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Niemi, Mari K. ; Karjalainen, Juha ; Liao, Rachel G. ; Neale, Benjamin M. ; Daly, Mark ; Ganna, Andrea ; Pathak, Gita A. ; Andrews, Shea J. ; Kanai, Masahiro ; Veerapen, Kumar ; Fernandez-Cadenas, Israel ; Schulte, Eva C. ; Striano, Pasquale ; Marttila, Minttu ; Minica, Camelia ; Marouli, Eirini ; Karim, Mohd Anisul ; Wendt, Frank R. ; Savage, Jeanne ; Sloofman, Laura ; Butler-Laporte, Guillaume ; Kim, Han-Na ; Kanoni, Stavroula ; Okada, Yukinori ; Byun, Jinyoung ; Han, Younghun ; Uddin, Mohammed Jashim ; Smith, George Davey ; Willer, Cristen J. ; Buxbaum, Joseph D. ; Mehtonen, Juha ; Finucane, Hilary ; Cordioli, Mattia ; Martin, Alicia R. ; Zhou, Wei ; Pasaniuc, Bogdan ; Julienne, Hanna ; Aschard, Hugues ; Shi, Huwenbo ; Yengo, Loic ; Polimanti, Renato ; Ghoussaini, Maya ; Schwartzentruber, Jeremy ; Dunham, Ian ; Chwialkowska, Karolina ; Francescatto, Margherita ; Trankiem, Amy ; Balaconis, Mary K. ; Davis, Lea ; Lee, Sulggi ; Priest, James ; Renieri, Alessandra ; Sankaran, Vijay G. ; van Heel, David ; Deelen, Patrick ; Richards, J. Brent ; Nakanishi, Tomoko ; Biesecker, Les ; Kerchberger, V. Eric ; Baillie, J. Kenneth ; Mari, Francesca ; Bernasconi, Anna ; Baillie, Stefano Ceri ; Canakoglu, Arif ; Wolford, Brooke ; Faucon, Annika ; Dutta, Atanu Kumar ; Schurmann, Claudia ; Harry, Emi ; Birney, Ewan ; Nguyen, Huy ; Nasir, Jamal ; Kaunisto, Mari ; Solomonson, Matthew ; Dueker, Nicole ; Vadgama, Nirmal ; Limou, Sophie ; Rahmouni, Souad ; Mbarek, Hamdi ; Darwish, Dima ; Uddin, Md Mesbah ; Albertos, Raquel ; Pérez-Tur, Jordi ; Li, Ruolin ; Folkersen, Lasse ; Moltke, Ida ; Koelling, Nils ; Teumer, Alexander ; Kousathanas, Athanasios ; Utrilla, Alicia ; Verdugo, Ricardo A. ; Zárate, Ruth ; Medina-Gómez, Carolina ; Gómez-Cabrero, David ; Carnero-Montoro, Elena ; Cadilla, Carmen L. ; Moreno-Estrada, Andrés ; Garmendia, Adriana ; Moya, Leire ; Sedaghati-Khayat, Bahar ; Boua, Palwendé Romuald ; Favé, Marie-Julie ; Francioli, Laurent ; Lemaçon, Audrey ; Migeotte, Isabelle ; Patel, Sanjay ; Varnai, Reka ; Szentpeteri, Jozsef L. ; Sipeky, Csilla ; Colombo, Francesca ; von Hohenstaufen, Kathrin ; Lio, Pietro ; Vallerga, Costanza ; Wang, Qingbo ; Tanigawa, Yosuke ; Im, Hogune ; Han, Chulho ; Song, Han ; Lim, Jiwoo ; Lee, Younhe ; Kim, Sugyeong ; Im, Sangyoon ; Atanasovska, Biljana ; Ahmad, Hajar Fauzan ; Boer, Cindy ; Jansen, Philip ; Franke, Lude ; Kaja, Elżbieta ; Pasko, Dorota ; Kennis-Szilagyi, Ingrid ; Kornilov, Sergey A. ; Prijatelj, Vid ; Prokić, Ivana ; Sivanadhan, Ilangkumaran ; Perumal, Sarala ; Esmaeeli, Sahar ; Pearson, Nathaniel M. ; Auton, Adam ; Shelton, Janie F. ; Shastri, Anjali J. ; Filshtein-Sonmez, Teresa ; Coker, Daniella ; Symons, Antony ; Esparza-Gordillo, Jorge ; Aslibekyan, Stella ; O’Connell, Jared ; Ye, Chelsea ; Weldon, Catherine H. ; Perera, Minoli ; O’Leary, Kevin ; Tuck, Matthew ; O’Brien, Travis ; Meltzer, David ; O’Donnell, Peter ; Nutescu, Edith ; Yang, Guang ; Alarcon, Cristina ; Herrmann, Stefanie ; Mazurek, Sophia ; Banagan, Jeff ; Hamidi, Zacharia ; Barbour, April ; Raffat, Noora ; Moreno, Diana ; Friedman, Paula ; Ferwerda, Bart ; van de Beek, Diederik ; Brouwer, Matthijs C. ; Vlaar, Alexander P. J. ; Wiersinga, W. Joost ; Posthuma, Danielle ; Tissink, Elleke ; Koos Zwinderman, A. H. ; Uffelmann, Emil ; van Agtmael, Michiel ; Algera, Anne Geke ; van Baarle, Frank ; Bax, Diane ; Beudel, Martijn ; Jan Bogaard, Harm ; Bomers, Marije ; Bonta, Peter I. ; Bos, Lieuwe ; Botta, Michela ; de Brabander, Justin ; de Bree, Godelieve ; de Bruin, Sanne ; Bugiani, Marianna ; Bulle, Esther ; Chouchane, Osoul ; Cloherty, Alex ; Dongelmans, Dave ; Elbers, Paul ; Fleuren, Lucas ; Geerlings, Suzanne ; Geerts, Bart ; Geijtenbeek, Theo ; Girbes, Armand ; Goorhuis, Bram ; Grobusch, Martin P. ; Hafkamp, Florianne ; Hagens, Laura ; Hamann, Jorg ; Harris, Vanessa ; Hemke, Robert ; Hermans, Sabine M. ; Heunks, Leo ; Hollmann, Markus ; Horn, Janneke ; Hovius, Joppe W. ; de Jong, Menno D. ; Koning, Rutger ; van Mourik, Niels ; Nellen, Jeannine ; Nossent, Esther J. ; Paulus, Frederique ; Peters, Edgar ; van der Poll, Tom ; Preckel, Bennedikt ; Prins, Jan M. ; Raasveld, Jorinde ; Reijnders, Tom ; Schinkel, Michiel ; Schultz, Marcus J. ; Schuurman, Alex ; Sigaloff, Kim ; Smit, Marry ; Stijnis, Cornelis S. ; Stilma, Willemke ; Teunissen, Charlotte ; Thoral, Patrick ; Tsonas, Anissa ; van der Valk, Marc ; Veelo, Denise ; de Vries, Heder ; van Vugt, Michèle ; Wouters, Dorien ; Minnaar, René P. ; Kromhout, Adrie ; van Uffelen, Kees W. J. ; Wolterman, Ruud A. ; Roberts, Genevieve ; Park, Danny ; Ball, Catherine A. ; Coignet, Marie ; McCurdy, Shannon ; Knight, Spencer ; Partha, Raghavendran ; Rhead, Brooke ; Zhang, Miao ; Berkowitz, Nathan ; Gaddis, Michael ; Noto, Keith ; Ruiz, Luong ; Pavlovic, Milos ; Hong, Eurie L. ; Rand, Kristin ; Girshick, Ahna ; Guturu, Harendra ; Baltzell, Asher Haug ; Rahmouni, Souad ; Guntz, Julien ; Beguin, Yves ; Pigazzini, Sara ; Nkambule, Lindokuhle ; Bouysran, Youssef ; Busson, Adeline ; Peyrassol, Xavier ; Wilkin, Françoise ; Pichon, Bruno ; Smits, Guillaume ; Vandernoot, Isabelle ; Goffard, Jean-Christophe ; Georges, Michel ; Moutschen, Michel ; Misset, Benoit ; Darcis, Gilles ; Guiot, Julien ; Jadot, Laurent ; Azarzar, Samira ; Dellot, Patricia ; Gofflot, Stéphanie ; Claassen, Sabine ; Bertrand, Axelle ; Parzibut, Gilles ; Clarinval, Mathilde ; Moermans, Catherine ; Malaise, Olivier ; El Kandoussi, Kamilia ; Thonon, Raphaël ; Huynen, Pascale ; Mesdagh, Alyssia ; Melo, Sofia ; Jacques, Nicolas ; Di Valentin, Emmanuel ; Giroule, François ; Collignon, Alice ; Radermecker, Coraline ; Lebrun, Marielle ; Perée, Hélène ; Latour, Samuel ; Barada, Olivia ; Sanchez, Judit ; Josse, Claire ; Boujemla, Bouchra ; Meunier, Margot ; Mariavelle, Emeline ; Anania, Sandy ; Gazon, Hélène ; Juszczak, Danusia ; Fadeur, Marjorie ; Camby, Séverine ; Meuris, Christelle ; Thys, Marie ; Jacques, Jessica ; Henket, Monique ; Léonard, Philippe ; Frippiat, Frederic ; Giot, Jean-Baptiste ; Sauvage, Anne-Sophie ; Von Frenckell, Christian ; Mni, Myriam ; Wéry, Marie ; Staderoli, Alicia ; Belhaj, Yasmine ; Lambermont, Bernard ; Morrison, David R. ; Mooser, Vincent ; Forgetta, Vincenzo ; Li, Rui ; Ghosh, Biswarup ; Laurent, Laetitia ; Belisle, Alexandre ; Henry, Danielle ; Abdullah, Tala ; Adeleye, Olumide ; Mamlouk, Noor ; Kimchi, Nofar ; Afrasiabi, Zaman ; Rezk, Nardin ; Vulesevic, Branka ; Bouab, Meriem ; Guzman, Charlotte ; Petitjean, Louis ; Tselios, Chris ; Xue, Xiaoqing ; Afilalo, Jonathan ; Afilalo, Marc ; Oliveira, Maureen ; Brenner, Bluma ; Brassard, Nathalie ; Durand, Madeleine ; Schurr, Erwin ; Lepage, Pierre ; Ragoussis, Jiannis ; Auld, Daniel ; Chassé, Michaël ; Kaufmann, Daniel E. ; Lathrop, G. Mark ; Adra, Darin ; Davis, Lea K. ; Cox, Nancy J. ; Below, Jennifer E. ; Sealock, Julia M. ; Faucon, Annika B. ; Shuey, Megan M. ; Polikowsky, Hannah G. ; Petty, Lauren E. ; Shaw, Douglas M. ; Chen, Hung-Hsin ; Zhu, Wanying ; Ludwig, Kerstin U. ; Schröder, Julia ; Maj, Carlo ; Rolker, Selina ; Nöthen, Markus M. ; Fazaal, Julia ; Keitel, Verena ; Jensen, Björn-Erik Ole ; Feldt, Torsten ; Kurth, Ingo ; Marx, Nikolaus ; Dreher, Michael ; Pink, Isabell ; Cornberg, Markus ; Illig, Thomas ; Lehmann, Clara ; Schommers, Philipp ; Augustin, Max ; Rybniker, Jan ; Knopp, Lisa ; Eggermann, Thomas ; Volland, Sonja ; Altmüller, Janine ; Berger, Marc M. ; Brenner, Thorsten ; Hinney, Anke ; Witzke, Oliver ; Bals, Robert ; Herr, Christian ; Ludwig, Nicole ; Walter, Jörn ; Fuchsberger, Christian ; Pattaro, Cristian ; De Grandi, Alessandro ; Pramstaller, Peter ; Emmert, David ; Melotti, Roberto ; Foco, Luisa ; Mascalzoni, Deborah ; Gögele, Martin ; Domingues, Francisco ; Hicks, Andrew ; Gignoux, Christopher R. ; Wicks, Stephen J. ; Crooks, Kristy ; Barnes, Kathleen C. ; Daya, Michelle ; Shortt, Jonathan ; Rafaels, Nicholas ; Chavan, Sameer ; Goldstein, David B. ; Kiryluk, Krzysztof ; Sengupta, Soumitra ; Chung, Wendy ; Reilly, Muredach P. ; Khan, Atlas ; Wang, Chen ; Povysil, Gundula ; Bhardwaj, Nitin ; Gharavi, Ali G. ; Ionita-Laza, Iuliana ; Shang, Ning ; O’Byrne, Sheila M. ; Nandakumar, Renu ; Menon, Amritha ; So, Yat S. ; Hod, Eldad ; Pendrick, Danielle ; Kim, Han-Na ; Park, Soo-Kyung ; Kim, Hyung-Lae ; Kang, Chang Kyung ; Lee, Hyo-Jung ; Song, Kyoung-Ho ; Jae Yoon, Kyung ; Paik, Nam-Jong ; Seok, Woojin ; Yoon, Heejun ; Joo, Eun-Jeong ; Chang, Yoosoo ; Ryu, Seungho ; Park, Wan Beom ; Su Park, Jeong ; Un Park, Kyoung ; Ham, Sin Young ; Jung, Jongtak ; Kim, Eu Suk ; Kim, Hong Bin ; Ellinghaus, David ; Degenhardt, Frauke ; Cáceres, Mario ; Juzenas, Simonas ; Lenz, Tobias L. ; Albillos, Agustín ; Julià, Antonio ; Heidecker, Bettina ; Garcia, Federico ; Kurth, Florian ; Tran, Florian ; Hanses, Frank ; Zoller, Heinz ; Holter, Jan C. ; Fernández, Javier ; Sander, Leif Erik ; Rosenstiel, Philip ; Koehler, Philipp ; de Cid, Rafael ; Asselta, Rosanna ; Schreiber, Stefan ; Hehr, Ute ; Prati, Daniele ; Baselli, Guido ; Valenti, Luca ; Bujanda, Luis ; Banales, Jesus M. ; Duga, Stefano ; D’Amato, Mauro ; Romero-Gómez, Manuel ; Buti, Maria ; Invernizzi, Pietro ; Franke, Andre ; Hov, Johannes R. ; Karlsen, Tom H. ; Folseraas, Trine ; Maya-Miles, Douglas ; Teles, Ana ; Azuure, Clinton ; Wacker, Eike Matthias ; Uellendahl-Werth, Florian ; ElAbd, Hesham ; Arora, Jatin ; Lerga-Jaso, Jon ; Wienbrandt, Lars ; Rühlemann, Malte Christoph ; Wendorff, Mareike ; Vadla, May Sissel ; Lenning, Ole Bernt ; Özer, Onur ; Myhre, Ronny ; Raychaudhuri, Soumya ; Tanck, Anja ; Gassner, Christoph ; Hemmrich-Stanisak, Georg ; Kässens, Jan ; Figuera Basso, Maria E. ; Schulzky, Martin ; Wittig, Michael ; Braun, Nicole ; Wesse, Tanja ; Albrecht, Wolfgang ; Yi, Xiaoli ; Ortiz, Aaron Blandino ; Chercoles, Adolfo Garrido ; Ruiz, Agustín ; Mantovani, Alberto ; Holten, Aleksander Rygh ; Mayer, Alena ; Cherubini, Alessandro ; Protti, Alessandro ; Aghemo, Alessio ; Gerussi, Alessio ; Ramirez, Alfredo ; Braun, Alice ; Barreira, Ana ; Lleo, Ana ; Kildal, Anders Benjamin ; Glück, Andreas ; Nolla, Anna Carreras ; Latiano, Anna ; Dyrhol-Riise, Anne Ma ; Muscatello, Antonio ; Voza, Antonio ; Rando-Segura, Ariadna ; Solier, Aurora ; Karina, Banasik ; Cortes, Beatriz ; Mateos, Beatriz ; Nafria-Jimenez, Beatriz ; Schaefer, Benedikt ; Bellinghausen, Carla ; Ferrando, Carlos ; Quereda, Carmen ; Skurk, Carsten ; Thibeault, Charlotte ; Spinner, Christoph D. ; Lange, Christoph ; Hu, Cinzia ; Cappadona, Claudio ; Bianco, Cristiana ; Sancho, Cristina ; Lihaug Hoff, Dag Arne ; Galimberti, Daniela ; Jiménez, David ; Pestaña, David ; Toapanta, David ; Azzolini, Elena ; Scarpini, Elio ; Helbig, Elisa T. ; Urrechaga, Eloisa ; Paraboschi, Elvezia Maria ; Pontali, Emanuele ; Reverter, Enric ; Navas, Enrique ; Arana, Eunate ; Sánchez, Félix García ; Ceriotti, Ferruccio ; Malvestiti, Francesco ; Mesonero, Francisco ; Pezzoli, Gianni ; Lamorte, Giuseppe ; Neb, Holger ; My, Ilaria ; Hernández, Isabel ; de Rojas, Itziar ; Galván-Femenia, Iván ; Heyckendorf, Jan ; Rybniker, Jan ; Badia, Joan Ramon ; Schneider, Jochen ; Goikoetxea, Josune ; Kraft, Julia ; Müller, Karl Erik ; Gaede, Karoline I. ; Garcia-Etxebarria, Koldo ; Tonby, Kristian ; Heggelund, Lars ; Izquierdo-Sanchez, Laura ; Sumoy, Lauro ; Lippert, Lena J. ; Terranova, Leonardo ; Garbarino, Lucia ; Téllez, Luis ; Roade, Luisa ; Ostadreza, Mahnoosh ; Intxausti, Maider ; Kogevinas, Manolis ; Gutiérrez-Stampa, María A. ; Vehreschild, Maria J. G. T. ; Marquié, Marta ; Castoldi, Massimo ; Cecconi, Maurizio ; Boada, Mercè ; Seilmaier, Michael J. ; Mazzocco, Michela ; Rodríguez-Gandía, Miguel ; Ayo, Natale Imaz ; Blay, Natalia ; Martínez, Nilda ; Cornely, Oliver A. ; Palmieri, Orazio ; Tentorio, Paolo ; Rodrigues, Pedro M. ; España, Pedro P. ; Hoffmann, Per ; Bacher, Petra ; Suwalski, Phillip ; de Pablo, Raúl ; Nieto, Rosa ; Badalamenti, Salvatore ; Ciesek, Sandra ; Bombace, Sara ; Wilfling, Sibylle ; Brunak, Søren ; Heilmann-Heimbach, Stefanie ; Ripke, Stephan ; Bahmer, Thomas ; Landmesser, Ulf ; Protzer, Ulrike ; Rimoldi, Valeria ; Skogen, Vegard ; Andrade, Victor ; Moreno, Victor ; Poller, Wolfgang ; Farre, Xavier ; Wang, Xiaomin ; Khodamoradi, Yascha ; Karadeniz, Zehra ; de Salazar, Adolfo ; Palom, Adriana ; Garcia-Fernandez, Alba-Estela ; Blanco-Grau, Albert ; Zanella, Alberto ; Bandera, Alessandra ; Nebel, Almut ; Biondi, Andrea ; Caballero-Garralda, Andrea ; Gori, Andrea ; Lind, Andreas ; Fracanzani, Anna Ludovica ; Peschuck, Anna ; Pesenti, Antonio ; de la Horra, Carmen ; Milani, Chiara ; Paccapelo, Cinzia ; Angelini, Claudio ; Cea, Cristina ; Muñiz-Diaz, Eduardo ; Sandoval, Elena ; Calderón, Enrique J. ; Solligård, Erik ; Aziz, Fátima ; Martinelli-Boneschi, Filippo ; Peyvandi, Flora ; Blasi, Francesco ; Medrano, Francisco J. ; Rodriguez-Frias, Francisco ; Müller, Fredrik ; Grasselli, Giacomo ; Costantino, Giorgio ; Cardamone, Giulia ; Foti, Giuseppe ; Matullo, Giuseppe ; Kurihara, Hayato ; Afset, Jan Egil ; Damås, Jan Kristian ; Ampuero, Javier ; Martín, Javier ; Erdmann, Jeanette ; Bergan, Jonas ; Goerg, Siegfried ; Ferrusquía-Acosta, Jose ; Quero, Jose Hernández ; Delgado, Juan ; Guerrero, Juan M. ; Risnes, Kari ; Bettini, Laura Rachele ; Moreira, Leticia ; Gustad, Lise Tuset ; Santoro, Luigi ; Scudeller, Luigia ; Riveiro-Barciela, Mar ; Schaefer, Marco ; Carrabba, Maria ; Valsecchi, Maria G. ; Hernandez-Tejero, María ; Acosta-Herrera, Marialbert ; D’Angiò, Mariella ; Baldini, Marina ; Cazzaniga, Marina ; Ciccarelli, Michele ; Bocciolone, Monica ; Miozzo, Monica ; Chueca, Natalia ; Montano, Nicola ; Faverio, Paola ; Preatoni, Paoletta ; Bonfanti, Paolo ; Omodei, Paolo ; Castro, Pedro ; Ferrer, Ricard ; Gualtierotti, Roberta ; Gallego-Durán, Rocío ; Morilla, Rubén ; Haider, Sammra ; Marsal, Sara ; Aneli, Serena ; Pelusi, Serena ; Bosari, Silvano ; Aliberti, Stefano ; Dudman, Susanne ; Zheng, Tenghao ; Pumarola, Tomas ; Cejudo, Trinidad Gonzalez ; Monzani, Valter ; Friaza, Vicente ; Peter, Wolfgang ; Dopazo, Ximo ; Duga, Stefano ; May, Sandra ; Grimsrud, Marit M. ; Gudbjartsson, Daniel F. ; Stefansson, Kari ; Sulem, Patrick ; Sveinbjornsson, Gardar ; Melsted, Pall ; Norddahl, Gudmundur ; Swerford Moore, Kristjan Helgi ; Thorsteinsdottir, Unnur ; Holm, Hilma ; Alarcón-Riquelme, Marta E. ; Bernardo, David ; Martínez-Bueno, Manuel ; Rello, Silvia Rojo ; Magi, Reedik ; Milani, Lili ; Metspalu, Andres ; Laisk, Triin ; Läll, Kristi ; Lepamets, Maarja ; Esko, Tõnu ; Reimann, Ene ; Naaber, Paul ; Laane, Edward ; Pesukova, Jaana ; Peterson, Pärt ; Kisand, Kai ; Tabri, Jekaterina ; Allos, Raili ; Hensen, Kati ; Starkopf, Joel ; Ringmets, Inge ; Tamm, Anu ; Kallaste, Anne ; Alavere, Helene ; Metsalu, Kristjan ; Puusepp, Mairo ; Kristiansson, Kati ; Koskelainen, Sami ; Perola, Markus ; Donner, Kati ; Kivinen, Katja ; Palotie, Aarno ; Palotie, Aarno ; Rivolta, Carlo ; Bochud, Pierre-Yves ; Bibert, Stéphanie ; Boillat, Noémie ; Nussle, Semira Gonseth ; Albrich, Werner ; Quinodoz, Mathieu ; Kamdar, Dhryata ; Suh, Noémie ; Neofytos, Dionysios ; Erard, Véronique ; Voide, Cathy ; Bochud, P. Y. ; Rivolta, C. ; Bibert, S. ; Quinodoz, M. ; Kamdar, D. ; Neofytos, D. ; Erard, V. ; Voide, C. ; Friolet, R. ; Vollenweider, P. ; Pagani, J. L. ; Oddo, M. ; zu Bentrup, F. Meyer ; Conen, A. ; Clerc, O. ; Marchetti, O. ; Guillet, A. ; Guyat-Jacques, C. ; Foucras, S. ; Rime, M. ; Chassot, J. ; Jaquet, M. ; Viollet, R. Merlet ; Lannepoudenx, Y. ; Portopena, L. ; Desgranges, F. ; Filippidis, P. ; Guéry, B. ; Haefliger, D. ; Kampouri, E. E. ; Manuel, O. ; Munting, A. ; Papadimitriou-Olivgeris, M. ; Regina, J. ; Rochat-Stettler, L. ; Suttels, V. ; Tadini, E. ; Tschopp, J. ; Van Singer, M. ; Viala, B. ; Boillat-Blanco, N. ; Brahier, T. ; Hügli, O. ; Meuwly, J. Y. ; Pantet, O. ; Nussle, S. Gonseth ; Bochud, M. ; D’Acremont, V. ; Younes, S. Estoppey ; Albrich, W. C. ; Suh, N. ; Cerny, A. ; O’Mahony, L. ; von Mering, C. ; Bochud, P. Y. ; Frischknecht, M. ; Kleger, G.-R. ; Filipovic, M. ; Kahlert, C. R. ; Wozniak, H. ; Negro, T. Rochat ; Pugin, J. ; Bouras, K. ; Knapp, C. ; Egger, T. ; Perret, A. ; Montillier, P. ; di Bartolomeo, C. ; Barda, B. ; de Cid, Rafael ; Carreras, Anna ; Moreno, Victor ; Galván-Femenía, Iván ; Blay, Natalia ; Farré, Xavier ; Sumoy, Lauro ; Cortés, Beatriz ; Mercader, Josep Maria ; Guindo-Martinez, Marta ; Torrents, David ; Garcia-Aymerich, Judith ; Castaño-Vinyals, Gemma ; Dobaño, Carlota ; Gori, Marco ; Renieri, Alessandra ; Mondelli, Mario Umberto ; Castelli, Francesco ; Vaghi, Massimo ; Rusconi, Stefano ; Montagnani, Francesca ; Bargagli, Elena ; Franchi, Federico ; Mazzei, Maria Antonietta ; Cantarini, Luca ; Tacconi, Danilo ; Feri, Marco ; Scala, Raffaele ; Spargi, Genni ; Nencioni, Cesira ; Bandini, Maria ; Caldarelli, Gian Piero ; Spagnesi, Maurizio ; Canaccini, Anna ; Ognibene, Agostino ; D’Arminio Monforte, Antonella ; Girardis, Massimo ; Antinori, Andrea ; Francisci, Daniela ; Schiaroli, Elisabetta ; Scotton, Pier Giorgio ; Panese, Sandro ; Scaggiante, Renzo ; Monica, Matteo Della ; Capasso, Mario ; Fiorentino, Giuseppe ; Castori, Marco ; Aucella, Filippo ; Di Biagio, Antonio ; Masucci, Luca ; Valente, Serafina ; Mandalà, Marco ; Zucchi, Patrizia ; Giannattasio, Ferdinando ; Coviello, Domenico A. ; Mussini, Cristina ; Bosio, Giancarlo ; Tavecchia, Luisa ; Crotti, Lia ; Rizzi, Marco ; La Rovere, Maria Teresa ; Sarzi-Braga, Simona ; Bussotti, Maurizio ; Ravaglia, Sabrina ; Artuso, Rosangela ; Perrella, Antonio ; Romani, Davide ; Bergomi, Paola ; Catena, Emanuele ; Vincenti, Antonella ; Ferri, Claudio ; Grassi, Davide ; Pessina, Gloria ; Tumbarello, Mario ; Di Pietro, Massimo ; Sabrina, Ravaglia ; Luchi, Sauro ; Barbieri, Chiara ; Acquilini, Donatella ; Andreucci, Elena ; Paciosi, Francesco ; Segala, Francesco Vladimiro ; Tiseo, Giusy ; Falcone, Marco ; Lista, Mirjam ; Poscente, Monica ; De Vivo, Oreste ; Petrocelli, Paola ; Guarnaccia, Alessandra ; Baroni, Silvia ; Perticaroli, Valentina ; Furini, Simone ; Dei, Simona ; Benetti, Elisa ; Picchiotti, Nicola ; Sanarico, Maurizio ; Ceri, Stefano ; Pinoli, Pietro ; Raimondi, Francesco ; Biscarini, Filippo ; Stella, Alessandra ; Bergomi, Mattia ; Zguro, Kristina ; Capitani, Katia ; Tanfoni, Marco ; Fallerini, Chiara ; Daga, Sergio ; Baldassarri, Margherita ; Fava, Francesca ; Frullanti, Elisa ; Valentino, Floriana ; Doddato, Gabriella ; Giliberti, Annarita ; Tita, Rossella ; Amitrano, Sara ; Bruttini, Mirella ; Croci, Susanna ; Meloni, Ilaria ; Mencarelli, Maria Antonietta ; Lo Rizzo, Caterina ; Pinto, Anna Maria ; Beligni, Giada ; Tommasi, Andrea ; Di Sarno, Laura ; Palmieri, Maria ; Carriero, Miriam Lucia ; Alaverdian, Diana ; Iuso, Nicola ; Inchingolo, Gabriele ; Busani, Stefano ; Bruno, Raffaele ; Vecchia, Marco ; Belli, Mary Ann ; Mantovani, Stefania ; Ludovisi, Serena ; Quiros-Roldan, Eugenia ; Antoni, Melania Degli ; Zanella, Isabella ; Siano, Matteo ; Emiliozzi, Arianna ; Fabbiani, Massimiliano ; Rossetti, Barbara ; Zanelli, Giacomo ; Bergantini, Laura ; D’Alessandro, Miriana ; Cameli, Paolo ; Bennet, David ; Anedda, Federico ; Marcantonio, Simona ; Scolletta, Sabino ; Guerrini, Susanna ; Conticini, Edoardo ; Frediani, Bruno ; Spertilli, Chiara ; Donati, Alice ; Guidelli, Luca ; Corridi, Marta ; Croci, Leonardo ; Piacentini, Paolo ; Desanctis, Elena ; Cappelli, Silvia ; Verzuri, Agnese ; Anemoli, Valentina ; Pancrazi, Alessandro ; Lorubbio, Maria ; Merlini, Esther ; Miraglia, Federica Gaia ; Venturelli, Sophie ; Cossarizza, Andrea ; Vergori, Alessandra ; Gabrieli, Arianna ; Riva, Agostino ; Paciosi, Francesco ; Andretta, Francesca ; Gatti, Francesca ; Parisi, Saverio Giuseppe ; Baratti, Stefano ; Piscopo, Carmelo ; Russo, Roberta ; Andolfo, Immacolata ; Iolascon, Achille ; Carella, Massimo ; Merla, Giuseppe ; Squeo, Gabriella Maria ; Raggi, Pamela ; Marciano, Carmen ; Perna, Rita ; Bassetti, Matteo ; Sanguinetti, Maurizio ; Giorli, Alessia ; Salerni, Lorenzo ; Parravicini, Pierpaolo ; Menatti, Elisabetta ; Trotta, Tullio ; Coiro, Gabriella ; Lena, Fabio ; Martinelli, Enrico ; Mancarella, Sandro ; Gabbi, Chiara ; Maggiolo, Franco ; Ripamonti, Diego ; Bachetti, Tiziana ; Suardi, Claudia ; Parati, Gianfranco ; Bottà, Giordano ; Di Domenico, Paolo ; Rancan, Ilaria ; Bianchi, Francesco ; Colombo, Riccardo ; van Heel, David A. ; Hunt, Karen A. ; Trembath, Richard C. ; Huang, Qin Qin ; Martin, Hilary C. ; Mason, Dan ; Trivedi, Bhavi ; Wright, John ; Finer, Sarah ; Griffiths, Christopher J. ; Akhtar, Shaheen ; Anwar, Mohammad ; Arciero, Elena ; Ashraf, Samina ; Breen, Gerome ; Chung, Raymond ; Curtis, Charles J. ; Chowdhury, Maharun ; Colligan, Grainne ; Deloukas, Panos ; Durham, Ceri ; Finer, Sarah ; Griffiths, Chris ; Huang, Qin Qin ; Hurles, Matt ; Hunt, Karen A. ; Hussain, Shapna ; Islam, Kamrul ; Khan, Ahsan ; Khan, Amara ; Lavery, Cath ; Lee, Sang Hyuck ; Lerner, Robin ; MacArthur, Daniel ; MacLaughlin, Bev ; Martin, Hilary ; Mason, Dan ; Miah, Shefa ; Newman, Bill ; Safa, Nishat ; Tahmasebi, Farah ; Trembath, Richard C. ; Trivedi, Bhavi ; van Heel, David A. ; Wright, John ; Smith, Albert V. ; Boughton, Andrew P. ; Li, Kevin W. ; LeFaive, Jonathon ; Annis, Aubrey ; Jannes, Cinthia E. ; Krieger, Jose E. ; Pereira, Alexandre C. ; Velho, Mariliza ; Marques, Emanuelle ; Lima, Isabella Ramos ; Tada, Mauricio Teruo ; Valino, Karina ; McCarthy, Mark ; Rosenberger, Carrie ; Lee, Jong Eun ; Chang, Diana ; Hammer, Christian ; Hunkapiller, Julie ; Mahajan, Anubha ; Pendergrass, Sarah ; Sucheston-Campbell, Lara ; Yaspan, Brian ; Lee, Hyun Soo ; Shin, Eunsoon ; Jang, Hye Yoon ; Kim, Sunmie ; Kym, Sungmin ; Kim, Yeon-Sook ; Jeong, Hyeongseok ; Kwon, Ki Tae ; Kim, Shin-Woo ; Kim, Jin Yong ; Jang, Young Rock ; Kim, Hyun ah ; Lee, Ji Yeon ; Lee, Jeong Eun ; Lee, Shinwon ; Choe, Kang-Won ; Kang, Yu Min ; Jee, Sun Ha ; Jung, Keum Ji ; Parikh, Victoria ; Ashley, Euan ; Wheeler, Matthew ; Rivas, Manuel ; Bustamante, Carlos ; Pinksy, Benjamin ; Febbo, Phillip ; Farh, Kyle ; Schroth, Gary P. ; deSouza, Francis ; Dalton, Karen ; Christle, Jeff ; Deboever, Christopher ; Szalma, Sándor ; Tanigawa, Yosuke ; Rubinacci, Simone ; Delaneau, Olivier ; Gorzynski, John ; de Jong, Hannah ; Sutton, Shirley ; Youlton, Nathan ; Joshi, Ruchi ; Jimenez-Morales, David ; Hughes, Christopher ; Amar, David ; Ioannidis, Alex ; Hershman, Steve ; Kirillova, Anna ; Seo, Kinya ; Huang, Yong ; Shoura, Massa ; Hammond, Nathan ; Watson, Nathaniel ; Raja, Archana ; Huang, ChunHong ; Sahoo, Malaya ; Wang, Hannah ; Zhen, Jimmy ; Rakitko, Alexander ; Ilinsky, Valery ; Yermakovich, Danat ; Popov, Iaroslav ; Chernitsov, Alexander ; Kovalenko, Elena ; Krasnenko, Anna ; Plotnikov, Nikolay ; Stetsenko, Ivan ; Kim, Anna ; Cirulli, Elizabeth T. ; Schiabor Barrett, Kelly M. ; Bolze, Alexandre ; White, Simon ; Washington, Nicole L. ; Lu, James T. ; Riffle, Stephen ; Tanudjaja, Francisco ; Wang, Xueqing ; Ramirez, Jimmy M. ; Leonetti, Nicole ; Sandoval, Efren ; Neveux, Iva ; Dabe, Shaun ; Grzymski, Joseph J. ; Esteban Miñano, Juan Ignacio ; Aguirre, Luis A. ; López-Collazo, Eduardo ; de la Mata Pazos, Manuel ; Cerrato, Luciano ; Folkersen, Lasse ; Lozano-Rodríguez, Roberto ; Avendaño-Ortiz, José ; Arcos, Verónica Terrón ; Montalbán-Hernández, Karla Marina ; Quiroga, Jaime Valentín ; Pascual-Iglesias, Alejandro ; Maroun-Eid, Charbel ; Martín-Quirós, Alejandro ; Namkoong, Ho ; Okada, Yukinori ; Imoto, Seiya ; Katayama, Kazuhiko ; Fukunaga, Koichi ; Kitagawa, Yuko ; Sato, Toshiro ; Hasegawa, Naoki ; Kumanogoh, Atsushi ; Kimura, Akinori ; Ai, Masumi ; Tokunaga, Katsushi ; Kanai, Takanori ; Miyano, Satoru ; Ogawa, Seishi ; Edahiro, Ryuya ; Sonehara, Kyuto ; Shirai, Yuya ; Kanai, Masahiro ; Ishii, Makoto ; Kabata, Hiroki ; Masaki, Katsunori ; Kamata, Hirofumi ; Ikemura, Shinnosuke ; Chubachi, Shotaro ; Okamori, Satoshi ; Terai, Hideki ; Tanaka, Hiromu ; Morita, Atsuho ; Lee, Ho ; Asakura, Takanori ; Sasaki, Junichi ; Morisaki, Hiroshi ; Uwamino, Yoshifumi ; Nanki, Kosaku ; Mikami, Yohei ; Tomono, Kazunori ; Kato, Kazuto ; Matsuda, Fumihiko ; Takahashi, Meiko ; Hizawa, Nobuyuki ; Takeda, Yoshito ; Hirata, Haruhiko ; Shiroyama, Takayuki ; Miyawaki, Satoru ; Suzuki, Ken ; Maeda, Yuichi ; Nii, Takuro ; Noda, Yoshimi ; Niitsu, Takayuki ; Adachi, Yuichi ; Enomoto, Takatoshi ; Amiya, Saori ; Hara, Reina ; Takahashi, Kunihiko ; Anzai, Tatsuhiko ; Hasegawa, Takanori ; Ito, Satoshi ; Koike, Ryuji ; Endo, Akifumi ; Uchimura, Yuji ; Miyazaki, Yasunari ; Honda, Takayuki ; Tateishi, Tomoya ; Tohda, Shuji ; Ichimura, Naoya ; Sonobe, Kazunari ; Sassa, Chihiro ; Nakajima, Jun ; Nannya, Yasuhito ; Omae, Yosuke ; Takahashi, Kazuhisa ; Harada, Norihiro ; Hiki, Makoto ; Takagi, Haruhi ; Nakamura, Ai ; Tagaya, Etsuko ; Kawana, Masatoshi ; Arimura, Ken ; Ishiguro, Takashi ; Takayanagi, Noboru ; Isono, Taisuke ; Takaku, Yotaro ; Takano, Kenji ; Anan, Ryusuke ; Nakajima, Yukiko ; Nakano, Yasushi ; Nishio, Kazumi ; Ueda, Soichiro ; Hayashi, Reina ; Tateno, Hiroki ; Hase, Isano ; Yoshida, Shuichi ; Suzuki, Shoji ; Mitamura, Keiko ; Saito, Fumitake ; Ueda, Tetsuya ; Azuma, Masanori ; Nagasaki, Tadao ; Yasui, Yoshinori ; Hasegawa, Yoshinori ; Mutoh, Yoshikazu ; Yoshiyama, Takashi ; Shoko, Tomohisa ; Kojima, Mitsuaki ; Adachi, Tomohiro ; Ishikawa, Motonao ; Takahashi, Kenichiro ; Watanabe, Kazuyoshi ; Manabe, Tadashi ; Ito, Fumimaro ; Fukui, Takahiro ; Funatsu, Yohei ; Koh, Hidefumi ; Hirai, Yoshihiro ; Kawashima, Hidetoshi ; Narita, Atsuya ; Niwa, Kazuki ; Sekikawa, Yoshiyuki ; Saito, Fukuki ; Yoshiya, Kazuhisa ; Yoshihara, Tomoyuki ; Suzuki, Yusuke ; Nakayama, Sohei ; Masuzawa, Keita ; Nishi, Koichi ; Nishitsuji, Masaru ; Tani, Maiko ; Inoue, Takashi ; Hirano, Toshiyuki ; Kobayashi, Keigo ; Miyazawa, Naoki ; Kimura, Yasuhiro ; Sado, Reiko ; Ogura, Takashi ; Kitamura, Hideya ; Murohashi, Kota ; Nakachi, Ichiro ; Baba, Rie ; Arai, Daisuke ; Fuke, Satoshi ; Saito, Hiroshi ; Kuwahara, Naota ; Fujiwara, Akiko ; Okada, Takenori ; Baba, Tomoya ; Noda, Junya ; Mashimo, Shuko ; Yagi, Kazuma ; Shiomi, Tetsuya ; Hashiguchi, Mizuha ; Odani, Toshio ; Mochimaru, Takao ; Oyamada, Yoshitaka ; Mori, Nobuaki ; Izumi, Namiki ; Nagata, Kaoru ; Taki, Reiko ; Murakami, Koji ; Yamada, Mitsuhiro ; Sugiura, Hisatoshi ; Hayashi, Kentaro ; Shimizu, Tetsuo ; Gon, Yasuhiro ; Fujitani, Shigeki ; Tsuchida, Tomoya ; Yoshida, Toru ; Kagaya, Takashi ; Kita, Toshiyuki ; Sakagami, Satoru ; Kimizuka, Yoshifumi ; Kawana, Akihiko ; Nakamura, Yoshihiko ; Ishikura, Hiroyasu ; Takata, Tohru ; Kikuchi, Takahide ; Taniyama, Daisuke ; Nakamura, Morio ; Kodama, Nobuhiro ; Kaneyama, Yasunari ; Maeda, Shunsuke ; Nagasaki, Yoji ; Okamoto, Masaki ; Ishihara, Sayoko ; Ito, Akihiro ; Chihara, Yusuke ; Takeuchi, Mayumi ; Onoi, Keisuke ; Hashimoto, Naozumi ; Wakahara, Keiko ; Ando, Akira ; Masuda, Makoto ; Wakabayashi, Aya ; Watanabe, Hiroki ; Sageshima, Hisako ; Nakada, Taka-Aki ; Abe, Ryuzo ; Shimada, Tadanaga ; Kawamura, Kodai ; Ichikado, Kazuya ; Nishiyama, Kenta ; Yamasaki, Masaki ; Hashimoto, Satoru ; Kusaka, Yu ; Ohba, Takehiko ; Isogai, Susumu ; Takada, Minoru ; Kanda, Hidenori ; Komase, Yuko ; Sano, Fumiaki ; Asano, Koichiro ; Oguma, Tsuyoshi ; Harada, Masahiro ; Takahashi, Takeshi ; Shibusawa, Takayuki ; Abe, Shinji ; Kono, Yuta ; Togashi, Yuki ; Izumo, Takehiro ; Inomata, Minoru ; Awano, Nobuyasu ; Ogawa, Shinichi ; Ogata, Tomouki ; Ishihara, Shoichiro ; Kanehiro, Arihiko ; Ozaki, Shinji ; Fuchimoto, Yasuko ; Kitagawa, Yuichiro ; Yoshida, Shozo ; Ogura, Shinji ; Nishiyama, Kei ; Yoshida, Kousuke ; Beppu, Satoru ; Fukuyama, Satoru ; Eriguchi, Yoshihiro ; Yonekawa, Akiko ; Inoue, Yoshiaki ; Yamagata, Kunihiro ; Chiba, Shigeru ; Narumoto, Osamu ; Nagai, Hideaki ; Ooshima, Nobuharu ; Motegi, Mitsuru ; Sagara, Hironori ; Tanaka, Akihiko ; Ohta, Shin ; Shibata, Yoko ; Tanino, Yoshinori ; Sato, Yuki ; Yamada, Yuichiro ; Hashino, Takuya ; Shinoki, Masato ; Iwagoe, Hajime ; Imamura, Tomonori ; Umeda, Akira ; Shimada, Hisato ; Endo, Mayu ; Hayashi, Shinichi ; Takahashi, Mai ; Nakano, Shigefumi ; Yatomi, Masakiyo ; Maeno, Toshitaka ; Ishii, Tomoo ; Utsugi, Mitsuyoshi ; Ono, Akihiro ; Kanaoka, Kensuke ; Ihara, Shoichi ; Komuta, Kiyoshi ; Franke, Lude ; Boezen, Marike ; Claringbould, Annique ; Lopera, Esteban ; Warmerdam, Robert ; Vonk, Judith. M. ; van Blokland, Irene ; Lanting, Pauline ; Ori, Anil P. S. ; Obeidat, Ma’en ; Hernández Cordero, Ana I. ; Sin, Don D. ; Bossé, Yohan ; Joubert, Philippe ; Hao, Ke ; Nickle, David ; Timens, Wim ; van den Berge, Maarten ; Feng, Yen-Chen Anne ; Mercader, Josep ; Weiss, Scott T. ; Karlson, Elizabeth W. ; Smoller, Jordan W. ; Murphy, Shawn N. ; Meigs, James B. ; Woolley, Ann E. ; Green, Robert C. ; Perez, Emma F. ; Wolford, Brooke ; Zöllner, Sebastian ; Wang, Jiongming ; Beck, Andrew ; Sloofman, Laura