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Mapping cortical brain asymmetry in 17,141 healthy individuals worldwide via the ENIGMA Consortium
(2017)
Kong, Xiang-Zhen ; Mathias, Samuel R. ; Guadalupe, Tulio ; Abé, Christoph ; Agartz, Ingrid ; Akudjedu, Theophilus N. ; Andre, Aleman ; Saud, Alhusaini ; Allen, Nicholas B. ; Ames, David ; Andreassen, Ole A. ; Arias Vásquez, Alejandro ; Armstrong, Nicola J. ; Bergo, Felipe ; Bastin, Mark E. ; Batalla, Albert ; Bauer, Jochen ; Baune, Bernhard T. ; Baur, Ramona ; Biederman, Joseph ; Blaine, Sara K. ; Boedhoe, Premika ; Bøen, Erlend ; Bose, Anushree ; Bralten, Janita ; Brandeis, Daniel ; Brem, Silvia ; Brodaty, Henry ; Bröhl, Henrieke ; Brooks, Samantha J. ; Buitelaar, Jan K. ; Bürger, Christian ; Bülow, Robin ; Calhoun, Vince D. ; Calvo, Anna ; Canales-Rodrı́guez, Erick Jorge ; Canive, Jose M. ; Cannon, Dara M. ; Caparelli, Elisabeth C. ; Castellanos, Francisco X. ; Cavalleri, Gianpiero L. ; Cendes, Fernando ; Chaim-Avancini, Tiffany Moukbel ; Chantiluke, Kaylita ; Chen, Qun-lin ; Chen, Xiayu ; Cheng, Yuqi ; Christakou, Anastasia ; Clark, Vincent P. ; Coghill, David ; Connolly, Colm G. ; Conzelmann, Annette ; Cόrdova-Palomera, Aldo ; Cousijn, Janna ; Crow, Tim ; Cubillo, Ana ; Dannlowski, Udo ; de Bruttopilo, Sara Ambrosino ; Zeeuw, Patrick de ; Deary, Ian J. ; Delanty, Norman ; Demeter, Damion V. ; Di Martino, Adriana ; Dickie, Erin W ; Dietsche, Bruno ; Doan, N. Trung ; Doherty, Colin P. ; Doyle, Alysa ; Durston, Sarah ; Earl, Eric ; Ehrlich, Stefan ; Ekman, Carl Johan ; Elvsåshagen, Torbjørn ; Epstein, Jeffery N. ; Fair, Damien A. ; Faraone, Stephen V. ; Fatouros-Bergman, Helena ; Fernndez, Guillen ; Busatto Filho, Geraldo ; Flyckt, Lena ; Forster, Katharina ; Jean-Paul, Fouche ; Foxe, John J. ; Fuentes-Claramonte, Paola ; Fullerton, Janice M. ; Garavan, Hugh ; Garcia, Danielle do Santos ; Gotlib, Ian H. ; Goudriaan, Anna E. ; Grabe, Hans Jörgen ; Groenewold, Nynke A. ; Grotegerd, Dominik ; Gruber, Oliver ; Gurholt, Tiril ; Haavik, Jan ; Hahn, Tim ; Hansell, Narelle K. ; Harris, Mathew A. ; Hartman, Catharina ; Hernandez, Maria del Carmen Valdes ; Heslenfeld, Dirk ; Hester, Robert ; Hibar, Derrek Paul ; Ho, Beng-Choon ; Ho, Tiffany C. ; Hoekstra, Pieter J. ; van Holst, Ruth J. ; Hoogman, Martine ; Hovik, Marie F. ; Howells, Fleur M. ; Hugdahl, Kenneth ; Huyser, Chaim ; Ingvar, Martind ; Irwin, Lourdes ; Ishikawa, Akari ; James, Anthony ; Jahanshad, Neda ; Jernigan, Terry L. ; Jönsson, Erik G. ; Kahler, Claas ; Kaleda, Vasily ; Kelly, Clare ; Kerich, Michael ; Keshavan, Matcheri S ; Khadka, Sabin ; Kircher, Tilo ; Kohls, Gregor ; Konrad, Kerstin ; Korucuoglu, Ozlem ; Krämer, Bernd ; Krug, Axel ; Kwon, Jun Soo ; Lambregts-Rommelse, Nanda ; Landén, Mikael ; Lázaro, Luisa ; Lebedeva, Irina ; Lenroot, Rhoshel ; Lesch, Klaus-Peter J. ; Li, Qinqin ; Lim, Kelvin O. ; Liu, Jia ; Lochner, Christine ; London, Edythe D. ; Lonning, Vera ; Lorenzetti, Valentina ; Luciano, Michelle ; Luijten, Maartje ; Lundervold, Astri J. ; Mackey, Scott ; MacMaster, Frank P. ; Maingault, Sophie ; Malpas, Charles B. ; Malt, Ulrik F. ; Mataix-Cols, David ; Martin-Santos, Rocio ; Mayer, Andrew R. ; McCarthy, Hazel ; Mitchell, Philip B. ; Mueller, Bryon A. ; Maniega, Susana Munoz ; Mazoyer, Bernard ; McDonald, Colm ; McLellan, Quinn ; McMahon, Katie L. ; McPhilemy, Genevieve ; Momenan, Reza ; Morales, Angelica M. ; Narayanaswamy, Janardhanan C. ; Moreira, José Carlos Vasques ; Nerland, Stener ; Nestor, Liam ; Nigg, Joel T. ; Nordvik, Jan-Egil ; Novotny, Stephanie ; Oberwelland, Eileen ; O’Gorman, Ruth L. ; Oosterlaan, Jaap ; Oranje, Bob ; Orr, Catherine ; Overs, Bronwyn ; Pauli, Paul ; Paulus, Martin ; Plessen, Kerstin ; Polier, Georg von ; Pomarol-Clotet, Edith ; Qiu, Jiang ; Radua, Joaquim ; Ramos-Quiroga, J. Antoni ; Reddy, Y.C. Janardhan ; Reif, Andreas ; Roberts, Gloria ; Rosa, Pedro ; Rubia, Katya ; Sacchet, Matthew D. ; Sachdev, Perminder