Novel genetic loci associated with hippocampal volume

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Nj van der Wee, D. van 't Ent, Jl L. Stein, Me E. (Miguel) Renteria, Hieab H. Hh Adams, Mw W. (Meike) Vernooij, Neda Jahanshad, Kn N. (Kjetil N.) Jørgensen, Ganesh Chauhan, Kjetil N. Jorgensen, M. Kamran Ikram, Edith Hofer, Ph H. (Phil) Lee, Alejandro Arias-Vasquez, Dc C. (David C.) Liewald, Lm M. (Lorna) Lopez, Sylvane Desrivières, Af F. (Andre F.) Marquand, R. Mather, Lucija Abramovic, Ka Mather, Saud Alhusaini, Dr R. (David R.) McKay, Najaf Amin, Susanna Muñoz Maniega, Micael Andersson, Konstantinos A. Arfanakis, Susana Munoz Maniega, Ac C. (Allison) Nugent, Lavinia Athanasiu, Tomas Axelsson, Lm M. O. (Loes M. Olde) LoohuisORCID, Loes M. Olde Loohuis, Js S. (Jennifer S.) Richards, Manon Bernard, Benno Puetz, Alexa Beiser, Marc Mm Bohlken, Sl L. (Shannon) Risacher, Marco P. M. (Marco) BoksORCID, Ej J. (Emma) Rose, Janita Bralten, Na A. (Natalie) Royle, Owen Carmichael, Pg G. (Philipp) Sämann, Mm Mallar Chakravarty, Qiang Chen, Anouk den Braber, Vincent Chouraki, Philipp G. Samann, Gabriel Cuellar-Partida, Cl L. (Claudia L.) SatizabalORCID, Fabrice Crivello, Philipp G. Saemann, Stefan M. (Stefan) Ehrlich, Michael E. Griswold, Sudheer Giddaluru, N. J. (Nicholas) Schork, Aj Schork, Oliver Grimm, R. (Roy) Sprooten, Tulio Guadalupe, Av V. (Albert Vernon) Smith, Boris A. (Boris A.) Gutman, Johanna Hass, V. M. (Vanessa) Strike, Lt Strike, David Hoehn, Deborah Janowitz, Avram J. Ho, Tianye JiaORCID, Martine Hoogman, J. (Jeroen) van der Grond, Nazanin Karbalai, Dalia Kasperaviciute, S. (Sven) van der Lee, Sungeun Kim, Marieke KleinORCID, Bernd Kraemer, David C. M. Liewald, Michelle Luciano, Sven J. Van Der Lee, Christine Macare, Mar Matarin, Sj Van der LeeORCID, Manuel MattheisenORCID, Mm Van Donkelaar, Yuri Milaneschi, Kr Van Eijk, Kwangsik Nho, Tg Van Erp, Paul Nyquist, Lt T. (Lars) WestlyeORCID, Cd D. (Christopher) Whelan, Jaap Oosterlaan, Martina Papmeyer, Lukas Pirpamer, Bg G. (B Gwen) Windham, Benno Pütz, Adaikalavan Ramasamy, Roberto Roiz-Santiañez, Am M. (Anderson) WinklerORCID, Lr R. (Lisa) Yanek, Nanda Rommelse, Dennis van't Ent, Stefan Ropele, G. I. (Greig) de Zubicaray, Hilleke E. Hulshoff Pol, Tatjana Rundek, He H. Pol, Arvin Saremi, S. (Sarah) Jenkinson, Lianne Schmaal, Erik G. Joensson, Eg G. (Erik G.) Jönsson, Li ShenORCID, Jean Shin, Elena Shumskaya, Rs Kahn, Emma Sprooten, Ds S. (David S.) Knopman, Alexander TeumerORCID, Diana Tordesillas-Gutierrez, Roberto Toro, Jb B. (John B.) Kwok, Sm Lawrie, Daniah TrabzuniORCID, Stella Trompet, Jeroen Van der Grond, Dhananjay Vaidya, Dl L. (Dan L.) Longo, Ol L. (Oscar L.) Lopez, Jl-L. (Jean-Luc) Martinot, Dennis Van der Meer, Marjolein M. J. (Marjolein M. J.) Van Donkelaar, Vs S. (Venkata S.) Mattay, Daan Van Rooij, Am M. (Andrew) McIntoshORCID, Fj J. (Francis J.) McMahonORCID, Esther Walton, Kl L. (Katie L.) McMahon, Gw W. (Grant W.) Montgomery, Katharina Wittfeld, Girma Woldehawariat, Dw W. (Derek W) Morris, Christiane Wolf, Th H. (Thomas H.) Mosley, Thomas Wolfers, Tw W. (Thomas) Mühleisen, Jingyun Yang, Thomas W. Muhleisen, Bertram