G. ; Ascolillo, Steven ; Sebra, Robert P. ; Collins, Brett L. ; Levy, Tess ; Sealfon, Stuart C. ; Jordan, Daniel M. ; Thompson, Ryan C. ; Gettler, Kyle ; Chaudhary, Kumardeep ; Belbin, Gillian M. ; Preuss, Michael ; Hoggart, Clive ; Choi, Sam ; Underwood, Slayton J. ; Salib, Irene ; Britvan, Bari ; Keller, Katherine ; Tang, Lara ; Peruggia, Michael ; Hiester, Liam L. ; Niblo, Kristi ; Aksentijevich, Alexandra ; Labkowsky, Alexander ; Karp, Avrohom ; Zlatopolsky, Menachem ; Zyndorf, Marissa ; Charney, Alexander W. ; Beckmann, Noam D. ; Schadt, Eric E. ; Abul-Husn, Noura S. ; Cho, Judy H. ; Itan, Yuval ; Kenny, Eimear E. ; Loos, Ruth J. F. ; Nadkarni, Girish N. ; Do, Ron ; O’Reilly, Paul ; Huckins, Laura M. ; Ferreira, Manuel A. R. ; Abecasis, Goncalo R. ; Leader, Joseph B. ; Cantor, Michael N. ; Justice, Anne E. ; Carey, Dave J. ; Chittoor, Geetha ; Josyula, Navya Shilpa ; Kosmicki, Jack A. ; Horowitz, Julie E. ; Baras, Aris ; Gass, Matthew C. ; Yadav, Ashish ; Mirshahi, Tooraj ; Jan Hottenga, Jouke ; Bartels, Meike ; de Geus, Eco J. C. ; Nivard, Michel G. ; Verma, Anurag ; Ritchie, Marylyn D. ; Rader, Daniel ; Li, Binglan ; Verma, Shefali S. ; Lucas, Anastasia ; Bradford, Yuki ; Zara, Federico ; Salpietro, Vincenzo ; Scala, Marcello ; Iacomino, Michele ; Scudieri, Paolo ; Bocciardi, Renata ; Minetti, Carlo ; Riva, Antonella ; Vari, Maria Stella ; Rahier, Jean-François ; Giorgio, Elisa ; Carli, Diana ; Louis, Edouad ; Bulik, Cynthia M. ; Landén, Mikael ; Brusco, Alfredo ; Ferrero, Giovanni Battista ; Madia, Francesca ; Fundín, Bengt ; Ismail, Said I. ; Saad, Chadi ; Al-Sarraj, Yaser ; Badji, Radja Messai ; Al-Muftah, Wadha ; Al Thani, Asma ; Afifi, Nahla ; Klovins, Janis ; Rovite, Vita ; Rescenko, Raimonds ; Peculis, Raitis ; Ustinova, Monta ; Zeberg, Hugo ; Frithiof, Robert ; Hultström, Michael ; Lipcsey, Miklos ; Johnson, Ruth ; Geschwind, Daniel H. ; Freimer, Nelson ; Butte, Manish J. ; Geschwind, Daniel H. ; Pasaniuc, Bogdan ; Ding, Yi ; Chiu, Alec ; Chang, Timothy S. ; Boutros, Paul ; Moutsianas, Loukas ; Caulfield, Mark J. ; Scott, Richard H. ; Walker, Susan ; Stuckey, Alex ; Odhams, Christopher A. ; Rhodes, Daniel ; Fowler, Tom ; Rendon, Augusto ; Chan, Georgia ; Arumugam, Prabhu ; Karczewski, Konrad J. ; Wilson, Daniel J. ; Spencer, Chris A. ; Crook, Derrick W. ; Wyllie, David H. ; O’Connell, Anne Marie ; Atkinson, Elizabeth G. ; Kanai, Masahiro ; Tsuo, Kristin ; Baya, Nikolas ; Turley, Patrick ; Gupta, Rahul ; Walters, Raymond K. ; Palmer, Duncan S. ; Sarma, Gopal ; Solomonson, Matthew ; Cheng, Nathan ; Lu, Wenhan ; Churchhouse, Claire ; Goldstein, Jacqueline I. ; King, Daniel ; Seed, Cotton ; Daly, Mark J. ; Neale, Benjamin M. ; Bryant, Sam ; Satterstrom, F. Kyle ; Band, Gavin ; Earle, Sarah G. ; Lin, Shang-Kuan ; Arning, Nicolas ; Armstrong, Jacob ; Rudkin, Justine K. ; Callier, Shawneequa ; Bryant, Sam ; Cusick, Caroline ; Soranzo, Nicole ; Zhao, Jing Hua ; Danesh, John ; Di Angelantonio, Emanuele ; Butterworth, Adam S. ; Sun, Yan V. ; Huffman, Jennifer E. ; Cho, Kelly ; O’Donnell, Christopher J. ; Tsao, Phil ; Gaziano, J. Michael ; Peloso, Gina ; Ho, Yuk-Lam ; Mian, Michael ; Scaggiante, Federica ; Chang, Xiao ; Glessner, Joseph R. ; Hakonarson, Hakon ; McGuigan, Peter J. ; Prockter Moore, Luke Stephen ; Vizcaychipi, Marcela Paola ; Hall, Kathryn ; Campbell, Andy ; Nichol, Ailstair ; Ward, Geraldine ; Page, Valerie Joan ; Semple, Malcolm G. ; Adeniji, Kayode ; Agranoff, Daniel ; Agwuh, Ken ; Ail, Dhiraj ; Aldera, Erin L. ; Alegria, Ana ; Angus, Brian ; Ashish, Abdul ; Atkinson, Dougal ; Bari, Shahedal ; Barlow, Gavin ; Barnass, Stella ; Barrett, Nicholas ; Bassford, Christopher ; Basude, Sneha ; Baxter, David ; Beadsworth, Michael ; Bernatoniene, Jolanta ; Berridge, John ; Best, Nicola ; Bothma, Pieter ; Chadwick, David ; Brittain-Long, Robin ; Bulteel, Naomi ; Burden, Tom ; Burtenshaw, Andrew ; Caruth, Vikki ; Chambler, Duncan ; Chee, Nigel ; Child, Jenny ; Chukkambotla, Srikanth ; Clark, Tom ; Collini, Paul ; Cosgrove, Catherine ; Cupitt, Jason ; Cutino-Moguel, Maria-Teresa ; Dark, Paul ; Dawson, Chris ; Dervisevic, Samir ; Donnison, Phil ; Douthwaite, Sam ; Drummond, Andrew ; DuRand, Ingrid ; Dushianthan, Ahilanadan ; Dyer, Tristan ; Evans, Cariad ; Eziefula, Chi ; Fegan, Christopher ; Finn, Adam ; Fullerton, Duncan ; Garg, Sanjeev ; Garg, Atul ; Gkrania-Klotsas, Effrossyni ; Godden, Jo ; Goldsmith, Arthur ; Graham, Clive ; Hardy, Elaine ; Hartshorn, Stuart ; Harvey, Daniel ; Havalda, Peter ; Hawcutt, Daniel B. ; Hobrok, Maria ; Hodgson, Luke ; Hormis, Anil ; Jacobs, Michael ; Jain, Susan ; Jennings, Paul ; Kaliappan, Agilan ; Kasipandian, Vidya ; Kegg, Stephen ; Kelsey, Michael ; Kendall, Jason ; Kerrison, Caroline ; Kerslake, Ian ; Koch, Oliver ; Koduri, Gouri ; Koshy, George ; Laha, Shondipon ; Laird, Steven
The genetic make-up of an individual contributes to the susceptibility and response to viral infection. Although environmental, clinical and social factors have a role in the chance of exposure to SARS-CoV-2 and the severity of COVID-191,2, host genetics may also be important. Identifying host-specific genetic factors may reveal biological mechanisms of therapeutic relevance and clarify causal relationships of modifiable environmental risk factors for SARS-CoV-2 infection and outcomes. We formed a global network of researchers to investigate the role of human genetics in SARS-CoV-2 infection and COVID-19 severity. Here we describe the results of three genome-wide association meta-analyses that consist of up to 49,562 patients with COVID-19 from 46 studies across 19 countries. We report 13 genome-wide significant loci that are associated with SARS-CoV-2 infection or severe manifestations of COVID-19. Several of these loci correspond to previously documented associations to lung or autoimmune and inflammatory diseases3,4,5,6,7. They also represent potentially actionable mechanisms in response to infection. Mendelian randomization analyses support a causal role for smoking and body-mass index for severe COVID-19 although not for type II diabetes. The identification of novel host genetic factors associated with COVID-19 was made possible by the community of human genetics researchers coming together to prioritize the sharing of data, results, resources and analytical frameworks. This working model of international collaboration underscores what is possible for future genetic discoveries in emerging pandemics, or indeed for any complex human disease.
Forstner, Andreas Josef ; Hecker, Julian ; Hofmann, Andrea ; Maaser, Anna ; Reinbold, Céline S. ; Mühleisen, Thomas W. ; Leber, Markus ; Strohmaier, Jana ; Degenhardt, Franziska ; Treutlein, Jens ; Mattheisen, Manuel ; Schumacher, Johannes ; Streit, Fabian ; Meier, Sandra ; Herms, Stefan ; Hoffmann, Per ; Lacour, André ; Witt, Stephanie ; Reif, Andreas ; Müller-Myhsok, Bertram ; Lucae, Susanne ; Maier, Wolfgang ; Schwarz, Markus ; Vedder, Helmut ; Kammerer-Ciernioch, Jutta ; Pfennig, Andrea ; Bauer, Michael ; Hautzinger, Martin ; Moebus, Susanne ; Schenk, Lorena M. ; Fischer, Sascha B. ; Sivalingam, Sugirthan ; Czerski, Piotr M. ; Hauser, Joanna ; Lissowska, Jolanta ; Szeszenia-Dabrowska, Neonila ; Brennan, Paul E. ; McKay, James D. ; Wright, Adam ; Mitchell, Philip B. ; Fullerton, Janice M. ; Schofield, Peter R. ; Montgomery, Grant W. ; Medland, Sarah E. ; Gordon, Scott D. ; Martin, Nicholas Gordon ; Krasnov, Valery ; Chuchalin, Alexander ; Babadjanova, Gulja ; Pantelejeva, Galina ; Abramova, Lilia I. ; Tiganov, Alexander S. ; Polonikov, Alexey ; Khusnutdinova, Elza ; Alda, Martin ; Cruceanu, Cristiana ; Rouleau, Guy A. ; Turecki, Gustavo ; Laprise, Catherine ; Rivas, Fabio ; Mayoral, Fermı́n ; Kogevinas, Manolis ; Grigoroiu-Serbanescu, Maria ; Becker, Tim ; Schulze, Thomas Gerd ; Rietschel, Marcella ; Cichon, Sven ; Fier, Heide ; Nöthen, Markus Maria
Bipolar disorder (BD) is a highly heritable neuropsychiatric disease characterized by recurrent episodes of mania and depression. BD shows substantial clinical and genetic overlap with other psychiatric disorders, in particular schizophrenia (SCZ). The genes underlying this etiological overlap remain largely unknown. A recent SCZ genome wide association study (GWAS) by the Psychiatric Genomics Consortium identified 128 independent genome-wide significant single nucleotide polymorphisms (SNPs). The present study investigated whether these SCZ-associated SNPs also contribute to BD development through the performance of association testing in a large BD GWAS dataset (9747 patients, 14278 controls). After re-imputation and correction for sample overlap, 22 of 107 investigated SCZ SNPs showed nominal association with BD. The number of shared SCZ-BD SNPs was significantly higher than expected (p = 1.46x10-8). This provides further evidence that SCZ-associated loci contribute to the development of BD. Two SNPs remained significant after Bonferroni correction. The most strongly associated SNP was located near TRANK1, which is a reported genome-wide significant risk gene for BD. Pathway analyses for all shared SCZ-BD SNPs revealed 25 nominally enriched gene-sets, which showed partial overlap in terms of the underlying genes. The enriched gene-sets included calcium- and glutamate signaling, neuropathic pain signaling in dorsal horn neurons, and calmodulin binding. The present data provide further insights into shared risk loci and disease-associated pathways for BD and SCZ. This may suggest new research directions for the treatment and prevention of these two major psychiatric disorders.
