP data set. The genetic data analysis workflow was created using the Software InforSense. Genetic data were stored using the database Cach{\'e} (InterSystems). Funding Information: LBC1936: We thank the participants in LBC1936. We thank C. Murray, A.J. Gow, S.E. Harris, M. Luciano, P. Redmond, E. Sandeman, I. Gerrish, J. BoydEllison, N. Leslie, A. Howden and C. Scott for data collection and preparation. This project is funded by the Age UK{\textquoteright}s Disconnected Mind programme and also by Research Into Ageing (251 and 285). The entire genome association part of the study was funded by the Biotechnology and Biological Sciences Research Council (BBSRC) (BB/F019394/1). Analysis of brain images was funded by UK MRC grants (G1001401 and 8200). The work was undertaken by The University of Edinburgh Centre for Cognitive Ageing and Cognitive Epidemiology, part of the cross council Lifelong Health and Wellbeing Initiative (G0700704/84698). Imaging was performed at the Brain Research Imaging Centre, Edinburgh, a center in the SINAPSE Collaboration. Funding from BBSRC, the Engineering and Physical Sciences Research Council (EPSRC), the Economic and Social Research Council (ESRC) and the MRC and Scottish Funding Council through the SINAPSE Collaboration is gratefully acknowledged. L.M.L. is the beneficiary of a postdoctoral grant from the AXA Research Fund. Funding Information: EPIGEN: Work from the London Cohort was supported by research grants from the Wellcome Trust (grant 084730 to S.M.S.), University College London (UCL)/University College London Hospitals (UCLH) Comprehensive Biomedical Research Centre/Specialist Biomedical Research Centres (CBRC/SBRC) (grant 114 to S.M.S.), the European Union Marie Curie Reintegration (to M. Matarin and S.M.S.), the UK NIHR (0808SCC), the Comprehensive Local Research Network (CLRN) Flexibility and Sustainability Funding (FSF) (grant CEL1300 to S.M.S.), The Big Lottery Fund, the Wolfson Trust and the Epilepsy Society. This work was undertaken at UCLH/UCL, which received a proportion of funding from the UK Department of Health{\textquoteright}s NIHR Biomedical Research Centres funding scheme. Work from the Royal College of Surgeons in Ireland was supported by research grants from the Science Foundation Ireland (Research Frontiers Programme award 08/RFP/GEN1538) and Brainwave–the Irish Epilepsy Association. The collection of Belgian subjects was supported by the Fonds National de la Recherche Scientifique (grant FC 63574 / 3.4.620.06 F) and the Fonds Erasme pour la Recherche M{\'e}dicale at the Universit{\'e} Libre de Bruxelles. Funding Information: SYS: The Saguenay Youth Study Group wishes to thank the following individuals for their contribution in acquiring and analyzing the data: N. Arbour, M.{\`E}. Bouchard, A. Houde, A. Gauthier and H. Simard for the recruitment and assessment of participating families, M. B{\'e}rub{\'e}, S. Masson, S. Castonguay and M.J. Morin for MRI acquisition and E. Ding and N. Qiu for MR data management. We thank J. Mathieu for the medical follow up of participants in whom we detected any medically relevant abnormalities. We are grateful to all families for participating in the study. The Saguenay Youth Study Group is supported by the Canadian Institutes of Health Research, the Heart and Stroke Foundation of Quebec and the Canadian Foundation for Innovation. For more information, please see the study website (see URLs). Funding Information: (project grant 496682). Genotyping was funded by the NHMRC (Medical Bioinformatics Genomics Proteomics Program, 389891). G.M. was supported by an NHMRC Fellowship (613667), and G.Z. was supported by Australian Research Council (ARC) Future Fellowship (FT0991634). S.E.M. is funded by an