Schizophrenia is a highly heritable disorder. Genetic risk is conferred by a large number of alleles, including common alleles of small effect that might be detected by genome-wide association studies. Here we report a multi-stage schizophrenia genome-wide association study of up to 36,989 cases and 113,075 controls. We identify 128 independent associations spanning 108 conservatively defined loci that meet genome-wide significance, 83 of which have not been previously reported. Associations were enriched among genes expressed in brain, providing biological plausibility for the findings. Many findings have the potential to provide entirely new insights into aetiology, but associations at DRD2 and several genes involved in glutamatergic neurotransmission highlight molecules of known and potential therapeutic relevance to schizophrenia, and are consistent with leading pathophysiological hypotheses. Independent of genes expressed in brain, associations were enriched among genes expressed in tissues that have important roles in immunity, providing support for the speculated link between the immune system and schizophrenia.

Biological insights from 108 schizophrenia-associated genetic loci

Domenici, Enrico;
2014-01-01

Abstract

Schizophrenia is a highly heritable disorder. Genetic risk is conferred by a large number of alleles, including common alleles of small effect that might be detected by genome-wide association studies. Here we report a multi-stage schizophrenia genome-wide association study of up to 36,989 cases and 113,075 controls. We identify 128 independent associations spanning 108 conservatively defined loci that meet genome-wide significance, 83 of which have not been previously reported. Associations were enriched among genes expressed in brain, providing biological plausibility for the findings. Many findings have the potential to provide entirely new insights into aetiology, but associations at DRD2 and several genes involved in glutamatergic neurotransmission highlight molecules of known and potential therapeutic relevance to schizophrenia, and are consistent with leading pathophysiological hypotheses. Independent of genes expressed in brain, associations were enriched among genes expressed in tissues that have important roles in immunity, providing support for the speculated link between the immune system and schizophrenia.
2014
7510
Ripke, Stephan; Neale Benjamin, M.; Corvin, Aiden; Walters James, T. R.; Farh Kai, How; Holmans Peter, A.; Lee, Phil; Bulik Sullivan, Brendan; Collier David, A.; Huang, Hailiang; Pers Tune, H.; Agartz, Ingrid; Agerbo, Esben; Albus, Margot; Alexander, Madeline; Amin, Farooq; Bacanu Silviu, A.; Begemann, Martin; Belliveau Richard, A. J. r.; Bene, Judit; Bergen Sarah, E.; Bevilacqua, Elizabeth; Bigdeli Tim, B.; Black Donald, W.; Bruggeman, Richard; Buccola Nancy, G.; Buckner Randy, L.; Byerley, William; Cahn, Wiepke; Cai, Guiqing; Campion, Dominique; Cantor Rita, M.; Carr Vaughan, J.; Carrera, Noa; Catts Stanley, V.; Chambert Kimberly, D.; Chan Raymond, C. K.; Chen Ronald, Y. L.; Chen Eric, Y. H.; Cheng, Wei; Cheung Eric, F. C.; Chong Siow, Ann; Cloninger C., Robert; Cohen, David; Cohen, Nadine; Cormican, Paul; Craddock, Nick; Crowley James, J.; Curtis, David; Davidson, Michael; Davis Kenneth, L.; Degenhardt, Franziska; Del Favero, Jurgen; Demontis, Ditte; Dikeos, Dimitris; Dinan, Timothy; Djurovic, Srdjan; Donohoe, Gary; Drapeau, Elodie; Duan, Jubao; Dudbridge, Frank; Durmishi, Naser; Eichhammer, Peter; Eriksson, Johan; Escott Price, Valentina; Essioux, Laurent; Fanous Ayman, H.; Farrell Martilias, S.; Frank, Josef; Franke, Lude; Freedman, Robert; Freimer Nelson, B.; Friedl, Marion; Friedman Joseph, I.; Fromer, Menachem; Genovese, Giulio; Georgieva, Lyudmila; Giegling, Ina; Giusti Rodriguez, Paola; Godard, Stephanie; Goldstein Jacqueline, I.; Golimbet, Vera; Gopal, Srihari; Gratten, Jacob; de Haan, Lieuwe; Hammer, Christian; Hamshere