O’Connell, Kevin S. ; Koromina, Maria ; van der Veen, Tracey ; Boltz, Toni ; David, Friederike S. ; Kay Yang, Jessica Mei ; Lin, Keng-Han ; Wang, Xin ; Coleman, Jonathan R. I. ; Mitchell, Brittany L. ; McGrouther, Caroline C. ; Rangan, Aaditya V. ; Lind, Penelope A. ; Koch, Elise ; Harder, Arvid ; Parker, Nadine ; Bendl, Jaroslav ; Adorjan, Kristina ; Agerbo, Esben ; Albani, Diego ; Alemany, Silvia ; Alliey-Rodriguez, Ney ; Als, Thomas D. ; Andlauer, Till F. M. ; Antoniou, Anastasia ; Ask, Helga ; Bass, Nicholas ; Bauer, Michael ; Beins, Eva C. ; Bigdeli, Tim B. ; Pedersen, Carsten Bøcker ; Boks, Marco P. ; Børte, Sigrid ; Bosch, Rosa ; Brum, Murielle ; Brumpton, Ben M. ; Brunkhorst-Kanaan, Nathalie ; Budde, Monika ; Bybjerg-Grauholm, Jonas ; Byerley, William ; Cabana-Domínguez, Judit ; Cairns, Murray J. ; Carpiniello, Bernardo ; Casas, Miquel ; Cervantes, Pablo ; Chatzinakos, Chris ; Chen, Hsi-Chung ; Clarence, Tereza ; Clarke, Toni-Kim ; Claus, Isabelle ; Coombes, Brandon ; Corfield, Elizabeth C. ; Cruceanu, Cristiana ; Cuellar-Barboza, Alfredo ; Czerski, Piotr M. ; Dafnas, Konstantinos ; Dale, Anders M. ; Dalkner, Nina ; Degenhardt, Franziska ; DePaulo, J. Raymond ; Djurovic, Srdjan ; Drange, Ole Kristian ; Escott-Price, Valentina ; Fanous, Ayman H. ; Fellendorf, Frederike T. ; Ferrier, I. Nicol ; Forty, Liz ; Frank, Josef ; Frei, Oleksandr ; Freimer, Nelson B. ; Fullard, John F. ; Garnham, Julie ; Gizer, Ian R. ; Gordon, Scott D. ; Gordon-Smith, Katherine ; Greenwood, Tiffany A. ; Grove, Jakob ; Guzman-Parra, José ; Ha, Tae Hyon ; Hahn, Tim ; Haraldsson, Magnus ; Hautzinger, Martin ; Havdahl, Alexandra ; Heilbronner, Urs ; Hellgren, Dennis ; Herms, Stefan ; Hickie, Ian B. ; Hoffmann, Per ; Holmans, Peter A. ; Huang, Ming-Chyi ; Ikeda, Masashi ; Jamain, Stéphane ; Johnson, Jessica S. ; Jonsson, Lina ; Kalman, Janos L. ; Kamatani, Yoichiro ; Kennedy, James L. ; Kim, Euitae ; Kim, Jaeyoung ; Kittel-Schneider, Sarah ; Knowles, James A. ; Kogevinas, Manolis ; Kranz, Thorsten M. ; Krebs, Kristi ; Kushner, Steven A. ; Lavebratt, Catharina ; Lawrence, Jacob ; Leber, Markus ; Lee, Heon-Jeong ; Liao, Calwing ; Lucae, Susanne ; Lundberg, Martin ; MacIntyre, Donald J. ; Maier, Wolfgang ; Maihofer, Adam X. ; Malaspina, Dolores ; Manchia, Mirko ; Maratou, Eirini ; Martinsson, Lina ; Mattheisen, Manuel ; McGregor, Nathaniel W. ; McInnis, Melvin G. ; McKay, James D. ; Medeiros, Helena ; Meyer-Lindenberg, Andreas ; Millischer, Vincent ; Morris, Derek W. ; Moutsatsou, Paraskevi ; Mühleisen, Thomas W. ; O’Donovan, Claire ; Olsen, Catherine M. ; Panagiotaropoulou, Georgia ; Papiol, Sergi ; Pardiñas, Antonio F. ; Park, Hye Youn ; Perry, Amy ; Pfennig, Andrea ; Pisanu, Claudia ; Potash, James B. ; Quested, Digby ; Rapaport, Mark H. ; Regeer, Eline J. ; Rice, John P. ; Rivera, Margarita ; Schulte, Eva Christina ; Senner, Fanny ; Shadrin, Alexey ; Shilling, Paul D. ; Sigurdsson, Engilbert ; Sindermann, Lisa ; Sirignano, Lea ; Siskind, Dan ; Slaney, Claire ; Sloofman, Laura G. ; Smeland, Olav B. ; Smith, Daniel J. ; Sobell, Janet L. ; Soler Artigas, Maria ; Stein, Dan J. ; Stein, Frederike ; Su, Mei-Hsin ; Sung, Heejong ; Świątkowska, Beata ; Terao, Chikashi ; Tesfaye, Markos ; Tesli, Martin ; Thorgeirsson, Thorgeir E. ; Thorp, Jackson G. ; Toma, Claudio ; Tondo, Leonardo ; Tooney, Paul A. ; Tsai, Shih-Jen ; Tsermpini, Evangelia Eirini ; Vawter, Marquis P. ; Vedder, Helmut ; Vreeker, Annabel ; Walters, James T. R. ; Winsvold, Bendik S. ; Witt, Stephanie H. ; Won, Hong-Hee ; Ye, Robert ; Young, Allan H. ; Zandi, Peter P. ; Zillich, Lea ; Adolfsson, Rolf ; Alda, Martin ; Alfredsson, Lars ; Backlund, Lena ; Baune, Bernhard T. ; Bellivier, Frank ; Bengesser, Susanne ; Berrettini, Wade H. ; Biernacka, Joanna M. ; Boehnke, Michael ; Børglum, Anders D. ; Breen, Gerome ; Carr, Vaughan J. ; Catts, Stanley ; Cichon, Sven ; Corvin, Aiden ; Craddock, Nicholas ; Dannlowski, Udo ; Dikeos, Dimitris ; Etain, Bruno ; Ferentinos, Panagiotis ; Frye, Mark ; Fullerton, Janice M. ; Gawlik, Micha ; Gershon, Elliot S. ; Goes, Fernando S. ; Green, Melissa J. ; Grigoroiu-Serbanescu, Maria ; Hauser, Joanna ; Henskens, Frans A. ; Hjerling-Leffler, Jens ; Hougaard, David M. ; Hveem, Kristian ; Iwata, Nakao ; Jones, Ian ; Jones, Lisa A. ; Kahn, René S. ; Kelsoe, John R. ; Kircher, Tilo ; Kirov, George ; Kuo, Po-Hsiu ; Landén, Mikael ; Leboyer, Marion ; Li, Qingqin S. ; Lissowska, Jolanta ; Lochner, Christine ; Loughland, Carmel ; Luykx, Jurjen J. ; Martin, Nicholas G. ; Mathews, Carol A. ; Mayoral, Fermin ; McElroy, Susan L. ; McIntosh, Andrew M. ; McMahon, Francis J. ; Medland, Sarah E. ; Melle, Ingrid ; Milani, Lili ; Mitchell, Philip B. ; Morken, Gunnar ; Mors, Ole ; Mortensen, Preben Bo ; Müller-Myhsok, Bertram ; Myers, Richard M. ; Myung, Woojae ; Neale, Benjamin M. ; Nievergelt, Caroline M. ; Nordentoft, Merete ; Nöthen, Markus M. ; Nurnberger, John I. ; O’Donovan, Michael C. ; Oedegaard, Ketil J. ; Olsson, Tomas ; Owen, Michael J. ; Paciga, Sara A. ; Pantelis, Christos ; Pato, Carlos N. ; Pato, Michele T. ; Patrinos, George P. ; Pawlak, Joanna M. ; Ramos-Quiroga, Josep Antoni ; Reif, Andreas ; Reininghaus, Eva Z. ; Ribasés, Marta ; Rietschel, Marcella ; Ripke, Stephan ; Rouleau, Guy A. ; Roussos, Panos ; Saito, Takeo ; Schall, Ulrich ; Schalling, Martin ; Schofield, Peter R. ; Schulze, Thomas G. ; Scott, Laura J. ; Scott, Rodney J. ; Serretti, Alessandro ; Smoller, Jordan W. ; Squassina, Alessio ; Stahl, Eli A. ; Stefansson, Hreinn ; Stefansson, Kari ; Stordal, Eystein ; Streit, Fabian ; Sullivan, Patrick F. ; Turecki, Gustavo ; Vaaler, Arne E. ; Vieta, Eduard ; Vincent, John B. ; Waldman, Irwin D. ; Weickert, Cynthia S. ; Weickert, Thomas W. ; Werge, Thomas ; Whiteman, David C. ; Zwart, John-Anker ; Edenberg, Howard J. ; McQuillin, Andrew ; Forstner, Andreas J. ; Mullins, Niamh ; Di Florio, Arianna ; Ophoff, Roel A. ; Andreassen, Ole A.
Randall, Joshua C. ; Winkler, Thomas W. ; Kutalik, Zoltán ; I. Berndt, Sonja ; Jackson, Anne U. ; Monda, Keri L. ; Kilpeläinen, Tuomas O. ; Esko, Tõnu ; Mägi, Reedik ; Li, Shengxu ; Workalemahu, Tsegaselassie ; Feitosa, Mary F. ; Croteau-Chonka, Damien C. ; Day, Felix R. ; Fall, Tove ; Ferreira, Teresa ; Gustafsson, Stefan ; Locke, Adam E. ; Mathieson, Iain ; Scherag, André ; Vedantam, Sailaja ; Wood, Andrew R. ; Liang, Liming ; Steinthorsdottir, Valgerdur ; Thorleifsson, Gudmar ; Dermitzakis, Emmanouil T. ; Dimas, Antigone S. ; Karpe, Fredrik ; Min, Josine L. ; Nicholson, George ; Clegg, Deborah J. ; Person, Thomas ; Krohn, Jon P. ; Bauer, Sabrina ; Buechler, Christa ; Eisinger, Kristina ; Bonnefond, Amélie ; Froguel, Philippe ; Hottenga, Jouke-Jan ; Prokopenko, Inga ; Waite, Lindsay L. ; Harris, Tamara B. ; Smith, Albert Vernon ; Shuldiner, Alan R. ; McArdle, Wendy L. ; Caulfield, Mark J. ; Munroe, Patricia B. ; Grönberg, Henrik ; Chen, Yii-Der Ida ; Li, Guo ; Beckmann, Jacques S. ; Johnson, Toby ; Thorsteinsdottir, Unnur ; Teder-Laving, Maris ; Khaw, Kay-Tee ; Wareham, Nicholas J. ; Zhao, Jing Hua ; Amin, Najaf ; Oostra, Ben A. ; Kraja, Aldi T. ; Province, Michael A. ; Cupples, L. Adrienne ; Heard-Costa, Nancy L. ; Kaprio, Jaakko ; Ripatti, Samuli ; Surakka, Ida ; Collins, Francis S. ; Saramies, Jouko ; Tuomilehto, Jaakko ; Jula, Antti ; Salomaa, Veikko ; Erdmann, Jeanette ; Hengstenberg, Christian ; Loley, Christina ; Schunkert, Heribert ; Lamina, Claudia ; Wichmann, Heinz Erich ; Albrecht, Eva ; Gieger, Christian ; Hicks, Andrew A. ; Johansson, Åsa ; Pramstaller, Peter P. ; Kathiresan, Sekar ; Speliotes, Elizabeth K. ; Penninx, Brenda W. J. H. ; Hartikainen, Anna-Liisa ; Jarvelin, Marjo-Riitta ; Gyllensten, Ulf ; Boomsma, Dorret I. ; Campbell, Harry ; Wilson, James F. ; Chanock, Stephen J. ; Farrall, Martin ; Goel, Anuj ; Medina-Gomez, Carolina ; Rivadeneira, Fernando ; Estrada, Karol ; Uitterlinden, André G. ; Hofman, Albert ; Zillikens, M. Carola ; Heijer, Martin den ; Kiemeney, Lambertus Adrianus ; Maschio, Andrea ; Hall, Per ; Tyrer, Jonathan ; Teumer, Alexander ; Völzke, Henry ; Kovacs, Peter ; Tönjes, Anke ; Mangino, Massimo ; Spector, Tim D. ; Hayward, Caroline ; Rudan, Igor ; Hall, Alistair S. ; Samani, Nilesh J. ; Attwood, Antony Paul ; Sambrook, Jennifer G. ; Hung, Joseph ; Palmer, Lyle J. ; Lokki, Marja-Liisa ; Sinisalo, Juha ; Boucher, Gabrielle ; Huikuri, Heikki ; Lorentzon, Mattias ; Ohlsson, Claes ; Eklund, Niina ; Eriksson, Johan G. ; Barlassina, Cristina ; Rivolta, Carlo ; Nolte, Ilja M. ; Snieder, Harold ; Klauw, Melanie M. van der ; Vliet-Ostaptchouk, Jana V. van ; Gejman, Pablo V. ; Shi, Jianxin ; Jacobs, Kevin B. ; Wang, Zhaoming ; Bakker, Stephan J. L. ; Mateo Leach, Irene ; Navis, Gerjan ; Harst, Pim van der ; Martin, Nicholas Gordon ; Medland, Sarah E. ; Montgomery, Grant W. ; Yang, Jian ; Chasman, Daniel I. ; Ridker, Paul M. ; Rose, Lynda M. ; Lehtimäki, Terho ; Raitakari, Olli ; Absher, Devin ; Iribarren, Carlos ; Basart, Hanneke ; Hovingh, Kees G. ; Hyppönen, Elina ; Power, Chris ; Power, Chris ; Anderson, Denise ; Beilby, John P. ; Hui, Jennie ; Jolley, Jennifer ; Sager, Hendrik ; Bornstein, Stefan R. ; Schwarz, Peter E. H. ; Kristiansson, Kati ; Perola, Markus ; Lindström, Jaana ; Swift, Amy J. ; Uusitupa, Matti ; Atalay, Mustafa ; Lakka, Timo A. ; Rauramaa, Rainer ; Bolton, Jennifer L. ; Fowkes, Gerry ; Fraser, Ross M. ; Price, Jackie F. ; Fischer, Krista ; KrjutÅ¡kov, Kaarel ; Metspalu, Andres ; Mihailov, Evelin ; Langenberg, Claudia ; Luan, Jian'an ; Ong, Ken K. ; Chines, Peter S. ; Keinanen-Kiukaanniemi, Sirkka M. ; Saaristo, Timo E. ; Edkins, Sarah ; Franks, Paul W. ; Hallmans, Göran ; Shungin, Dmitry ; Morris, Andrew David ; Palmer, Colin N. A. ; Erbel, Raimund ; Moebus, Susanne ; Nöthen, Markus Maria ; Pechlivanis, Sonali ; Hveem, Kristian ; Narisu, Narisu ; Hamsten, Anders ; Humphries, Steve E. ; Strawbridge, Rona J. ; Tremoli, Elena ; Grallert, Harald ; Thorand, Barbara ; Illig, Thomas ; Koenig, Wolfgang ; Müller-Nurasyid, Martina ; Peters, Annette ; Böhm, Bernhard O. ; Kleber, Marcus E. ; März, Winfried ; Winkelmann, Bernhard R. ; Kuusisto, Johanna ; Laakso, Markku ; Arveiler, Dominique ; Cesana, Giancarlo ; Kuulasmaa, Kari ; Virtamo, Jarmo ; Yarnell, John W. G. ; Kuh, Diana ; Wong, Andrew ; Lind, Lars ; Faire, Ulf de ; Gigante, Bruna ; Magnusson, Patrik K. E. ; Pedersen, Nancy L. ; Dedoussis, George ; Dimitriou, Maria ; Kolovou, Genovefa ; Kanoni, Stavroula ; Stirrups, Kathleen ; Bonnycastle, Lori L. ; Njølstad, Inger ; Wilsgaard, Tom ; Ganna, Andrea ; Rehnberg, Emil ; Hingorani, Aroon ; Kivimaki, Mika ; Kumari, Meena ; Assimes, Themistocles L. ; Barroso, Inês ; Boehnke, Michael ; Borecki, Ingrid B. ; Deloukas, Panos ; Fox, Caroline S. ; Frayling, Timothy ; Groop, Leif C. ; Haritunians, Talin ; Hunter, David ; Ingelsson, Erik ; Kaplan, Robert ; Mohlke, Karen L. ; North, Kari E. ; Lindgren, Cecilia M. ; Qi, Lu ; Loos, Ruth J. F. ; Heid, Iris M. ; Hirschhorn, Joel N. ; McCarthy, Mark I. ; Abecasis, Gonçalo R. ; Stefansson, Kari ; Strachan, David P. ; Schlessinger, David ; O'Connell, Jeffrey R. ; Duijn, Cornelia M. van
Men and women differ substantially regarding height, weight, and body fat. Interestingly, previous work detecting genetic effects for waist-to-hip ratio, to assess body fat distribution, has found that many of these showed sex-differences. However, systematic searches for sex-differences in genetic effects have not yet been conducted. Therefore, we undertook a genome-wide search for sexually dimorphic genetic effects for anthropometric traits including 133,723 individuals in a large meta-analysis and followed promising variants in further 137,052 individuals, including a total of 94 studies. We identified seven loci with significant sex-difference including four previously established (near GRB14/COBLL1, LYPLAL1/SLC30A10, VEGFA, ADAMTS9) and three novel anthropometric trait loci (near MAP3K1, HSD17B4, PPARG), all of which were significant in women, but not in men. Of interest is that sex-difference was only observed for waist phenotypes, but not for height or body-mass-index. We found no evidence for sex-differences with opposite effect direction for men and women. The PPARG locus is of specific interest due to its link to diabetes genetics and therapy. Our findings demonstrate the importance of investigating sex differences, which may lead to a better understanding of disease mechanisms with a potential relevance to treatment options.