ARC Future Fellowship (FT110100548). J.L.S. was supported by the Achievement Rewards for College Scientists foundation and the US NIMH (F31 MH087061). D.P.H. is partially supported by a National Science Foundation (NSF) Graduate Research Fellowhip Program (GRFP) grant (DGE0707424). P.T. was also supported by the NIH (grants U01 AG024904, AG040060, EB008432, P41 RR013642, HD050735, AG036535, AG020098 and EB008281). Funding Information: NCNG: We would like to thank the personnel involved in recruitment and data collection and, in particular, P. DueT{\o}nnessen for clinical assessment of the MRI images. The NCNG study was supported by Research Council of Norway grants (154313/V50 and 177458/V50). The NCNG GWAS was financed by grants from the Bergen Research Foundation, the University of Bergen, the Research Council of Norway (FUGE; Psykisk Helse), Helse Vest Regionalt Helseforetak (RHF) and the Dr Einar Martens Fund. Funding Information: provided by the UK MRC (grant G0901254), the MRC Sudden Death Brain and Tissue Bank and the Sun Health Research Institute Brain Bank. Funding Information: Superstruct: We thank the investigators and participants who contributed to the brain genomics data collection for Superstruct at Massachusetts General Hospital and Harvard University, with funding from the Simons Foundation, the Howard Hughes Medical Institute and the US NIH (grant MH079799). Funding Information: Bipolar Family Study: The Bipolar Family Study wishes to thank the Scottish Mental Health Research Network for research assistant support, the Brain Research Imaging Centre Edinburgh (see URLs), a center in the Scottish Funding Council Scottish Imaging Network–A Platform for Scientific Excellence (SINAPSE) Collaboration (see URLs), for image acquisition and the Wellcome Trust Clinical Research Facility for genotyping. Genotyping was supported by the National Alliance for Research on Schizophrenia and Depression (NARSAD) Independent Investigator Award (to A.M.M.), and data collection was supported by the Health Foundation Clinician Scientist Fellowship. Funding Information: TOP: We thank the study participants of TOP and the personnel involved in data collection and logistics, especially T.D. Bjella. This work was supported by the Oslo University Hospital–Ullev{\aa}l, the Eastern Norway Health Authority (2004123), the Research Council of Norway (167153/V50, 163070/V50 and 183782/V50), and by Eli Lilly & Company (who covered part of the genotyping costs). Funding Information: BIG: The BIG study wishes to acknowledge S. Kooijman for coordination of sample collection and A. Heister, M. Naber, R. Makkinje, M. Hakobjan and M. Steehouwer for genotyping. The BIG study was supported by a Biobanking and Biomolecular Resources Research Infrastructure Netherlands (BBMRINL) complementation grant for brain segmentation and the Netherlands Organisation for Scientific Research (NWO) Horizon Breakthrough grant (grant number 93511010 (to A.A.V.). Funding Information: UMCU: The UMCU study was supported by the Netherlands Organization for Health Research and Development ZonMw (917.46.370 to H.E.H.) and the US NIMH (MH078075 to R.A.O.). Funding Information: GOBS: The GOBS study was supported by the US NIH (MH0708143 and MH083824 to D.C.G., MH078111 and MH59490 to J.B., C06 RR13556 and C06 RR017515). P.K. was also supported by an NIH grant (EB006395). Funding Information: MooDS: This work was funded by the German Federal Ministry of Education and Research (BMBF) in the National Genome Research Network (NGFNplus) through the MooDs grant Molecular Causes of Major Mood Disorders and Schizophrenia (coordinator M.M.N.). Additional funding for genotyping was provided by a NARSAD Distinguished Investigator award to A.M.L.",