S. ; Salvador, Raymond ; Schmaal, Lianne ; Schweren, Lisanne ; Seidman, Larry J. ; Seitz, Jochen ; Serpa, Mauricio Henriques ; Shaw, Philip ; Shumskaya, Elena ; Silk, Timothy J. ; Simmons, Alan N. ; Simulionyte, Egle ; Sinha, Rajita ; Sjoerds, Zsuzsika ; Smelror, Runar Elle ; Soliva, Joan Carlos ; Solowij, Nadia ; Sponheim, Scott R. ; Stein, Dan J. ; Stein, Elliot A. ; Stevens, Michael ; Strike, Lachlan T. ; Sudre, Gustavo ; Sui, Jing ; Tamm, Leanne ; Temmingh, Hendrik S. ; Thoma, Robert J. ; Tomyshev, Alexander S. ; Tronchin, Giulia ; Turner, Jessica A. ; Uhlmann, Anne ; van Erp, Theo G.M. ; van den Heuvel, Odile ; van der Meer, Dennis ; Eijk, Liza van ; Vance, Alasdair ; Veer, Ilya M. ; Veltman, Dick J. ; Venkatasubramanian, Ganesan ; Vilarroya, Oscar ; Vives-Gilabert, Yolanda ; Voineskos, Aristotle N. ; Völzke, Henry ; Vuletic, Daniella ; Walitza, Susanne ; Walter, Henrik ; Walton, Esther ; Wardlaw, Joanna M. ; Wen, Wei ; Westlye, Lars T. ; Whelan, Christopher D. ; White, Tonya ; Wiers, Reinout W. ; Wright, Margaret J. ; Wittfeld, Katharina ; Yang, Tony T. ; Yasuda, Clarissa L. ; Yoncheva, Yuliya ; Yucel, Murat ; Yun, Je-Yeon ; Zanetti, Marcus Vinicius ; Zhen, Zonglei ; Zhu, Xing-xing ; Ziegler, Georg Christoph ; Zierhut, Kathrin ; De Zubicaray, Greig ; Zwiers, Marcel P. ; Glahn, David C. ; Franke, Barbara ; Crivello, Fabrice ; Tzourio-Mazoyer, Nathalie ; Fisher, Simon E. ; Thompson, Paul M. ; Francks, Clyde ; Farde, Lars ; Engberg, Goran ; Erhardt, Sophie ; Cervenka, Simon ; Schwieler, Lilly ; Piehl, Fredrik ; Collste, Karin ; Victorsson, Pauliina ; Malmqvist, Anna ; Hedberg, Mikael ; Orhan, Funda
Chang, Hong ; Hoshina, Naosuke ; Zhang, Chen ; Ma, Yina ; Cao, Hongxin ; Wang, Yaling ; Wu, Dong-Dong ; Bergen, Sarah E. ; Landén, Mikael ; Hultman, Christina M. ; Preisig, Martin ; Kutalik, Zoltán ; Castelao, Enrique ; Grigoroiu-Serbanescu, Maria ; Forstner, Andreas Josef ; Strohmaier, Jana ; Hecker, Julian ; Schulze, Thomas Gerd ; Müller-Myhsok, Bertram ; Reif, Andreas ; Mitchell, Philip B. ; Martin, Nicholas Gordon ; Schofield, Peter R. ; Cichon, Sven ; Nöthen, Markus Maria ; Walter, Henrik ; Erk, Susanne ; Heinz, Andreas ; Amin, Najaf ; Duijn, Cornelia M. van ; Meyer-Lindenberg, Andreas ; Tost, Heike ; Xiao, Xiao ; Yamamoto, Tadashi ; Rietschel, Marcella ; Li, Ming
Major mood disorders, which primarily include bipolar disorder and major depressive disorder, are the leading cause of disability worldwide and pose a major challenge in identifying robust risk genes. Here, we present data from independent large-scale clinical data sets (including 29 557 cases and 32 056 controls) revealing brain expressed protocadherin 17 (PCDH17) as a susceptibility gene for major mood disorders. Single-nucleotide polymorphisms (SNPs) spanning the PCDH17 region are significantly associated with major mood disorders; subjects carrying the risk allele showed impaired cognitive abilities, increased vulnerable personality features, decreased amygdala volume and altered amygdala function as compared with non-carriers. The risk allele predicted higher transcriptional levels of PCDH17 mRNA in postmortem brain samples, which is consistent with increased gene expression in patients with bipolar disorder compared with healthy subjects. Further, overexpression of PCDH17 in primary cortical neurons revealed significantly decreased spine density and abnormal dendritic morphology compared with control groups, which again is consistent with the clinical observations of reduced numbers of dendritic spines in the brains of patients with major mood disorders. Given that synaptic spines are dynamic structures which regulate neuronal plasticity and have crucial roles in myriad brain functions, this study reveals a potential underlying biological mechanism of a novel risk gene for major mood disorders involved in synaptic function and related intermediate phenotypes.
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