Escott-Price, Valentina ; Bellenguez, Céline ; Wang, Li-San ; Choi, Seung-Hoan ; Harold, Denise ; Jones, Lesley ; Holmans, Peter ; Gerrish, Amy ; Vedernikov, Alexey ; Richards, Alexander ; DeStefano, Anita L. ; Lambert, Jean-Charles ; Ibrahim-Verbaas, Carla A. ; Naj, Adam C. ; Sims, Rebecca ; Jun, Gyungah ; Bis, Joshua C. ; Beecham, Gary W. ; Grenier-Boley, Benjamin ; Russo, Giancarlo ; Thornton-Wells, Tricia A. ; Denning, Nicola ; Smith, Albert V. ; Chouraki, Vincent ; Thomas, Charlene ; Ikram, M. Arfan ; Zelenika, Diana ; Vardarajan, Badri N. ; Kamatani, Yoichiro ; Lin, Chiao-Feng ; Schmidt, Helena ; Kunkle, Brian ; Dunstan, Melanie L. ; Vronskaya, Maria ; Johnson, Andrew D. ; Ruiz, Agustin ; Bihoreau, Marie-Thérèse ; Reitz, Christiane ; Pasquier, Florence ; Hollingworth, Paul ; Hanon, Olivier ; Fitzpatrick, Annette L. ; Buxbaum, Joseph D. ; Campion, Dominique ; Crane, Paul K. ; Baldwin, Clinton ; Becker, Tim ; Gudnason, Vilmundur ; Cruchaga, Carlos ; Craig, David ; Amin, Najaf ; Berr, Claudine ; Lopez, Oscar L. ; Jager, Philip L. De ; Deramecourt, Vincent ; Johnston, Janet A. ; Evans, Denis ; Lovestone, Simon ; Letenneur, Luc ; Hernández, Isabel ; Rubinsztein, David C. ; Eiriksdottir, Gudny ; Sleegers, Kristel ; Goate, Alison M. ; Fiévet, Nathalie ; Huentelman, Matthew J. ; Gill, Michael ; Brown, Kristelle ; Kamboh, M. Ilyas ; Keller, Lina ; Barberger-Gateau, Pascale ; McGuinness, Bernadette ; Larson, Eric B. ; Myers, Amanda J. ; Dufouil, Carole ; Todd, Stephen ; Wallon, David ; Love, Seth ; Rogaeva, Ekaterina ; Gallacher, John ; St George-Hyslop, Peter ; Clarimon, Jordi ; Lleo, Alberto ; Bayer, Anthony ; Tsuang, Debby W. ; Yu, Lei ; Tsolaki, Magda ; Bossù, Paola ; Spalletta, Gianfranco ; Proitsi, Petra ; Collinge, John ; Sorbi, Sandro ; Sanchez Garcia, Florentino ; Fox, Nick C. ; Hardy, John ; Deniz Naranjo, Maria Candida ; Bosco, Paolo ; Clarke, Robert ; Brayne, Carol ; Galimberti, Daniela ; Scarpini, Elio ; Bonuccelli, Ubaldo ; Mancuso, Michelangelo ; Siciliano, Gabriele ; Moebus, Susanne ; Mecocci, Patrizia ; Del Zompo, Maria ; Maier, Wolfgang ; Hampel, Harald ; Pilotto, Alberto ; Frank-García, Ana ; Panza, Francesco ; Solfrizzi, Vincenzo ; Caffarra, Paolo ; Nacmias, Benedetta ; Perry, William ; Mayhaus, Manuel ; Lannfelt, Lars ; Hakonarson, Hakon ; Pichler, Sabrina ; Carrasquillo, Minerva M. ; Ingelsson, Martin ; Beekly, Duane ; Alvarez, Victoria ; Zou, Fanggeng ; Valladares, Otto ; Younkin, Steven G. ; Coto, Eliecer ; Hamilton-Nelson, Kara L. ; Gu, Wei ; Razquin, Cristina ; Pastor, Pau ; Mateo, Ignacio ; Owen, Michael J. ; Faber, Kelley M. ; Jonsson, Palmi V. ; Combarros, Onofre ; O'Donovan, Michael C. ; Cantwell, Laura B. ; Soininen, Hilkka ; Blacker, Deborah ; Mead, Simon ; Mosley, Thomas H. ; Bennett, David A. ; Harris, Tamara B. ; Fratiglioni, Laura ; Holmes, Clive ; Bruijn, Renee F. A. G. de ; Passmore, Peter ; Montine, Thomas J. ; Bettens, Karolien ; Rotter, Jerome I. ; Brice, Alexis ; Morgan, Kevin ; Foroud, Tatiana M. ; Kukull, Walter A. ; Hannequin, Didier ; Powell, John F. ; Nalls, Michael A. ; Ritchie, Karen ; Lunetta, Kathryn L. ; Kauwe, John S. K. ; Boerwinkle, Eric ; Riemenschneider, Matthias ; Boada, Mercè ; Hiltunen, Mikko ; Martin, Eden R. ; Schmidt, Reinhold ; Rujescu, Dan ; Dartigues, Jean-François ; Mayeux, Richard ; Tzourio, Christophe ; Hofman, Albert ; Nöthen, Markus Maria ; Graff, Caroline ; Psaty, Bruce M. ; Haines, Jonathan L. ; Lathrop, Mark ; Pericak-Vance, Margaret Ann ; Launer, Lenore J. ; Broeckhoven, Christine Van ; Farrer, Lindsay A. ; Duijn, Cornelia M. van ; Ramirez, Alfredo ; Seshadri, Sudha ; Schellenberg, Gerard D. ; Amouyel, Philippe ; Williams, Julie
Background: Alzheimer's disease is a common debilitating dementia with known heritability, for which 20 late onset susceptibility loci have been identified, but more remain to be discovered. This study sought to identify new susceptibility genes, using an alternative gene-wide analytical approach which tests for patterns of association within genes, in the powerful genome-wide association dataset of the International Genomics of Alzheimer's Project Consortium, comprising over 7 m genotypes from 25,580 Alzheimer's cases and 48,466 controls.
Principal findings: In addition to earlier reported genes, we detected genome-wide significant loci on chromosomes 8 (TP53INP1, p = 1.4×10−6) and 14 (IGHV1-67 p = 7.9×10−8) which indexed novel susceptibility loci.
Significance: The additional genes identified in this study, have an array of functions previously implicated in Alzheimer's disease, including aspects of energy metabolism, protein degradation and the immune system and add further weight to these pathways as potential therapeutic targets in Alzheimer's disease.
Hou, Liping ; Bergen, Sarah E. ; Akula, Nirmala ; Song, Jie ; Hultman, Christina M. ; Landén, Mikael ; Adli, Mazda ; Alda, Martin ; Ardau, Raffaella ; Arias, Bárbara ; Aubry, Jean-Michel ; Backlund, Lena ; Badner, Judith A. ; Barrett, Thomas B. ; Bauer, Michael ; Baune, Bernhard T. ; Bellivier, Frank ; Benabarre Hernandez, Antonio ; Bengesser, Susanne ; Berrettini, Wade H. ; Bhattacharjee, Abesh Kumar ; Biernacka, Joanna ; Birner, Armin ; Bloss, Cinnamon S. ; Brichant-Petitjean, Clara ; Bui, Elise T. ; Byerley, William ; Cervantes, Pablo ; Chillotti, Caterina ; Cichon, Sven ; Colom, Francesc ; Coryell, William ; Craig, David W. ; Cruceanu, Cristiana ; Czerski, Piotr M. ; Davis, Tony ; Dayer, Alexandre ; Degenhardt, Franziska ; Del Zompo, Maria ; DePaulo, J. Raymond ; Edenberg, Howard J. ; Étain, Bruno ; Falkai, Peter ; Foroud, Tatiana ; Forstner, Andreas Josef ; Frisén, Louise ; Frye, Mark A. ; Fullerton, Janice M. ; Gard, Sébastien ; Garnham, Julie S. ; Gershon, Elliot S. ; Goes, Fernando S. ; Greenwood, Tiffany A. ; Grigoroiu-Serbanescu, Maria ; Hauser, Joanna ; Heilbronner, Urs ; Heilmann-Heimbach, Stefanie ; Herms, Stefan ; Hipolito, Maria ; Hitturlingappa, Shashi ; Hoffmann, Per ; Hofmann, Andrea ; Jamain, Stephane ; Jiménez, Esther ; Kahn, Jean-Pierre ; Kassem, Layla ; Kelsoe, John R. ; Kittel-Schneider, Sarah ; Kliwicki, Sebastian ; Koller, Daniel L. ; König, Barbara ; Lackner, Nina ; Laje, Gonzalo ; Lang, Maren ; Lavebratt, Catharina ; Lawson, William B. ; Leboyer, Marion ; Leckband, Susan G. ; Liu, Chunyu ; Maaser, Anna ; Mahon, Pamela B. ; Maier, Wolfgang ; Maj, Mario ; Manchia, Mirko ; Martinsson, Lina ; McCarthy, Michael J. ; McElroy, Susan L. ; McInnis, Melvin G. ; McKinney, Rebecca ; Mitchell, Philip B. ; Mitjans, Marina ; Mondimore, Francis Mark ; Monteleone, Palmiero ; Mühleisen, Thomas W. ; Nievergelt, Caroline M. ; Nöthen, Markus Maria ; Novák, Tomas ; Nurnberger, John I. ; Nwulia, Evaristus A. ; Ösby, Urban ; Pfennig, Andrea ; Potash, James B. ; Propping, Peter ; Reif, Andreas ; Reininghaus, Eva ; Rice, John ; Rietschel, Marcella ; Rouleau, Guy A. ; Rybakowski, Janusz K. ; Schalling, Martin ; Scheftner, William A. ; Schofield, Peter R. ; Schork, Nicholas J. ; Schulze, Thomas Gerd ; Schumacher, Johannes ; Schweizer, Barbara W. ; Severino, Giovanni ; Shekhtman, Tatyana ; Shilling, Paul D. ; Simhandl, Christian ; Slaney, Claire M. ; Smith, Erin N. ; Squassina, Alessio ; Stamm, Thomas ; Stopkova, Pavla ; Streit, Fabian ; Strohmaier, Jana ; Szelinger, Szabolcs ; Tighe, Sarah K. ; Tortorella, Alfonso ; Turecki, Gustavo ; Vieta, Eduard ; Volkert, Julia ; Witt, Stephanie H. ; Wright, Adam ; Zandi, Peter P. ; Zhang, Peng ; Zollner, Sebastian ; McMahon, Francis J.
Bipolar disorder (BD) is a genetically complex mental illness characterized by severe oscillations of mood and behavior. Genome-wide association studies (GWAS) have identified several risk loci that together account for a small portion of the heritability. To identify additional risk loci, we performed a two-stage meta-analysis of >9 million genetic variants in 9,784 bipolar disorder patients and 30,471 controls, the largest GWAS of BD to date. In this study, to increase power we used ~2,000 lithium-treated cases with a long-term diagnosis of BD from the Consortium on Lithium Genetics, excess controls, and analytic methods optimized for markers on the Xchromosome. In addition to four known loci, results revealed genome-wide significant associations at two novel loci: an intergenic region on 9p21.3 (rs12553324, p = 5.87×10-9; odds ratio = 1.12) and markers within ERBB2 (rs2517959, p = 4.53×10-9; odds ratio = 1.13). No significant X-chromosome associations were detected and X-linked markers explained very little BD heritability. The results add to a growing list of common autosomal variants involved in BD and illustrate the power of comparing well-characterized cases to an excess of controls in GWAS.