year = "2012",

month = may,

doi = "10.1038/ng.2250",

language = "English (US)",

volume = "44",

pages = "552--561",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Publishing Group",

number = "5",

}

TY - JOUR

T1 - Identification of common variants associated with human hippocampal and intracranial volumes

AU - Stein, Jason L.

AU - Medland, Sarah E.

AU - Vasquez, Alejandro Arias

AU - Hibar, Derrek P.

AU - Senstad, Rudy E.

AU - Winkler, Anderson M.

AU - Toro, Roberto

AU - Appel, Katja

AU - Bartecek, Richard

AU - Bergmann, Ørjan

AU - Bernard, Manon

AU - Brown, Andrew A.

AU - Cannon, Dara M.

AU - Chakravarty, M. Mallar

AU - Christoforou, Andrea

AU - Domin, Martin

AU - Grimm, Oliver

AU - Hollinshead, Marisa

AU - Holmes, Avram J.

AU - Homuth, Georg

AU - Hottenga, Jouke Jan

AU - Langan, Camilla

AU - Lopez, Lorna M.

AU - Hansell, Narelle K.

AU - Hwang, Kristy S.

AU - Kim, Sungeun

AU - Laje, Gonzalo

AU - Lee, Phil H.

AU - Liu, Xinmin

AU - Loth, Eva

AU - Lourdusamy, Anbarasu

AU - Mattingsdal, Morten

AU - Mohnke, Sebastian

AU - Maniega, Susana Muñoz

AU - Nho, Kwangsik

AU - Nugent, Allison C.

AU - O'brien, Carol

AU - Papmeyer, Martina

AU - Pütz, Benno

AU - Ramasamy, Adaikalavan

AU - Rasmussen, Jerod

AU - Rijpkema, Mark

AU - Risacher, Shannon L.

AU - Roddey, J. Cooper

AU - Rose, Emma J.

AU - Ryten, Mina

AU - Shen, Li

AU - Sprooten, Emma

AU - Strengman, Eric

AU - Teumer, Alexander

AU - Trabzuni, Daniah

AU - Turner, Jessica

AU - Van Eijk, Kristel

AU - Van Erp, Theo G.M.

AU - Van Tol, Marie Jose

AU - Wittfeld, Katharina

AU - Wolf, Christiane

AU - Woudstra, Saskia

AU - Aleman, Andre

AU - Alhusaini, Saud

AU - Almasy, Laura A

AU - Binder, Elisabeth B.

AU - Brohawn, David G.

AU - Cantor, Rita M.

AU - Carless, Melanie A

AU - Corvin, Aiden

AU - Czisch, Michael

AU - Curran, Joanne E

AU - Davies, Gail

AU - De Almeida, Marcio A.A.

AU - Delanty, Norman

AU - Depondt, Chantal

AU - Duggirala, Ravindranath

AU - Dyer, Thomas D.

AU - Erk, Susanne

AU - Fagerness, Jesen

AU - Fox, Peter T.

AU - Freimer, Nelson B.

AU - Gill, Michael

AU - Goring, Harald HH

AU - Hagler, Donald J.

AU - Hoehn, David

AU - Holsboer, Florian

AU - Hoogman, Martine

AU - Hosten, Norbert

AU - Jahanshad, Neda

AU - Johnson, Matthew P

AU - Kasperaviciute, Dalia

AU - Kent, Jack W.

AU - Kochunov, Peter

AU - Lancaster, Jack L.

AU - Lawrie, Stephen M.

AU - Liewald, David C.

AU - Mandl, René

AU - Matarin, Mar

AU - Mattheisen, Manuel

AU - Meisenzahl, Eva

AU - Melle, Ingrid

AU - Moses, Eric K

AU - Mühleisen, Thomas W.

AU - Nauck, Matthias

AU - Nöthen, Markus M.

AU - Olvera, Rene L.

AU - Pandolfo, Massimo

AU - Pike, G. Bruce

AU - Puls, Ralf

AU - Reinvang, Ivar

AU - Rentería, Miguel E.

AU - Rietschel, Marcella

AU - Roffman, Joshua L.

AU - Royle, Natalie A.

AU - Rujescu, Dan

AU - Savitz, Jonathan

AU - Schnack, Hugo G.

