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, Mw W. (Meike) Vernooij, Hieab H. Hh Adams, Kn N. (Kjetil N.) Jørgensen, Kjetil N. Jorgensen, Neda Jahanshad, M. Kamran Ikram, Ganesh Chauhan, Ph H. (Phil) Lee, Edith Hofer, Dc C. (David C.) Liewald, Lm M. (Lorna) Lopez, Alejandro Arias-Vasquez, Af F. (Andre F.) Marquand, R. Mather, Sylvane Desrivières, Ka Mather, Lucija Abramovic, Dr R. (David R.) McKay, Susanna Muñoz Maniega, Saud Alhusaini, Susana Munoz Maniega, Najaf Amin, Micael Andersson, Ac C. (Allison) Nugent, Konstantinos A. Arfanakis, Lm M. O. (Loes M. Olde) LoohuisORCID, Loes M. Olde Loohuis, Lavinia Athanasiu, Js S. (Jennifer S.) Richards, Tomas Axelsson, Benno Puetz, Sl L. (Shannon) Risacher, Manon Bernard, Ej J. (Emma) Rose, Marc Mm Bohlken, Na A. (Natalie) Royle, Marco P. M. (Marco) BoksORCID, Alexa Beiser, Pg G. (Philipp) Sämann, Janita Bralten, Anouk den Braber, Owen Carmichael, Philipp G. Samann, Mm Mallar Chakravarty, Cl L. (Claudia L.) SatizabalORCID, Qiang Chen, Philipp G. Saemann, Vincent Chouraki, Michael E. Griswold, Gabriel Cuellar-Partida, Fabrice Crivello, N. J. (Nicholas) Schork, Aj Schork, Stefan M. (Stefan) Ehrlich, R. (Roy) Sprooten, Sudheer Giddaluru, Av V. (Albert Vernon) Smith, Oliver Grimm, V. M. (Vanessa) Strike, Tulio Guadalupe, Lt Strike, Boris A. (Boris A.) Gutman, Avram J. Ho, Johanna Hass, J. (Jeroen) van der Grond, Deborah Janowitz, David Hoehn, Tianye JiaORCID, S. (Sven) van der Lee, Nazanin Karbalai, Martine Hoogman, Dalia Kasperaviciute, Sungeun Kim, Marieke KleinORCID, Bernd Kraemer, Sven J. Van Der Lee, David C. M. Liewald, Michelle Luciano, Christine Macare, Sj Van der LeeORCID, Mar Matarin, Mm Van Donkelaar, Manuel MattheisenORCID, Yuri Milaneschi, Kr Van Eijk, Kwangsik Nho, Tg Van Erp, Paul Nyquist, Lt T. (Lars) WestlyeORCID, Cd D. (Christopher) Whelan, Jaap Oosterlaan, Martina Papmeyer, Bg G. (B Gwen) Windham, Lukas Pirpamer, 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, Roberto Toro, Diana Tordesillas-Gutierrez, Jb B. (John B.) Kwok, Sm Lawrie, Daniah TrabzuniORCID, Jeroen Van der Grond, Stella Trompet, 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, Te E. (Thomas) NicholsORCID, Laura Almasy, Wj J. (Wiro) Niessen, David Ames, Markus M. Nothen, Philippe AmouyelORCID, Rl L. (Rene) Olvera, Ra A. (Roel) Ophoff, Sampath Arepalli, Amelia Aa Assareh, Bw W. J. H. (Brenda) Penninx, Sandra Barral, Hans van Bokhoven, Sg G. (Steven) Potkin, Bm M. (Bruce) Psaty, Jl L. (Joshua) Roffman, N. (Nina) Seiferth, John Blangero, Ji I. (Jerome I.) Rotter, Rl L. (Ralph L.) Sacco, Perminder S. Sachdev, Randy L. Buckner, Henry BrodatyORCID, Ps S. (Perminder) SachdevORCID, Aj J. (Andrew) SaykinORCID, C. J. (Christopher) Schofield, Wiepke Cahn, Pr Schofield, Peter R. Schofield, Andy Simmons, Sm M. (Sanjay) Sisodiya, Jw W. Smoller, Sven Cichon, Vm M. (Vidar) Steen, Dj J. (David J.) Stott, Aiden Corvin, Je Sussmann, Aw W. (Arthur W.) Toga, Benedicto Crespo-Facorro, Bj Traynor, Michael Czisch, 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, Eco J. C. de Geus, Stéphanie Debette, Ne Van Haren, Dennis Van 'T Ent, Charles DeCarli, M. J. D. (Marie-José) van Tol, Norman Delanty, Dennis Van’t Ent, Gary Donohoe, Chantal Depondt, Mj Van Tol, Wayne C. Drevets, Anita L. (Anita) DeStefano, Bn N. (Badri) Vardarajan, Thomas D. DyerORCID, Allissa Dillman, Srdjan Djurovic, Henry