HLA-DRB1 and HLA-DQB1 genetic diversity modulates response to lithium in bipolar affective disorders
(2021)
Le Clerc, Sigrid ; Lombardi, Laura ; Amare, Azmeraw T. ; Schubert, Klaus Oliver ; Hou, Liping ; Clark, Scott R. ; Papiol, Sergi ; Cearns, Micah ; Heilbronner, Urs ; Degenhardt, Franziska ; Tekola-Ayele, Fasil ; Hsu, Yi-Hsiang ; Shekhtman, Tatyana ; Adli, Mazda ; Akula, Nirmala ; Akiyama, Kazufumi ; Ardau, Raffaella ; Arias, Bárbara ; Aubry, Jean-Michel ; Backlund, Lena ; Bhattacharjee, Abesh Kumar ; Bellivier, Frank ; Benabarre, Antonio ; Bengesser, Susanne ; Biernacka, Joanna ; Birner, Armin ; Brichant-Petitjean, Clara ; Cervantes, Pablo ; Chen, Hsi-Chung ; Chillotti, Caterina ; Cichon, Sven ; Cruceanu, Cristiana ; Czerski, Piotr M. ; Dalkner, Nina ; Dayer, Alexandre ; Baune, Bernhard T. ; Del Zompo, Maria ; DePaulo, J. Raymond ; Étain, Bruno ; Jamain, Stephane ; Falkai, Peter ; Forstner, Andreas Josef ; Frisen, Louise ; Frye, Mark A. ; Fullerton, Janice M. ; Gard, Sébastien ; Garnham, Julie S. ; Goes, Fernando S. ; Grigoroiu-Serbanescu, Maria ; Grof, Paul ; Hashimoto, Ryota ; Hauser, Joanna ; Herms, Stefan ; Hoffmann, Per ; Jiménez, Esther ; Kahn, Jean-Pierre ; Kassem, Layla ; Kuo, Po-Hsiu ; Kato, Tadafumi ; Kelsoe, John R. ; Kittel-Schneider, Sarah ; Ferensztajn-Rochowiak, Ewa ; König, Barbara ; Kusumi, Ichiro ; Laje, Gonzalo ; Landén, Mikael ; Lavebratt, Catharina ; Leckband, Susan G. ; Tortorella, Alfonso ; Manchia, Mirko ; Martinsson, Lina ; McCarthy, Michael J. ; McElroy, Susan ; Colom, Francesc ; Millischer, Vincent ; Mitjans, Marina ; Mondimore, Francis Mark ; Monteleone, Palmiero ; Nievergelt, Caroline M. ; Nöthen, Markus Maria ; Novák, Tomas ; O'Donovan, Claire ; Ozaki, Norio ; Ösby, Urban ; Pfennig, Andrea ; Potash, James B. ; Reif, Andreas ; Reininghaus, Eva ; Rouleau, Guy A. ; Rybakowski, Janusz K. ; Schalling, Martin ; Schofield, Peter R. ; Schweizer, Barbara W. ; Severino, Giovanni ; Shilling, Paul D. ; Shimoda, Katzutaka ; Simhandl, Christian ; Slaney, Claire M. ; Pisanu, Claudia ; Squassina, Alessio ; Stamm, Thomas ; Stopkova, Pavla ; Maj, Mario ; Turecki, Gustavo ; Vieta, Eduard ; Veeh, Julia ; Witt, Stephanie H. ; Wright, Adam ; Zandi, Peter P. ; Mitchell, Philip B. ; Bauer, Michael ; Alda, Martin ; Rietschel, Marcella ; McMahon, Francis J. ; Schulze, Thomas Gerd ; Spadoni, Jean-Louis ; Boukouaci, Wahid ; Richard, Jean-Romain ; Le Corvoisier, Philippe ; Barrau, Caroline ; Zagury, Jean-François ; Leboyer, Marion ; Tamouza, Ryad
Bipolar affective disorder (BD) is a severe psychiatric illness, for which lithium (Li) is the gold standard for acute and maintenance therapies. The therapeutic response to Li in BD is heterogeneous and reliable biomarkers allowing patients stratification are still needed. A GWAS performed by the International Consortium on Lithium Genetics (ConLiGen) has recently identified genetic markers associated with treatment responses to Li in the human leukocyte antigens (HLA) region. To better understand the molecular mechanisms underlying this association, we have genetically imputed the classical alleles of the HLA region in the European patients of the ConLiGen cohort. We found our best signal for amino-acid variants belonging to the HLA-DRB1*11:01 classical allele, associated with a better response to Li (p < 1 × 10−3; FDR < 0.09 in the recessive model). Alanine or Leucine at position 74 of the HLA-DRB1 heavy chain was associated with a good response while Arginine or Glutamic acid with a poor response. As these variants have been implicated in common inflammatory/autoimmune processes, our findings strongly suggest that HLA-mediated low inflammatory background may contribute to the efficient response to Li in BD patients, while an inflammatory status overriding Li anti-inflammatory properties would favor a weak response.
Koromina, Maria ; Ravi, Ashvin ; Panagiotaropoulou, Georgia ; Schilder, Brian M. ; Humphrey, Jack ; Braun, Alice ; Bidgeli, Tim ; Chatzinakos, Chris ; Coombes, Brandon ; Kim, Jaeyoung ; Liu, Xiaoxi ; Terao, Chikashi ; O'Connell, Kevin S. ; Adams, Mark ; Adolfsson, Rolf ; Alda, Martin ; Alfredsson, Lars ; Andlauer, Till ; Andreassen, Ole A. ; Antoniou, Anastasia ; Baune, Bernhard T. ; Bengesser, Susanne ; Biernacka, Joanna ; Boehnke, Michael ; Bosch, Rosa ; Cairns, Murray ; Carr, Vaughan J. ; Casas Brugué, Miquel ; Catts, Stanley ; Cichon, Sven ; Corvin, Aiden ; Craddock, Nicholas ; Dafnas, Konstantinos ; Dalkner, Nina ; Dannlowski, Udo ; Degenhardt, Franziska ; Di Florio, Arianna ; Dikeos, Dimitris ; Fellendorf, Frederike Tabea ; Ferentinos, Panagiotis ; Forstner, Andreas Josef ; Forty, Liz ; Frye, Mark ; Fullerton, Janice M. ; Gawlik, Micha ; Gizer, Ian R. ; Gordon-Smith, Katherine ; Green, Melissa J. ; Grigoroiu-Serbanescu, Maria ; Guzman-Parra, José ; Hahn, Tim ; Henskens, Frans ; Hillert, Jan ; Jablensky, Assen V. ; Jones, Lisa ; Jones, Ian ; Jonsson, Lina ; Kelsoe, John R. ; Kircher, Tilo ; Kirov, George ; Kittel-Schneider, Sarah ; Kogevinas, Manolis ; Landén, Mikael ; Leboyer, Marion ; Lenger, Melanie ; Lissowska, Jolanta ; Lochner, Christine ; Loughland, Carmel ; MacIntyre, Donald ; Martin, Nicholas G. ; Maratou, Eirini ; Mathews, Carol A. ; Mayoral, Fermı́n ; McElroy, Susan L. ; McGregor, Nathaniel W. ; McIntosh, Andrew M. ; McQuillin, Andrew ; Michie, Patricia ; Milanova, Vihra ; Mitchell, Philip B. ; Moutsatsou, Paraskevi ; Mowry, Bryan ; Müller-Myhsok, Bertram ; Myers, Richard M. ; Nenadić, Igor ; Nöthen, Markus Maria ; O'Donovan, Claire ; O'Donovan, Michael ; Ophoff, Roel André ; Owen, Michael J. ; Pantelis, Christos ; Pato, Carlos ; Pato, Michele T. ; Patrinos, George P. ; Pawlak, Joanna M. ; Perlis, Roy H. ; Porichi, Evgenia ; Posthuma, Danielle ; Ramos-Quiroga, Josep Antoni ; Reif, Andreas ; Reininghaus, Eva Z. ; Ribasés, Marta ; Rietschel, Marcella ; Schall, Ulrich ; Schulze, Thomas Gerd ; Scott, Laura J. ; Scott, Rodney J. ; Serretti, Alessandro ; Shannon Weickert, Cynthia ; Smoller, Jordan W. ; Soler Artigas, Marı́a ; Stein, Dan J. ; Streit, Fabian ; Toma, Claudio ; Tooney, Paul ; Vieta, Eduard ; Vincent, John B. ; Waldman, Irwin D. ; Weickert, Thomas ; Witt, Stephanie H. ; Hong, Kyung Sue ; Ikeda, Masashi ; Iwata, Nakao ; Świątkowska, Beata ; Won, Hong-Hee ; Edenberg, Howard J. ; Ripke, Stephan ; Raj, Towfique ; Coleman, Jonathan R. I. ; Mullins, Niamh
Bipolar disorder (BD) is a heritable mental illness with complex etiology. While the largest published genome-wide association study identified 64 BD risk loci, the causal SNPs and genes within these loci remain unknown. We applied a suite of statistical and functional fine-mapping methods to these loci, and prioritized 22 likely causal SNPs for BD. We mapped these SNPs to genes, and investigated their likely functional consequences by integrating variant annotations, brain cell-type epigenomic annotations, brain quantitative trait loci, and results from rare variant exome sequencing in BD. Convergent lines of evidence supported the roles of SCN2A, TRANK1, DCLK3, INSYN2B, SYNE1, THSD7A, CACNA1B, TUBBP5, PLCB3, PRDX5, KCNK4, AP001453.3, TRPT1, FKBP2, DNAJC4, RASGRP1, FURIN, FES, YWHAE, DPH1, GSDMB, MED24, THRA, EEF1A2, and KCNQ2 in BD. These represent promising candidates for functional experiments to understand biological mechanisms and therapeutic potential. Additionally, we demonstrated that fine-mapping effect sizes can improve performance and transferability of BD polygenic risk scores across ancestrally diverse populations, and present a high-throughput fine-mapping pipeline (https://github.com/mkoromina/SAFFARI).
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.
Jarick, Ivonne ; Volckmar, Anna-Lena ; Pütter, Carolin ; Pechlivanis, Sonali ; Nguyen, Trang T. ; Dauvermann, Maria R. ; Beck, Sebastian ; Albayrak, Özgür ; Scherag, Susann ; Gilsbach, Susanne ; Cichon, Sven ; Hoffmann, Per ; Degenhardt, Franziska ; Nöthen, Markus Maria ; Schreiber, Stefan ; Wichmann, Heinz Erich ; Jöckel, Karl-Heinz ; Heinrich, Joachim ; Tiesler, Carla Marie Thérèse ; Faraone, Stephen V. ; Walitza, Susanne ; Sinzig, Judith ; Freitag, Christine M. ; Meyer, Jobst ; Herpertz-Dahlmann, Beate ; Lehmkuh, Gerd ; Renner, Tobias J. ; Warnke, Andreas ; Romanos, Marcel ; Lesch, Klaus-Peter J. ; Reif, Andreas ; Schimmelmann, Benno G. ; Hebebrand, Johannes ; Scherag, André ; Hinney, Anke
Attention-deficit/hyperactivity disorder (ADHD) is a common, highly heritable neurodevelopmental disorder. Genetic loci have not yet been identified by genome-wide association studies. Rare copy number variations (CNVs), such as chromosomal deletions or duplications, have been implicated in ADHD and other neurodevelopmental disorders. To identify rare (frequency ≤1%) CNVs that increase the risk of ADHD, we performed a whole-genome CNV analysis based on 489 young ADHD patients and 1285 adult population-based controls and identified one significantly associated CNV region. In tests for a global burden of large (>500 kb) rare CNVs, we observed a nonsignificant (P=0.271) 1.126-fold enriched rate of subjects carrying at least one such CNV in the group of ADHD cases. Locus-specific tests of association were used to assess if there were more rare CNVs in cases compared with controls. Detected CNVs, which were significantly enriched in the ADHD group, were validated by quantitative (q)PCR. Findings were replicated in an independent sample of 386 young patients with ADHD and 781 young population-based healthy controls. We identified rare CNVs within the parkinson protein 2 gene (PARK2) with a significantly higher prevalence in ADHD patients than in controls (P=2.8 × 10(-4) after empirical correction for genome-wide testing). In total, the PARK2 locus (chr 6: 162 659 756-162 767 019) harboured three deletions and nine duplications in the ADHD patients and two deletions and two duplications in the controls. By qPCR analysis, we validated 11 of the 12 CNVs in ADHD patients (P=1.2 × 10(-3) after empirical correction for genome-wide testing). In the replication sample, CNVs at the PARK2 locus were found in four additional ADHD patients and one additional control (P=4.3 × 10(-2)). Our results suggest that copy number variants at the PARK2 locus contribute to the genetic susceptibility of ADHD. Mutations and CNVs in PARK2 are known to be associated with Parkinson disease.