AU - Schnell, Knut

AU - Seiferth, Nina

AU - Smith, Colin

AU - Steen, Vidar M.

AU - Hernández, Maria C.Valdés

AU - Van Den Heuvel, Martijn

AU - Van Der Wee, Nic J.

AU - Van Haren, Neeltje E.M.

AU - Veltman, Joris A.

AU - Völzke, Henry

AU - Walker, Robert

AU - Westlye, Lars T.

AU - Whelan, Christopher D.

AU - Agartz, Ingrid

AU - Boomsma, Dorret I.

AU - Cavalleri, Gianpiero L.

AU - Dale, Anders M.

AU - Djurovic, Srdjan

AU - Drevets, Wayne C.

AU - Hagoort, Peter

AU - Hall, Jeremy

AU - Heinz, Andreas

AU - Jack, Clifford R.

AU - Foroud, Tatiana M.

AU - Le Hellard, Stephanie

AU - Macciardi, Fabio

AU - Montgomery, Grant W.

AU - Poline, Jean Baptiste

AU - Porteous, David J.

AU - Sisodiya, Sanjay M.

AU - Starr, John M.

AU - Sussmann, Jessika

AU - Toga, Arthur W.

AU - Veltman, Dick J.

AU - Walter, Henrik

AU - Weiner, Michael W.

AU - Bis, Joshua C.

AU - Ikram, M. Arfan

AU - Smith, Albert V.

AU - Gudnason, Vilmundur

AU - Tzourio, Christophe

AU - Vernooij, Meike W.

AU - Launer, Lenore J.

AU - Decarli, Charles

AU - Seshadri, Sudha

AU - Andreassen, Ole A.

AU - Apostolova, Liana G.

AU - Bastin, Mark E.

AU - Blangero, John C

AU - Brunner, Han G.

AU - Buckner, Randy L.

AU - Cichon, Sven

AU - Coppola, Giovanni

AU - De Zubicaray, Greig I.

AU - Deary, Ian J.

AU - Donohoe, Gary

AU - De Geus, Eco J.C.

AU - Espeseth, Thomas

AU - Fernéndez, Guillén

AU - Glahn, David C.

AU - Grabe, Hans J.

AU - Hardy, John

AU - Hulshoff Pol, Hilleke E.

AU - Jenkinson, Mark

AU - Kahn, René S.

AU - Mcdonald, Colm

AU - Mcintosh, Andrew M.

AU - Mcmahon, Francis J.

AU - Mcmahon, Katie L.

AU - Meyer-Lindenberg, Andreas

AU - Morris, Derek W.

AU - Müller-Myhsok, Bertram

AU - Nichols, Thomas E.

AU - Ophoff, Roel A.

AU - Paus, Tomas

AU - Pausova, Zdenka

AU - Penninx, Brenda W.

AU - Potkin, Steven G.

AU - Sämann, Philipp G.

AU - Saykin, Andrew J.

AU - Schumann, Gunter

AU - Smoller, Jordan W.

AU - Wardlaw, Joanna M.

AU - Weale, Michael E.

AU - Martin, Nicholas G.

AU - Franke, Barbara

AU - Wright, Margaret J.

AU - Thompson, Paul M.