Marian, L.; Hansen, Mark; Hansen, Thomas; Haroutunian, Vahram; Hartmann Annette, M.; Henskens Frans, A.; Herms, Stefan; Hirschhorn Joel, N.; Hoffmann, Per; Hofman, Andrea; Hollegaard Mads, V.; Hougaard David, M.; Ikeda, Masashi; Joa, Inge; Julia, Antonio; Kahn Rene, S.; Kalaydjieva, Luba; Karachanak Yankova, Sena; Karjalainen, Juha; Kavanagh, David; Keller Matthew, C.; Kennedy James, L.; Khrunin, Andrey; Kim, Yunjung; Klovins, Janis; Knowles James, A.; Konte, Bettina; Kucinskas, Vaidutis; Kucinskiene Zita, Ausrele; Kuzelova Ptackova, Hana; Kahler Anna, K.; Laurent, Claudine; Keong Jimmy Lee, Chee; Lee S., Hong; Legge Sophie, E.; Lerer, Bernard; Li, Miaoxin; Li, Tao; Liang Kung, Yee; Lieberman, Jeffrey; Limborska, Svetlana; Loughland Carmel, M.; Lubinski, Jan; Lonnqvist, Jouko; Macek Milan, J. r.; Magnusson Patrik, K. E.; Maher Brion, S.; Maier, Wolfgang; Mallet, Jacques; Marsal, Sara; Mattheisen, Manuel; Mattingsdal, Morten; McCarley Robert, W.; Mcdonald, Colm; McIntosh Andrew, M.; Meier, Sandra; Meijer Carin, J.; Melegh, Bela; Melle, Ingrid; Mesholam Gately Raquelle, I.; Metspalu, Andres; Michie Patricia, T.; Milani, Lili; Milanova, Vihra; Mokrab, Younes; Morris Derek, W.; Mors, Ole; Murphy Kieran, C.; Murray Robin, M.; Myin Germeys, Inez; Mueller Myhsok, Bertram; Nelis, Mari; Nenadic, Igor; Nertney Deborah, A.; Nestadt, Gerald; Nicodemus Kristin, K.; Nikitina Zake, Liene; Nisenbaum, Laura; Nordin, Annelie; O'Callaghan, Eadbhard; O'Dushlaine, Colm; O'Neill F., Anthony; Oh Sang, Yun; Olincy, Ann; Olsen, Line; Van Os, Jim; Pantelis, Christos; Papadimitriou George, N.; Papiol, Sergi; Parkhomenko, Elena; Pato Michele, T.; Paunio, Tiina; Pejovic Milovancevic, Milica; Perkins Diana, O.; Pietilainen, Olli; Pimm, Jonathan; Pocklington Andrew, J.; Powell, John; Price, Alkes; Pulver Ann, E.; Purcell Shaun, M.; Quested, Digby; Rasmussen Henrik, B.; Reichenberg, Abraham; Reimers Mark, A.; Richards Alexander, L.; Roffman Joshua, L.; Roussos, Panos; Ruderfer Douglas, M.; Salomaa, Veikko; Sanders Alan, R.; Schall, Ulrich; Schubert Christian, R.; Schulze Thomas, G.; Schwab Sibylle, G.; Scolnick Edward, M.; Scott Rodney, J.; Seidman Larry, J.; Shi, Jianxin; Sigurdsson, Engilbert; Silagadze, Teimuraz; Silverman Jeremy, M.; Sim, Kang; Slominsky, Petr; Smoller Jordan, W.; So Hon, Cheong; Spencer Chris, C. A.; Stahl Eli, A.; Stefansson, Hreinn; Steinberg, Stacy; Stogmann, Elisabeth; Straub Richard, E.; Strengman, Eric; Strohmaier, Jana; Stroup T., Scott; Subramaniam, Mythily; Suvisaari, Jaana; Svrakic Dragan, M.; Szatkiewicz Jin, P.; Soderman, Erik; Thirumalai, Srinivas; Toncheva, Draga; Tosato, Sarah; Veijola, Juha; Waddington, John; Walsh, Dermot; Wang, Dai; Wang, Qiang; Webb Bradley, T.; Weiser, Mark; Wildenauer Dieter, B.; Williams Nigel, M.; Williams, Stephanie; Witt Stephanie, H.; Wolen Aaron, R.; Wong Emily, H. M.; Wormley Brandon, K.; Xi Hualin, Simon; Zai Clement, C.; Zheng, Xuebin; Zimprich, Fritz; Wray Naomi, R.; Stefansson, Kari; Visscher Peter, M.; Adolfsson, Rolf; Andreassen Ole, A.; Blackwood Douglas, H. R.; Bramon, Elvira; Buxbaum Joseph, D.; Borglum Anders, D.; Cichon, Sven; Darvasi, Ariel; Domenici, Enrico; Ehrenreich, Hannelore; Esko, Tonu; Gejman Pablo, V.; Gill, Michael; Gurling, Hugh; Hultman Christina, M.; Iwata, Nakao; Jablensky Assen, V.; Jonsson Erik, G.; Kendler Kenneth, S.; Kirov, George; Knight, Jo; Lencz, Todd; Levinson Douglas, F.; Li Qingqin, S.; Liu, Jianjun; Malhotra Anil, K.; McCarroll Steven, A.; Mcquillin, Andrew; Moran Jennifer, L.; Mortensen Preben, B.; Mowry Bryan, J.; Noethen Markus, M.; Ophoff Roel, A.; Owen Michael, J.; Palotie, Aarno; Pato Carlos, N.; Petryshen Tracey, L.; Posthuma, Danielle; Rietschel, Marcella; Riley Brien, P.; Rujescu, Dan; Sham Pak, C.; Sklar, Pamela; St Clair, David; Weinberger Daniel, R.; Wendland Jens, R.; Werge, Thomas; Daly Mark, J.; Sullivan Patrick, F.; O'Donovan Michael, C.
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