Voelzke, Ravi Duggirala, Dj J. (Dick) Veltman, Christian Enzinger, Susanne Erk, Thomas H. Wassink, Thomas Espeseth, Guillén Fernández, A. M. J. (Annemarie) Wassink, Luigi U. V. M. Ferrucci, Jm WardlawORCID, Thomas Dyer, Ian Ford, Myriam Fornage, Th Wassink, Me E. (Michael) Weale, Clyde Francks, Dr R. (Daniel R.) Weinberger, Masaki Fukunaga, J. Raphael Gibbs, Mw W. (Michael W.) Weiner, Ty Y. (Tien Y.) Wong, Cb B. (Clinton B.) Wright, Harald H. Hh Göring, Oliver Gruber, Rh H. (Ronald H.) Zielke, Ng G. (Nicholas) Martin, Vilmundur Gudnason, Sebastian Guelfi, Cm Van Duijn, Mj J. (Margaret) Wright, John Hardy, Lj J. (Lenore) Launer, Ryota HashimotoORCID, Se E. (Sarah Elizabeth) Medland, Stephanie Le Hellard, Katrin Hegenscheid, Beng-Choon HoORCID, Dp P. (Derrek) Hibar, Andreas Heinz, Pm Thompson, Wolfgang Hoffmann, Albert Hofman, H. H. Adams Hieab, M. K. (M Kamran) Ikram, Florian Holsboer, Georg Homuth, Jc C. (Joshua) Bis, Norbert Hosten, Nj J. (Nicola J.) Armstrong, Matthew J. (Matthew) Huentelman, Mark Jenkinson, Robert Johnson, Masashi Ikeda, 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, Patrizia Mecocci, Me D. (Michael) Griswold, Ingrid Melle, Uk K. (Unn) Haukvik, Andreas Meyer-Lindenberg, David Höhn, Sebastian Mohnke, Aj J. (Avram) Holmes, K. R. (Kristel) van Eijk, Bertram Müller-Myhsok, Andrew Mcintosh, Michael A. (Michael) Nalls, T. G. M. (Theo G.) van Erp, Matthias Nauck, Katie L. Mcmahon, Markus Mm Nöthen, A. (Asgeir) Björnsson, Lars Nyberg, Oa A. (Ole A.) AndreassenORCID, Kazutaka Ohi, Me E. (Mark) Bastin, Massimo Pandolfo, Dm M. (Diane M.) Becker, Tomas Paus, Jt T. Becker, Zdenka Pausova, Da A. (David A.) Bennett, Gb Bruce PikeORCID, H. (Hans) van Bokhoven, Di I. (Dorret) Boomsma, Simone Reppermund, Rm M. (Rachel) Brouwer, Marcella Rietschel, Hg G. Brunner, Nina Romanczuk-Seiferth, M. Buckner, Rl Buckner, Mina Ryten, Jk K. (Jan) Buitelaar, Kb Bulayeva, Vd Calhoun, Reinhold Schmidt, Dm M. (Dara) Cannon, Helena Schmidt, Gl Cavalleri, Sigurdur Sigursson, Cy-Y. (Ching-Yu) Cheng, Mr R. (Mark) Cookson, Andrew Singleton, Je E. (Joanne) Curran, Am M. (Anders) Dale, Colin Smith, Ge E. (Gareth) Davies, Aj De Craen, Hilkka Soininen, A. J. (Anton) de Craen, Ej De Geus, Anbupalam Thalamuthu, E. J. C. (Eco) de Geus, Pl De Jager, Juan C. (Juan) Troncoso, Magda Tsolaki, P. L. (Philip) de Jager, Marcel Van der Brug, Gi De Zubicaray, Christophe TzourioORCID, Ij J. (Ian J.) Deary, Kamran Ikram, Mk Arfan Ikram, D. J. (Dennis) Donohoe, Aad van der Lugt, D. A. (Douglas) Drevets, Wc Drevets, M. D. (Matthew) Dyer, Td Dyer, Io O. (Iryna O.) Fedko, Bruno Vellas, Se E. (Simon) FisherORCID, Henry Völzke, Da Fleischman, Tm Foroud, Henrik J. (Henrik) Walter, Pt T. (Peter) Fox, Dc C. (David) Glahn, Harald H. H. Goring, Rl L. (Randy) Gollub, Wei Wen, Rc C. (Robert C.) Green, Asta K. Haberg, Eric WestmanORCID, Ak K. (Asta K.) Håberg, Tonya J. H. (Tonya) White, Nk K. (Narelle) Hansell, Ca A. (C.) Hartman, J. (Judith) Heinz, Dg G. (Dena) Hernandez, Alan B. Zonderman, Dj J. (Dirk) Heslenfeld, Bc-C. (Beng-Choon) Ho, Pj J. (Pieter) Hoekstra, Wt T. Longstreth, Jj J. (Jouke Jan) Hottenga, Gunter Schumann, Hilleke E. Hulshoff Pol, 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 ¼ À 0.155). Our findings suggest novel biological pathways through which human genetic variation influences hippocampal volume and risk for neuropsychiatric illness.