N1 - Funding Information: ImaGene: ImaGene wishes to acknowledge J. Lee and J. Lane for processing the blood samples, The Easton Consortium for Alzheimer’s Disease Drug Discovery and Biomarker Development and the Alzheimer’s Disease Research Center (ADRC) funded by the NIA at the University of California, Los Angeles (AG16570). Funding Information: IMAGEN: IMAGEN is funded by the European Commission Framework Programme 6 (FP6) Integrated Project IMAGEN (PL037286), the European Commission Framework Programme 7 (FP7) Project Alzheimer’s Disease, Alcoholism, Memory, Schizophrenia (ADAMS), the FP7 Innovative Medicine Initiative Project European Autism Interventions (AIMS), the UK Department of Health National Institute of Health Research (NIHR)–Biomedical Research Centre Mental Health program and the MRC programme grant Developmental Pathways into Adolescent Substance Abuse (93558). Funding Information: SHIP-TREND: The authors from SHIP are grateful to M. Stanke for the opportunity to use his Server Cluster for SNP Imputation. This cohort is part of the Community Medicine Research net (CMR) of the University of Greifswald, which is funded by the German Federal Ministry of Education and Research and the German Ministry of Cultural Affairs, as well as by the Social Ministry of the Federal State of Mecklenburg–West Pomerania. CMR encompasses several research projects that share data from the populationbased Study of Health in Pomerania (SHIP; see URLs). The work is also supported by the German Research Foundation (DFG; GR 1912/51) and the Greifswald Approach to Individualized Medicine (GANI_MED) network funded by the Federal Ministry of Education and Research (grant 03IS2061A). Genomewide data and MRI scans were supported by the Federal Ministry of Education and Research (grant 03ZIK012) and a joint grant from Siemens Healthcare, Erlangen, Germany, and the Federal State of Mecklenburg–West Pomerania. The University of Greifswald is a member of the Center of Knowledge Interchange program of the Siemens AG. Funding Information: Innogenetics, Johnson & Johnson, Eli Lilly & Company, Medpace, Merck and Cocpany, Novartis AG, Pfizer, F. Hoffman–La Roche, ScheringPlough and Synarc, as well as from nonprofit partners at the Alzheimer’s Association and the Alzheimer’s Drug Discovery Foundation, with participation from the US Food and Drug Administration (FDA). Private sector contributions to ADNI are facilitated by the Foundation for the NIH (see URLs). The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer’s Disease Cooperative Study at the University of California, San Diego. ADNI data are disseminated by the Laboratory of Neuro Imaging at the University of California, Los Angeles. This research was also supported by NIH grants (P30 AG010129 and K01 AG030514) and by the Dana Foundation. ADNI was launched in 2003 by the NIA, the NIBIB, the FDA, private pharmaceutical companies and nonprofit organizations as a 5year publicprivate partnership. The primary goal of ADNI has been to test whether serial MRI), positron emission tomography (PET), other biological markers and clinical and neuropsychological assessments can be combined to measure the progression of mild cognitive impairment (MCI) and early Alzheimer’s disease. Determination of sensitive and specific markers of very early Alzheimer’s disease progression is intended to aid researchers and clinicians in developing new treatments and monitoring their effectiveness, as well as lessening the time and cost of clinical trials. The Principal Investigator of this initiative is M.W. Weiner. ADNI is the result of efforts of many coinvestigators from a broad range of academic institutions and private corporations, and subjects have been recruited from over 50 sites across the United States and Canada. The initial goal of ADNI was to recruit 800 adults ages 55 to 90 to participate in the research—approximately 200 cognitively normal older individuals to be followed for 3 years, 400 people with MCI to be followed for 3 years and 200 people with early Alzheimer’s disease to be followed for 2 years. For uptodate information, please visit the ADNI website (see URLs). Funding Information: TCD: We wish to express our sincere thanks to all participants and to clinical staff who