Muller-Myhsok, Alex P. Zijdenbos, Marcel P. (Marcel) Zwiers, Bertram Mueller-Myhsok, Ingrid Agartz, Laura Almasy, Te E. (Thomas) NicholsORCID, David Ames, Wj J. (Wiro) Niessen, Philippe AmouyelORCID, Markus M. Nothen, Sampath Arepalli, Rl L. (Rene) Olvera, Amelia Aa Assareh, Ra A. (Roel) Ophoff, Sandra Barral, Bw W. J. H. (Brenda) Penninx, Hans van Bokhoven, Sg G. (Steven) Potkin, Bm M. (Bruce) Psaty, John Blangero, Jl L. (Joshua) Roffman, N. (Nina) Seiferth, Ji I. (Jerome I.) Rotter, Henry BrodatyORCID, Rl L. (Ralph L.) Sacco, Randy L. Buckner, Perminder S. Sachdev, Ps S. (Perminder) SachdevORCID, Aj J. (Andrew) SaykinORCID, Wiepke Cahn, C. J. (Christopher) Schofield, Pr Schofield, Peter R. Schofield, Andy Simmons, Sm M. (Sanjay) Sisodiya, Sven Cichon, Jw W. Smoller, Vm M. (Vidar) Steen, Aiden Corvin, Dj J. (David J.) Stott, Benedicto Crespo-Facorro, Je Sussmann, Aw W. (Arthur W.) Toga, Michael Czisch, Bj Traynor, Ag G. (André) Uitterlinden, Maria C. Valdés-Hernandez, A. (Aad) van der Lugt, N. J. (Nic) van der Wee, Anton J. M. de Craen, Nic J. A. Van Der Wee, Stéphanie Debette, Eco J. C. de Geus, Charles DeCarli, Ne Van Haren, Dennis Van 'T Ent, Norman Delanty, M. J. D. (Marie-José) van Tol, Chantal Depondt, Gary Donohoe, Dennis Van’t Ent, Anita L. (Anita) DeStefano, Wayne C. Drevets, Allissa Dillman, Mj Van Tol, Thomas D. DyerORCID, Srdjan Djurovic, Bn N. (Badri) Vardarajan, Ravi Duggirala, Christian Enzinger, Susanne Erk, Henry Voelzke, Thomas Espeseth, Dj J. (Dick) Veltman, Guillén Fernández, Luigi U. V. M. Ferrucci, Thomas H. Wassink, A. M. J. (Annemarie) Wassink, Ian Ford, Myriam Fornage, Jm WardlawORCID, Thomas Dyer, Clyde Francks, Th Wassink, Masaki Fukunaga, Me E. (Michael) Weale, J. Raphael Gibbs, Dr R. (Daniel R.) Weinberger, Harald H. Hh Göring, Mw W. (Michael W.) Weiner, Ty Y. (Tien Y.) Wong, Oliver Gruber, Cb B. (Clinton B.) Wright, Vilmundur Gudnason, Sebastian Guelfi, Rh H. (Ronald H.) Zielke, Ng G. (Nicholas) Martin, John Hardy, Cm Van Duijn, Ryota HashimotoORCID, Mj J. (Margaret) Wright, Katrin Hegenscheid, Lj J. (Lenore) Launer, Stephanie Le Hellard, Beng-Choon HoORCID, Se E. (Sarah Elizabeth) Medland, Andreas Heinz, Dp P. (Derrek) Hibar, Wolfgang Hoffmann, Albert Hofman, Pm Thompson, Florian Holsboer, H. H. Adams Hieab, Georg Homuth, M. K. (M Kamran) Ikram, Norbert Hosten, Matthew J. (Matthew) Huentelman, Jc C. (Joshua) Bis, Nj J. (Nicola J.) Armstrong, Masashi Ikeda, Mark Jenkinson, Robert Johnson, Jw Wouter Jukema, Bs Aribisala, Ryota Kanai, Ah H. (Ashley) Beecham, Iwona Kloszewska, Sh H. (Susan H.) Blanton, Peter Kochunov, L. B. C. (Linda) Bralten, Hervé Lemaître, Xinmin Liu, Am M. (Adam M.) Brickman, Cr R. K. (Christopher) Ching, Simon Lovestone, Oliver Martinez, A. (Anouk) den Braber, Nt T. (Nhat Trung) Doan, Colm McDonald, Al L. (Aaron L.) Goldman, Rf F. (Rebecca) Gottesman, Me D. (Michael) Griswold, Patrizia Mecocci, Uk K. (Unn) Haukvik, Ingrid Melle, David Höhn, Andreas Meyer-Lindenberg, Sebastian Mohnke, Aj J. (Avram) Holmes, K. R. (Kristel) van Eijk, Andrew Mcintosh, Bertram Müller-Myhsok, T. G. M. (Theo G.) van Erp, Michael A. (Michael) Nalls, Katie L. Mcmahon, Matthias