Andlauer, Till ; Guzman-Parra, José ; Streit, Fabian ; Strohmaier, Jana ; González, Maria José ; Flores, Susana Gil ; Cabaleiro Fabeiro, Francisco J. ; Rı́o Noriega, Francisco del ; Perez, Fermin Perez ; González, Jesus Haro ; Orozco Diaz, Guillermo ; de Diego-Otero, Yolanda ; Moreno-Kuestner, Berta ; Auburger, Georg ; Degenhardt, Franziska ; Heilmann-Heimbach, Stefanie ; Herms, Stefan ; Hoffmann, Per ; Frank, Josef ; Foo, Jerome Clifford ; Treutlein, Jens ; Witt, Stephanie H. ; Cichon, Sven ; Kogevinas, Manolis ; Rivas, Fabio ; Mayoral, Fermı́n ; Müller-Myhsok, Bertram ; Forstner, Andreas Josef ; Nöthen, Markus Maria ; Rietschel, Marcella
Multiplex families with a high prevalence of a psychiatric disorder are often examined to identify rare genetic variants with large effect sizes. In the present study, we analysed whether the risk for bipolar disorder (BD) in BD multiplex families is influenced by common genetic variants. Furthermore, we investigated whether this risk is conferred mainly by BD-specific risk variants or by variants also associated with the susceptibility to schizophrenia or major depression. In total, 395 individuals from 33 Andalusian BD multiplex families (166 BD, 78 major depressive disorder, 151 unaffected) as well as 438 subjects from an independent, BD case/control cohort (161 unrelated BD, 277 unrelated controls) were analysed. Polygenic risk scores (PRS) for BD, schizophrenia (SCZ), and major depression were calculated and compared between the cohorts. Both the familial BD cases and unaffected family members had higher PRS for all three psychiatric disorders than the independent controls, with BD and SCZ being significant after correction for multiple testing, suggesting a high baseline risk for several psychiatric disorders in the families. Moreover, familial BD cases showed significantly higher BD PRS than unaffected family members and unrelated BD cases. A plausible hypothesis is that, in multiplex families with a general increase in risk for psychiatric disease, BD development is attributable to a high burden of common variants that confer a specific risk for BD. The present analyses demonstrated that common genetic risk variants for psychiatric disorders are likely to contribute to the high incidence of affective psychiatric disorders in the multiplex families. However, the PRS explained only part of the observed phenotypic variance, and rare variants might have also contributed to disease development.
Andlauer, Till ; Guzman-Parra, José ; Streit, Fabian ; Strohmaier, Jana ; González, Maria José ; Flores, Susana Gil ; Cabaleiro Fabeiro, Francisco J. ; Rı́o Noriega, Francisco del ; Perez, Fermin Perez ; González, Jesus Haro ; Orozco Diaz, Guillermo ; de Diego-Otero, Yolanda ; Moreno-Kuestner, Berta ; Auburger, Georg ; Degenhardt, Franziska ; Heilmann-Heimbach, Stefanie ; Herms, Stefan ; Hoffmann, Per ; Frank, Josef ; Foo, Jerome Clifford ; Treutlein, Jens ; Witt, Stephanie H. ; Cichon, Sven ; Kogevinas, Manolis ; Rivas, Fabio ; Mayoral, Fermı́n ; Müller-Myhsok, Bertram ; Forstner, Andreas Josef ; Nöthen, Markus Maria ; Rietschel, Marcella
Multiplex families with a high prevalence of a psychiatric disorder are often examined to identify rare genetic variants with large effect sizes. In the present study, we analysed whether the risk for bipolar disorder (BD) in BD multiplex families is influenced by common genetic variants. Furthermore, we investigated whether this risk is conferred mainly by BD-specific risk variants or by variants also associated with the susceptibility to schizophrenia or major depression. In total, 395 individuals from 33 Andalusian BD multiplex families as well as 438 subjects from an independent, sporadic BD case-control cohort were analysed. Polygenic risk scores (PRS) for BD, schizophrenia, and major depression were calculated and compared between the cohorts. Both the familial BD cases and unaffected family members had significantly higher PRS for all three psychiatric disorders than the independent controls, suggesting a high baseline risk for several psychiatric disorders in the families. Moreover, familial BD cases showed significantly higher BD PRS than unaffected family members and sporadic BD cases. A plausible hypothesis is that, in multiplex families with a general increase in risk for psychiatric disease, BD development is attributable to a high burden of common variants that confer a specific risk for BD. The present analyses, therefore, demonstrated that common genetic risk variants for psychiatric disorders are likely to contribute to the high incidence of affective psychiatric disorders in the multiplex families. The PRS explained only part of the observed phenotypic variance and rare variants might have also contributed to disease development.
Adam, Ronja ; Spier, Isabel ; Zhao, Bixiao ; Kloth, Michael ; Marquez, Jonathan ; Hinrichsen, Inga ; Kirfel, Jutta ; Tafazzoli, Aylar ; Horpaopan, Sukanya ; Uhlhaas, Siegfried ; Stienen, Dietlinde ; Friedrichs, Nicolaus ; Altmüller, Janine ; Laner, Andreas ; Holzapfel, Stefanie ; Peters, Sophia ; Kayser, Katrin ; Thiele, Holger ; Holinski-Feder, Elke ; Marra, Giancarlo ; Kristiansen, Glen ; Nöthen, Markus Maria ; Büttner, Reinhard ; Möslein, Gabriela ; Betz, Regina Christine ; Brieger, Angela ; Lifton, Richard P. ; Aretz, Stefan
In ∼30% of families affected by colorectal adenomatous polyposis, no germline mutations have been identified in the previously implicated genes APC, MUTYH, POLE, POLD1, and NTHL1, although a hereditary etiology is likely. To uncover further genes with high-penetrance causative mutations, we performed exome sequencing of leukocyte DNA from 102 unrelated individuals with unexplained adenomatous polyposis. We identified two unrelated individuals with differing compound-heterozygous loss-of-function (LoF) germline mutations in the mismatch-repair gene MSH3. The impact of the MSH3 mutations (c.1148delA, c.2319−1G>A, c.2760delC, and c.3001−2A>C) was indicated at the RNA and protein levels. Analysis of the diseased individuals’ tumor tissue demonstrated high microsatellite instability of di- and tetranucleotides (EMAST), and immunohistochemical staining illustrated a complete loss of nuclear MSH3 in normal and tumor tissue, confirming the LoF effect and causal relevance of the mutations. The pedigrees, genotypes, and frequency of MSH3 mutations in the general population are consistent with an autosomal-recessive mode of inheritance. Both index persons have an affected sibling carrying the same mutations. The tumor spectrum in these four persons comprised colorectal and duodenal adenomas, colorectal cancer, gastric cancer, and an early-onset astrocytoma. Additionally, we detected one unrelated individual with biallelic PMS2 germline mutations, representing constitutional mismatch-repair deficiency. Potentially causative variants in 14 more candidate genes identified in 26 other individuals require further workup. In the present study, we identified biallelic germline MSH3 mutations in individuals with a suspected hereditary tumor syndrome. Our data suggest that MSH3 mutations represent an additional recessive subtype of colorectal adenomatous polyposis.
Maaser, Anna ; Forstner, Andreas Josef ; Strohmaier, Jana ; Hecker, Julian ; Ludwig, Kerstin ; Sivalingam, Sugirthan ; Streit, Fabian ; Degenhardt, Franziska ; Witt, Stephanie ; Reinbold, Céline S. ; Koller, Anna C. ; Raff, Ruth ; Heilmann-Heimbach, Stefanie ; Fischer, Sascha B. ; Herms, Stefan ; Hoffmann, Per ; Thiele, Holger ; Nürnberg, Peter ; Fier, Heide ; Orozco-Díaz, Guillermo ; Carmenate-Naranjo, Deinys ; Proenza-Barzaga, Niurka ; Auburger, Georg ; Andlauer, Till ; Cichon, Sven ; Marcheco-Teruel, Beatriz ; Mors, Ole ; Rietschel, Marcella ; Nöthen, Markus Maria
Bipolar disorder (BD) is a major psychiatric illness affecting around 1% of the global population. BD is characterized by recurrent manic and depressive episodes, and has an estimated heritability of around 70%. Research has identified the first BD susceptibility genes. However, the underlying pathways and regulatory networks remain largely unknown. Research suggests that the cumulative impact of common alleles with small effects explains only around 25–38% of the phenotypic variance for BD. A plausible hypothesis therefore is that rare, high penetrance variants may contribute to BD risk. The present study investigated the role of rare, nonsynonymous, and potentially functional variants via whole exome sequencing in 15 BD cases from two large, multiply affected families from Cuba. The high prevalence of BD in these pedigrees renders them promising in terms of the identification of genetic risk variants with large effect sizes. In addition, SNP array data were used to calculate polygenic risk scores for affected and unaffected family members. After correction for multiple testing, no significant increase in polygenic risk scores for common, BD-associated genetic variants was found in BD cases compared to healthy relatives. Exome sequencing identified a total of 17 rare and potentially damaging variants in 17 genes. The identified variants were shared by all investigated BD cases in the respective pedigree. The most promising variant was located in the gene SERPING1 (p.L349F), which has been reported previously as a genome-wide significant risk gene for schizophrenia. The present data suggest novel candidate genes for BD susceptibility, and may facilitate the discovery of disease-relevant pathways and regulatory networks.
Yousaf, Afsheen ; Waltes, Regina ; Haslinger, Denise ; Klauck, Sabine M. ; Duketis, Eftichia ; Sachse, Michael ; Voran, Anette ; Biscaldi, Monica ; Schulte-Rüther, Martin ; Cichon, Sven ; Nöthen, Markus Maria ; Ackermann, Jörg ; Koch, Ina ; Freitag, Christine M. ; Geburtig-Chiocchetti, Andreas
Autism spectrum disorders (ASD) are highly heritable and are characterized by deficits in social communication and restricted and repetitive behaviors. Twin studies on phenotypic subdomains suggest a differing underlying genetic etiology. Studying genetic variation explaining phenotypic variance will help to identify specific underlying pathomechanisms. We investigated the effect of common variation on ASD subdomains in two cohorts including >2500 individuals. Based on the Autism Diagnostic Interview-Revised (ADI-R), we identified and confirmed six subdomains with a SNP-based genetic heritability h2SNP = 0.2–0.4. The subdomains nonverbal communication (NVC), social interaction (SI), and peer interaction (PI) shared genetic risk factors, while the subdomains of repetitive sensory-motor behavior (RB) and restricted interests (RI) were genetically independent of each other. The polygenic risk score (PRS) for ASD as categorical diagnosis explained 2.3–3.3% of the variance of SI, joint attention (JA), and PI, 4.5% for RI, 1.2% of RB, but only 0.7% of NVC. We report eight genome-wide significant hits—partially replicating previous findings—and 292 known and novel candidate genes. The underlying biological mechanisms were related to neuronal transmission and development. At the SNP and gene level, all subdomains showed overlap, with the exception of RB. However, no overlap was observed at the functional level. In summary, the ADI-R algorithm-derived subdomains related to social communication show a shared genetic etiology in contrast to restricted and repetitive behaviors. The ASD-specific PRS overlapped only partially, suggesting an additional role of specific common variation in shaping the phenotypic expression of ASD subdomains.
Marenholz, Ingo ; Grosche, Sarah ; Kalb, Birgit ; Rüschendorf, Franz ; Blümchen, Katharina ; Schlags, Rupert ; Harandi, Neda ; Price, Mareike ; Hansen, Gesine ; Seidenberg, Jürgen ; Röblitz, Holger ; Yürek, Songül ; Tschirner, Sebastian ; Hong, Xiumei ; Wang, Xiaobin ; Homuth, Georg ; Schmidt, Carsten ; Nöthen, Markus Maria ; Hübner, Norbert ; Niggemann, Bodo ; Beyer, Kirsten ; Lee, Young-Ae
Genetic factors and mechanisms underlying food allergy are largely unknown. Due to heterogeneity of symptoms a reliable diagnosis is often difficult to make. Here, we report a genome-wide association study on food allergy diagnosed by oral food challenge in 497 cases and 2387 controls. We identify five loci at genome-wide significance, the clade B serpin (SERPINB) gene cluster at 18q21.3, the cytokine gene cluster at 5q31.1, the filaggrin gene, the C11orf30/LRRC32 locus, and the human leukocyte antigen (HLA) region. Stratifying the results for the causative food demonstrates that association of the HLA locus is peanut allergy-specific whereas the other four loci increase the risk for any food allergy. Variants in the SERPINB gene cluster are associated with SERPINB10 expression in leukocytes. Moreover, SERPINB genes are highly expressed in the esophagus. All identified loci are involved in immunological regulation or epithelial barrier function, emphasizing the role of both mechanisms in food allergy.
Winter, Nils R. ; Blanke, Julian ; Leenings, Ramona ; Ernsting, Jan ; Fisch, Lukas ; Sarink, Kelvin ; Barkhau, Carlotta ; Thiel, Katharina ; Flinkenflügel, Kira ; Winter, Alexandra ; Goltermann, Janik ; Meinert, Susanne ; Dohm, Katharina ; Repple, Jonathan ; Gruber, Marius ; Leehr, Elisabeth Johanna ; Opel, Nils ; Grotegerd, Dominik ; Redlich, Ronny ; Nitsch, Robert ; Bauer, Jochen ; Heindel, Walter ; Groß, Joachim ; Andlauer, Till ; Forstner, Andreas Josef ; Nöthen, Markus Maria ; Rietschel, Marcella ; Hofmann, Stefan G. ; Pfarr, Julia-Katharina ; Teutenberg, Lea ; Usemann, Paula ; Thomas-Odenthal, Florian ; Wroblewski, Adrian ; Brosch, Katharina ; Stein, Frederike ; Jansen, Andreas ; Jamalabadi, Hamidreza ; Alexander, Nina ; Straube, Benjamin ; Nenadić, Igor ; Kircher, Tilo ; Dannlowski, Udo ; Hahn, Tim
Background: Biological psychiatry aims to understand mental disorders in terms of altered neurobiological pathways. However, for one of the most prevalent and disabling mental disorders, Major Depressive Disorder (MDD), patients only marginally differ from healthy individuals on the group-level. Whether Precision Psychiatry can solve this discrepancy and provide specific, reliable biomarkers remains unclear as current Machine Learning (ML) studies suffer from shortcomings pertaining to methods and data, which lead to substantial over-as well as underestimation of true model accuracy.
Methods: Addressing these issues, we quantify classification accuracy on a single-subject level in N=1,801 patients with MDD and healthy controls employing an extensive multivariate approach across a comprehensive range of neuroimaging modalities in a well-curated cohort, including structural and functional Magnetic Resonance Imaging, Diffusion Tensor Imaging as well as a polygenic risk score for depression.
Findings Training and testing a total of 2.4 million ML models, we find accuracies for diagnostic classification between 48.1% and 62.0%. Multimodal data integration of all neuroimaging modalities does not improve model performance. Similarly, training ML models on individuals stratified based on age, sex, or remission status does not lead to better classification. Even under simulated conditions of perfect reliability, performance does not substantially improve. Importantly, model error analysis identifies symptom severity as one potential target for MDD subgroup identification.
Interpretation: Although multivariate neuroimaging markers increase predictive power compared to univariate analyses, single-subject classification – even under conditions of extensive, best-practice Machine Learning optimization in a large, harmonized sample of patients diagnosed using state-of-the-art clinical assessments – does not reach clinically relevant performance. Based on this evidence, we sketch a course of action for Precision Psychiatry and future MDD biomarker research.
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