facilitated patients’ involvement. In particular, we acknowledge colleagues from the Trinity College Institute of Neuroscience A. Bodke, J. McGrath, F. Newell, H. Garavan, and J. O’Doherty for their support in sample collection. Collection and analysis of these samples were funded by the Wellcome Trust (072894/z/03/zGill) and the Science Foundation Ireland (08/IN.1/B1916_Corvin). Funding Information: NESDA-NTR: Funding was obtained from the NWO (MagW/ZonMW 90461090; 98510002; 90461193; 48004004; 40005717, Addiction31160008; 91109032; SPI 5646414192 and Geestkracht Program, 100001002), the Center for Medical Systems Biology (CMSB; NWO Genomics), NBIC/ BioAssist/RK/2008.024, BBMRINL, Biobanking and Biomolecular Resources Research Infrastructure, the VU University, the EMGO Institute for Health and Care Research and Neuroscience Campus Amsterdam, the European Science Foundation (EU/QLRT200101254), the European Community’s FP7 (HEALTHF42007201413), the European Science Council (ERC) Genetics of Mental Illness (230374), Rutgers University Cell and DNA Repository (cooperative agreement NIMH U24 MH06845706), the US NIH (R01D004215701A) and the Genetic Association Information Network (a publicprivate partnership between the NIH and Pfizer, Affymetrix and Abbott Laboratories). Funding Information: fBIRN: fBIRN wishes to acknowledge D.B. Keator for leading fBIRN neuroinformatics development, B.A. Mueller for image calibration and quality assurance and A. Belger, V.D. Calhoun, G.G. Brown, J.M. Ford, G.H. Glover, R. Kikinis, K. Lim, J. Laurriello, J. Bustillo, G. McCarthy, D.S. O’Leary, B. Rosen, A.W.T. and J.T. Voyvodic for their leadership contributions to fBIRN scanner and sequence calibration, tool development and data collection efforts. The fBIRN study was supported by the US NIH (U24 RR21992) for phenotypic data collection. Genotyping was performed with the support of the grant RBIN04SWHR to F.M. from the Italian Ministry of University and Research. Funding Information: NIMH-IRP: This study was supported by funding from the Intramural Research Program of the National Institute of Mental Health (NIMH) from the NIH and the US Department of Health and Human Services (K99 MH085098 to G.L., 1ZIA MH002810 to F.J.M. and 1ZIA MH002790 to W.C.D.). The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products or organizations imply endorsement by the US government. Funding Information: QTIM: We are extremely grateful to the twins for their participation, the radiographers at the Centre for Advanced Imaging at the University of Queensland for image acquisition and the many research assistants and support staff at the Queensland Institute of Medical Research for twin recruitment and daily management, and we especially thank K. Johnson for MRI scanning and processing, A. Henders for DNA processing and preparation and S. Gordon for quality control and management of the genotypes. Phenotyping was funded by the US National Institute of Child Health and Human Development (R01 HD050735) and the Australian National Health and Medical Research Council (NHMRC) Funding Information: MPIP: The MPIP Munich Morphometry Sample comprises images acquired as part of the Munich Antidepressant Response Signature Study and the Recurrent Unipolar Depression (RUD) CaseControl Study performed at the MPIP and control subjects acquired at the Department of Psychiatry at the LudwigMaximiliansUniversity. We wish to acknowledge A. Olynyik and radiographers R. Schirmer, E. Schreiter and R. Borschke for image acquisition and data preparation. We thank D.P. Auer for local study management in the initial phase of the RUD study. We are grateful to GlaxoSmithKline for providing the genotypes of the RUD CaseControl Sample. We thank the staff of the Center of Applied Genotyping (CAGT) for generating the genotypes of the MARS cohort. The study is supported by a grant from the ExzellenzStiftung of the Max Planck Society. This work has also been funded by the BMBF in the framework of the National Genome Research Network (NGFN) (FKZ 01GS0481). Funding Information: SHIP: The Study of Health in Pomerania (SHIP) is supported by the German Federal Ministry of Education and Research (grants 01ZZ9603, 01ZZ0103 and 01ZZ0403) and the German Research Foundation (DFG; GR 