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.
| Original language | English |
|---|---|
| Pages (from-to) | 421-427 |
| Number of pages | 7 |
| Journal | Nature |
| Volume | 511 |
| Issue number | 7510 |
| DOIs | |
| State | Published - 2014 |
| Externally published | Yes |
Funding
| Funders | Funder number |
|---|---|
| National Institute of Mental Health | U01MH096296 |
| National Institute of Mental Health |
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In: Nature, Vol. 511, No. 7510, 2014, p. 421-427.
Research output: Contribution to journal › Article › peer-review
TY - JOUR
T1 - Biological insights from 108 schizophrenia-associated genetic loci
AU - Ripke, Stephan
AU - Neale, Benjamin M.
AU - Corvin, Aiden
AU - Walters, James T.R.
AU - Farh, Kai How
AU - Holmans, Peter A.
AU - Lee, Phil
AU - Bulik-Sullivan, Brendan
AU - Collier, David A.
AU - Huang, Hailiang
AU - Pers, Tune H.
AU - Agartz, Ingrid
AU - Agerbo, Esben
AU - Albus, Margot
AU - Alexander, Madeline
AU - Amin, Farooq
AU - Bacanu, Silviu A.
AU - Begemann, Martin
AU - Belliveau, Richard A.
AU - Bene, Judit
AU - Bergen, Sarah E.
AU - Bevilacqua, Elizabeth
AU - Bigdeli, Tim B.
AU - Black, Donald W.
AU - Bruggeman, Richard
AU - Buccola, Nancy G.
AU - Buckner, Randy L.
AU - Byerley, William
AU - Cahn, Wiepke
AU - Cai, Guiqing
AU - Campion, Dominique
AU - Cantor, Rita M.
AU - Carr, Vaughan J.
AU - Carrera, Noa
AU - Catts, Stanley V.
AU - Chambert, Kimberly D.
AU - Chan, Raymond C.K.
AU - Chen, Ronald Y.L.
AU - Chen, Eric Y.H.
AU - Cheng, Wei
AU - Cheung, Eric F.C.
AU - Chong, Siow Ann
AU - Cloninger, C. Robert
AU - Cohen, David
AU - Cohen, Nadine
AU - Cormican, Paul
AU - Craddock, Nick
AU - Crowley, James J.
AU - Curtis, David
AU - Davidson, Michael
AU - Davis, Kenneth L.
AU - Degenhardt, Franziska
AU - Del Favero, Jurgen
AU - Demontis, Ditte
AU - Dikeos, Dimitris
AU - Dinan, Timothy
AU - Djurovic, Srdjan
AU - Donohoe, Gary
AU - Drapeau, Elodie
AU - Duan, Jubao
AU - Dudbridge, Frank
AU - Durmishi, Naser
AU - Eichhammer, Peter
AU - Eriksson, Johan
AU - Escott-Price, Valentina
AU - Essioux, Laurent
AU - Fanous, Ayman H.
AU - Farrell, Martilias S.
AU - Frank, Josef
AU - Franke, Lude
AU - Freedman, Robert
AU - Freimer, Nelson B.
AU - Friedl, Marion
AU - Friedman, Joseph I.
AU - Fromer, Menachem
AU - Genovese, Giulio
AU - Georgieva, Lyudmila
AU - Giegling, Ina
AU - Giusti-Rodríguez, Paola
AU - Godard, Stephanie
AU - Goldstein, Jacqueline I.
AU - Golimbet, Vera
AU - Gopal, Srihari
AU - Gratten, Jacob
AU - De Haan, Lieuwe
AU - Hammer, Christian
AU - Hamshere, Marian L.
AU - Hansen, Mark
AU - Hansen, Thomas
AU - Haroutunian, Vahram
AU - Hartmann, Annette M.
AU - Henskens, Frans A.
AU - Herms, Stefan
AU - Hirschhorn, Joel N.
AU - Hoffmann, Per
AU - Hofman, Andrea
AU - Hollegaard, Mads V.
AU - Hougaard, David M.
AU - Ikeda, Masashi
AU - Joa, Inge
AU - Julià, Antonio
AU - Kahn, René S.
AU - Kalaydjieva, Luba
AU - Karachanak-Yankova, Sena
AU - Karjalainen, Juha
AU - Kavanagh, David
AU - Keller, Matthew C.
AU - Kennedy, James L.
AU - Khrunin, Andrey
AU - Kim, Yunjung
AU - Klovins, Janis
AU - Knowles, James A.
AU - Konte, Bettina
AU - Kucinskas, Vaidutis
AU - Kucinskiene, Zita Ausrele
AU - Kuzelova-Ptackova, Hana
AU - Kähler, Anna K.
AU - Laurent, Claudine
AU - Keong, Jimmy Lee Chee
AU - Lee, S. Hong
AU - Legge, Sophie E.
AU - Lerer, Bernard
AU - Li, Miaoxin
AU - Li, Tao
AU - Liang, Kung Yee
AU - Lieberman, Jeffrey
AU - Limborska, Svetlana
AU - Loughland, Carmel M.
AU - Lubinski, Jan
AU - Lönnqvist, Jouko
AU - Macek, Milan
AU - Magnusson, Patrik K.E.
AU - Maher, Brion S.
AU - Maier, Wolfgang
AU - Mallet, Jacques
AU - Marsal, Sara
AU - Mattheisen, Manuel
AU - Mattingsdal, Morten
AU - McCarley, Robert W.
AU - McDonald, Colm
AU - McIntosh, Andrew M.
AU - Meier, Sandra
AU - Meijer, Carin J.
AU - Melegh, Bela
AU - Melle, Ingrid
AU - Mesholam-Gately, Raquelle I.
AU - Metspalu, Andres
AU - Michie, Patricia T.