Nauck, A. (Asgeir) Björnsson, Markus Mm Nöthen, Oa A. (Ole A.) AndreassenORCID, Lars Nyberg, Me E. (Mark) Bastin, Kazutaka Ohi, Dm M. (Diane M.) Becker, Massimo Pandolfo, Jt T. Becker, Tomas Paus, Da A. (David A.) Bennett, Zdenka Pausova, H. (Hans) van Bokhoven, Gb Bruce PikeORCID, Di I. (Dorret) Boomsma, Rm M. (Rachel) Brouwer, Simone Reppermund, Hg G. Brunner, Marcella Rietschel, M. Buckner, Rl Buckner, Nina Romanczuk-Seiferth, Jk K. (Jan) Buitelaar, Mina Ryten, Kb Bulayeva, Vd Calhoun, Dm M. (Dara) Cannon, Reinhold Schmidt, Gl Cavalleri, Helena Schmidt, Cy-Y. (Ching-Yu) Cheng, Mr R. (Mark) Cookson, Sigurdur Sigursson, Je E. (Joanne) Curran, Andrew Singleton, Am M. (Anders) Dale, Ge E. (Gareth) Davies, Colin Smith, Aj De Craen, A. J. (Anton) de Craen, Hilkka Soininen, Ej De Geus, E. J. C. (Eco) de Geus, Pl De Jager, Anbupalam Thalamuthu, P. L. (Philip) de Jager, Juan C. (Juan) Troncoso, Magda Tsolaki, Gi De Zubicaray, Ij J. (Ian J.) Deary, Christophe TzourioORCID, Kamran Ikram, Marcel Van der Brug, Mk Arfan Ikram, D. J. (Dennis) Donohoe, D. A. (Douglas) Drevets, Aad van der Lugt, Wc Drevets, M. D. (Matthew) Dyer, Td Dyer, Io O. (Iryna O.) Fedko, Se E. (Simon) FisherORCID, Bruno Vellas, Da Fleischman, Tm Foroud, Henry Völzke, Pt T. (Peter) Fox, Henrik J. (Henrik) Walter, Dc C. (David) Glahn, Harald H. H. Goring, Rl L. (Randy) Gollub, Rc C. (Robert C.) Green, Asta K. Haberg, Wei Wen, Ak K. (Asta K.) Håberg, Eric WestmanORCID, Nk K. (Narelle) Hansell, Tonya J. H. (Tonya) White, Ca A. (C.) Hartman, J. (Judith) Heinz, Dg G. (Dena) Hernandez, Dj J. (Dirk) Heslenfeld, Alan B. Zonderman, Bc-C. (Beng-Choon) Ho, Pj J. (Pieter) Hoekstra, Jj J. (Jouke Jan) Hottenga, Wt T. Longstreth, Hilleke E. Hulshoff Pol, Gunter Schumann, Cr R. (Clifford R.) Jack, Mc C. V. (Maria C. Valdés) Hernández, M. P. (Marcel) van der Brug, Barbara FrankeORCID, N. E. M. (Neeltje E.) van Haren, Sudha Seshadri, D. (Dennis) van 't Ent, C. M. (Cock) van Duijn, Hj J. (Hans Jörgen) Grabe, M. Arfan Ikram

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Abstract
The hippocampal formation is a brain structure integrally involved in episodic memory, spatial navigation, cognition and stress responsiveness. Structural abnormalities in hippocampal volume and shape are found in several common neuropsychiatric disorders. To identify the genetic underpinnings of hippocampal structure here we perform a genome-wide association study (GWAS) of 33,536 individuals and discover six independent loci significantly associated with hippocampal volume, four of them novel. Of the novel loci, three lie within genes (ASTN2, DPP4 and MAST4) and one is found 200 kb upstream of SHH. A hippocampal subfield analysis shows that a locus within the MSRB3 gene shows evidence of a localized effect along the dentate gyrus, subiculum, CA1 and fissure. Further, we show that genetic variants associated with decreased hippocampal volume are also associated with increased risk for Alzheimer's disease (r(g) = -0.155). Our findings suggest novel biological pathways through which human genetic variation influences hippocampal volume and risk for neuropsychiatric illness.