1912/51). Genomewide data and MRI scans were supported by the Federal Ministry of Education and Research (grant 03ZIK012) and a joint grant from Siemens Healthcare, Erlangen, Germany, and the Federal State of Mecklenburg–West Pomerania. The University of Greifswald is a member of the Center of Knowledge Interchange program of the Siemens AG. We thank all staff members and participants of the SHIP study, as well as all of the genotyping staff for generating the SHIP SNP data set. The genetic data analysis workflow was created using the Software InforSense. Genetic data were stored using the database Caché (InterSystems). Funding Information: LBC1936: We thank the participants in LBC1936. We thank C. Murray, A.J. Gow, S.E. Harris, M. Luciano, P. Redmond, E. Sandeman, I. Gerrish, J. BoydEllison, N. Leslie, A. Howden and C. Scott for data collection and preparation. This project is funded by the Age UK’s Disconnected Mind programme and also by Research Into Ageing (251 and 285). The entire genome association part of the study was funded by the Biotechnology and Biological Sciences Research Council (BBSRC) (BB/F019394/1). Analysis of brain images was funded by UK MRC grants (G1001401 and 8200). The work was undertaken by The University of Edinburgh Centre for Cognitive Ageing and Cognitive Epidemiology, part of the cross council Lifelong Health and Wellbeing Initiative (G0700704/84698). Imaging was performed at the Brain Research Imaging Centre, Edinburgh, a center in the SINAPSE Collaboration. Funding from BBSRC, the Engineering and Physical Sciences Research Council (EPSRC), the Economic and Social Research Council (ESRC) and the MRC and Scottish Funding Council through the SINAPSE Collaboration is gratefully acknowledged. L.M.L. is the beneficiary of a postdoctoral grant from the AXA Research Fund. Funding Information: EPIGEN: Work from the London Cohort was supported by research grants from the Wellcome Trust (grant 084730 to S.M.S.), University College London (UCL)/University College London Hospitals (UCLH) Comprehensive Biomedical Research Centre/Specialist Biomedical Research Centres (CBRC/SBRC) (grant 114 to S.M.S.), the European Union Marie Curie Reintegration (to M. Matarin and S.M.S.), the UK NIHR (0808SCC), the Comprehensive Local Research Network (CLRN) Flexibility and Sustainability Funding (FSF) (grant CEL1300 to S.M.S.), The Big Lottery Fund, the Wolfson Trust and the Epilepsy Society. This work was undertaken at UCLH/UCL, which received a proportion of funding from the UK Department of Health’s NIHR Biomedical Research Centres funding scheme. Work from the Royal College of Surgeons in Ireland was supported by research grants from the Science Foundation Ireland (Research Frontiers Programme award 08/RFP/GEN1538) and Brainwave–the Irish Epilepsy Association. The collection of Belgian subjects was supported by the Fonds National de la Recherche Scientifique (grant FC 63574 / 3.4.620.06 F) and the Fonds Erasme pour la Recherche Médicale at the Université Libre de Bruxelles. Funding Information: SYS: The Saguenay Youth Study Group wishes to thank the following individuals for their contribution in acquiring and analyzing the data: N. Arbour, M.È. Bouchard, A. Houde, A. Gauthier and H. Simard for the recruitment and assessment of participating families, M. Bérubé, S. Masson, S. Castonguay and M.J. Morin for MRI acquisition and E. Ding and N. Qiu for MR data management. We thank J. Mathieu for the medical follow up of participants in whom we detected any medically relevant abnormalities. We are grateful to all families for participating in the study. The Saguenay Youth Study Group is supported by the Canadian Institutes of Health Research, the Heart and Stroke Foundation of Quebec and the Canadian Foundation for Innovation. For more information, please see the study website (see URLs). Funding Information: (project grant 496682). Genotyping was funded by the NHMRC (Medical Bioinformatics Genomics Proteomics Program, 389891). G.M. was supported by an NHMRC Fellowship (613667), and G.Z. was supported by Australian Research Council (ARC) Future Fellowship (FT0991634). S.E.M. is funded by an ARC Future Fellowship (FT110100548). J.L.S. was supported by the Achievement Rewards for College Scientists