AU - Milani, Lili
AU - Milanova, Vihra
AU - Mokrab, Younes
AU - Morris, Derek W.
AU - Mors, Ole
AU - Murphy, Kieran C.
AU - Murray, Robin M.
AU - Myin-Germeys, Inez
AU - Müller-Myhsok, Bertram
AU - Nelis, Mari
AU - Nenadic, Igor
AU - Nertney, Deborah A.
AU - Nestadt, Gerald
AU - Nicodemus, Kristin K.
AU - Nikitina-Zake, Liene
AU - Nisenbaum, Laura
AU - Nordin, Annelie
AU - O'Callaghan, Eadbhard
AU - O'Dushlaine, Colm
AU - O'Neill, F. Anthony
AU - Oh, Sang Yun
AU - Olincy, Ann
AU - Olsen, Line
AU - Van Os, Jim
AU - Pantelis, Christos
AU - Papadimitriou, George N.
AU - Papiol, Sergi
AU - Parkhomenko, Elena
AU - Pato, Michele T.
AU - Paunio, Tiina
AU - Pejovic-Milovancevic, Milica
AU - Perkins, Diana O.
AU - Pietiläinen, Olli
AU - Pimm, Jonathan
AU - Pocklington, Andrew J.
AU - Powell, John
AU - Price, Alkes
AU - Pulver, Ann E.
AU - Purcell, Shaun M.
AU - Quested, Digby
AU - Rasmussen, Henrik B.
AU - Reichenberg, Abraham
AU - Reimers, Mark A.
AU - Richards, Alexander L.
AU - Roffman, Joshua L.
AU - Roussos, Panos
AU - Ruderfer, Douglas M.
AU - Salomaa, Veikko
AU - Sanders, Alan R.
AU - Schall, Ulrich
AU - Schubert, Christian R.
AU - Schulze, Thomas G.
AU - Schwab, Sibylle G.
AU - Scolnick, Edward M.
AU - Scott, Rodney J.
AU - Seidman, Larry J.
AU - Shi, Jianxin
AU - Sigurdsson, Engilbert
AU - Silagadze, Teimuraz
AU - Silverman, Jeremy M.
AU - Sim, Kang
AU - Slominsky, Petr
AU - Smoller, Jordan W.
AU - So, Hon Cheong
AU - Spencer, Chris C.A.
AU - Stahl, Eli A.
AU - Stefansson, Hreinn
AU - Steinberg, Stacy
AU - Stogmann, Elisabeth
AU - Straub, Richard E.
AU - Strengman, Eric
AU - Strohmaier, Jana
AU - Stroup, T. Scott
AU - Subramaniam, Mythily
AU - Suvisaari, Jaana
AU - Svrakic, Dragan M.
AU - Szatkiewicz, Jin P.
AU - Söderman, Erik
AU - Thirumalai, Srinivas
AU - Toncheva, Draga
AU - Tosato, Sarah
AU - Veijola, Juha
AU - Waddington, John
AU - Walsh, Dermot
AU - Wang, Dai
AU - Wang, Qiang
AU - Webb, Bradley T.
AU - Weiser, Mark
AU - Wildenauer, Dieter B.
AU - Williams, Nigel M.
AU - Williams, Stephanie
AU - Witt, Stephanie H.
AU - Wolen, Aaron R.
AU - Wong, Emily H.M.
AU - Wormley, Brandon K.
AU - Xi, Hualin Simon
AU - Zai, Clement C.
AU - Zheng, Xuebin
AU - Zimprich, Fritz
AU - Wray, Naomi R.
AU - Stefansson, Kari
AU - Visscher, Peter M.
AU - Adolfsson, Rolf
AU - Andreassen, Ole A.
AU - Blackwood, Douglas H.R.
AU - Bramon, Elvira
AU - Buxbaum, Joseph D.
AU - Børglum, Anders D.
AU - Cichon, Sven
AU - Darvasi, Ariel
AU - Domenici, Enrico
AU - Ehrenreich, Hannelore
AU - Esko, Tõnu
AU - Gejman, Pablo V.
AU - Gill, Michael
AU - Gurling, Hugh
AU - Hultman, Christina M.
AU - Iwata, Nakao
AU - Jablensky, Assen V.
AU - Jönsson, Erik G.
AU - Kendler, Kenneth S.
AU - Kirov, George
AU - Knight, Jo
AU - Lencz, Todd
AU - Levinson, Douglas F.
AU - Li, Qingqin S.
AU - Liu, Jianjun
AU - Malhotra, Anil K.
AU - McCarroll, Steven A.
AU - McQuillin, Andrew
AU - Moran, Jennifer L.
AU - Mortensen, Preben B.
AU - Mowry, Bryan J.
AU - Nöthen, Markus M.
AU - Ophoff, Roel A.
AU - Owen, Michael J.
AU - Palotie, Aarno
AU - Pato, Carlos N.
AU - Petryshen, Tracey L.
AU - Posthuma, Danielle
AU - Rietschel, Marcella
AU - Riley, Brien P.
AU - Rujescu, Dan
AU - Sham, Pak C.
AU - Sklar, Pamela
AU - St Clair, David
AU - Weinberger, Daniel R.
AU - Wendland, Jens R.
AU - Werge, Thomas
AU - Daly, Mark J.
AU - Sullivan, Patrick F.
AU - O'Donovan, Michael C.
PY - 2014
Y1 - 2014
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84904804929&partnerID=8YFLogxK
U2 - 10.1038/nature13595
DO - 10.1038/nature13595
M3 - ???researchoutput.researchoutputtypes.contributiontojournal.article???
C2 - 25056061
AN - SCOPUS:84904804929
SN - 0028-0836
VL - 511
SP - 421
EP - 427
JO - Nature
JF - Nature
IS - 7510
ER -