foundation and the US NIMH (F31 MH087061). D.P.H. is partially supported by a National Science Foundation (NSF) Graduate Research Fellowhip Program (GRFP) grant (DGE0707424). P.T. was also supported by the NIH (grants U01 AG024904, AG040060, EB008432, P41 RR013642, HD050735, AG036535, AG020098 and EB008281). Funding Information: NCNG: We would like to thank the personnel involved in recruitment and data collection and, in particular, P. DueTønnessen for clinical assessment of the MRI images. The NCNG study was supported by Research Council of Norway grants (154313/V50 and 177458/V50). The NCNG GWAS was financed by grants from the Bergen Research Foundation, the University of Bergen, the Research Council of Norway (FUGE; Psykisk Helse), Helse Vest Regionalt Helseforetak (RHF) and the Dr Einar Martens Fund. Funding Information: provided by the UK MRC (grant G0901254), the MRC Sudden Death Brain and Tissue Bank and the Sun Health Research Institute Brain Bank. Funding Information: Superstruct: We thank the investigators and participants who contributed to the brain genomics data collection for Superstruct at Massachusetts General Hospital and Harvard University, with funding from the Simons Foundation, the Howard Hughes Medical Institute and the US NIH (grant MH079799). Funding Information: Bipolar Family Study: The Bipolar Family Study wishes to thank the Scottish Mental Health Research Network for research assistant support, the Brain Research Imaging Centre Edinburgh (see URLs), a center in the Scottish Funding Council Scottish Imaging Network–A Platform for Scientific Excellence (SINAPSE) Collaboration (see URLs), for image acquisition and the Wellcome Trust Clinical Research Facility for genotyping. Genotyping was supported by the National Alliance for Research on Schizophrenia and Depression (NARSAD) Independent Investigator Award (to A.M.M.), and data collection was supported by the Health Foundation Clinician Scientist Fellowship. Funding Information: TOP: We thank the study participants of TOP and the personnel involved in data collection and logistics, especially T.D. Bjella. This work was supported by the Oslo University Hospital–Ullevål, the Eastern Norway Health Authority (2004123), the Research Council of Norway (167153/V50, 163070/V50 and 183782/V50), and by Eli Lilly & Company (who covered part of the genotyping costs). Funding Information: BIG: The BIG study wishes to acknowledge S. Kooijman for coordination of sample collection and A. Heister, M. Naber, R. Makkinje, M. Hakobjan and M. Steehouwer for genotyping. The BIG study was supported by a Biobanking and Biomolecular Resources Research Infrastructure Netherlands (BBMRINL) complementation grant for brain segmentation and the Netherlands Organisation for Scientific Research (NWO) Horizon Breakthrough grant (grant number 93511010 (to A.A.V.). Funding Information: UMCU: The UMCU study was supported by the Netherlands Organization for Health Research and Development ZonMw (917.46.370 to H.E.H.) and the US NIMH (MH078075 to R.A.O.). Funding Information: GOBS: The GOBS study was supported by the US NIH (MH0708143 and MH083824 to D.C.G., MH078111 and MH59490 to J.B., C06 RR13556 and C06 RR017515). P.K. was also supported by an NIH grant (EB006395). Funding Information: MooDS: This work was funded by the German Federal Ministry of Education and Research (BMBF) in the National Genome Research Network (NGFNplus) through the MooDs grant Molecular Causes of Major Mood Disorders and Schizophrenia (coordinator M.M.N.). Additional funding for genotyping was provided by a NARSAD Distinguished Investigator award to A.M.L.

PY - 2012/5

Y1 - 2012/5

N2 - 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).

AB - 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).

UR - http://www.scopus.com/inward/record.url?scp=84860351742&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84860351742&partnerID=8YFLogxK

U2 - 10.1038/ng.2250

DO - 10.1038/ng.2250

M3 - Article

C2 - 22504417

AN - SCOPUS:84860351742

SN - 1061-4036

VL - 44

SP - 552

EP - 561

JO - Nature Genetics

JF - Nature Genetics

IS - 5

ER -

Identification of common variants associated with human hippocampal and intracranial volumes

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