Mapping genomic loci implicates genes and synaptic biology in schizophrenia

Scientific publication - Journal Article uoadl:3219140 78 Read counter

Unit:
NKUA research material
Title:
Mapping genomic loci implicates genes and synaptic biology in schizophrenia
Languages of Item:
English
Abstract:
Schizophrenia has a heritability of 60-80%1, much of which is attributable to common risk alleles. Here, in a two-stage genome-wide association study of up to 76,755 individuals with schizophrenia and 243,649 control individuals, we report common variant associations at 287 distinct genomic loci. Associations were concentrated in genes that are expressed in excitatory and inhibitory neurons of the central nervous system, but not in other tissues or cell types. Using fine-mapping and functional genomic data, we identify 120 genes (106 protein-coding) that are likely to underpin associations at some of these loci, including 16 genes with credible causal non-synonymous or untranslated region variation. We also implicate fundamental processes related to neuronal function, including synaptic organization, differentiation and transmission. Fine-mapped candidates were enriched for genes associated with rare disruptive coding variants in people with schizophrenia, including the glutamate receptor subunit GRIN2A and transcription factor SP4, and were also enriched for genes implicated by such variants in neurodevelopmental disorders. We identify biological processes relevant to schizophrenia pathophysiology; show convergence of common and rare variant associations in schizophrenia and neurodevelopmental disorders; and provide a resource of prioritized genes and variants to advance mechanistic studies. © 2022. The Author(s), under exclusive licence to Springer Nature Limited.
Publication year:
2022
Authors:
Trubetskoy, V.
Pardiñas, A.F.
Qi, T.
Panagiotaropoulou, G.
Awasthi, S.
Bigdeli, T.B.
Bryois, J.
Chen, C.-Y.
Dennison, C.A.
Hall, L.S.
Lam, M.
Watanabe, K.
Frei, O.
Ge, T.
Harwood, J.C.
Koopmans, F.
Magnusson, S.
Richards, A.L.
Sidorenko, J.
Wu, Y.
Zeng, J.
Grove, J.
Kim, M.
Li, Z.
Voloudakis, G.
Zhang, W.
Adams, M.
Agartz, I.
Atkinson, E.G.
Agerbo, E.
Al Eissa, M.
Albus, M.
Alexander, M.
Alizadeh, B.Z.
Alptekin, K.
Als, T.D.
Amin, F.
Arolt, V.
Arrojo, M.
Athanasiu, L.
Azevedo, M.H.
Bacanu, S.A.
Bass, N.J.
Begemann, M.
Belliveau, R.A.
Bene, J.
Benyamin, B.
Bergen, S.E.
Blasi, G.
Bobes, J.
Bonassi, S.
Braun, A.
Bressan, R.A.
Bromet, E.J.
Bruggeman, R.
Buckley, P.F.
Buckner, R.L.
Bybjerg-Grauholm, J.
Cahn, W.
Cairns, M.J.
Calkins, M.E.
Carr, V.J.
Castle, D.
Catts, S.V.
Chambert, K.D.
Chan, R.C.K.
Chaumette, B.
Cheng, W.
Cheung, E.F.C.
Chong, S.A.
Cohen, D.
Consoli, A.
Cordeiro, Q.
Costas, J.
Curtis, C.
Davidson, M.
Davis, K.L.
de Haan, L.
Degenhardt, F.
DeLisi, L.E.
Demontis, D.
Dickerson, F.
Dikeos, D.
Dinan, T.
Djurovic, S.
Duan, J.
Ducci, G.
Dudbridge, F.
Eriksson, J.G.
Fañanás, L.
Faraone, S.V.
Fiorentino, A.
Forstner, A.
Frank, J.
Freimer, N.B.
Fromer, M.
Frustaci, A.
Gadelha, A.
Genovese, G.
Gershon, E.S.
Giannitelli, M.
Giegling, I.
Giusti-Rodríguez, P.
Godard, S.
Goldstein, J.I.
González Peñas, J.
González-Pinto, A.
Gopal, S.
Gratten, J.
Green, M.F.
Greenwood, T.A.
Guillin, O.
Gülöksüz, S.
Gur, R.E.
Gur, R.C.
Gutiérrez, B.
Hahn, E.
Hakonarson, H.
Haroutunian, V.
Hartmann, A.M.
Harvey, C.
Hayward, C.
Henskens, F.A.
Herms, S.
Hoffmann, P.
Howrigan, D.P.
Ikeda, M.
Iyegbe, C.
Joa, I.
Julià, A.
Kähler, A.K.
Kam-Thong, T.
Kamatani, Y.
Karachanak-Yankova, S.
Kebir, O.
Keller, M.C.
Kelly, B.J.
Khrunin, A.
Kim, S.-W.
Klovins, J.
Kondratiev, N.
Konte, B.
Kraft, J.
Kubo, M.
Kučinskas, V.
Kučinskiene, Z.A.
Kusumawardhani, A.
Kuzelova-Ptackova, H.
Landi, S.
Lazzeroni, L.C.
Lee, P.H.
Legge, S.E.
Lehrer, D.S.
Lencer, R.
Lerer, B.
Li, M.
Lieberman, J.
Light, G.A.
Limborska, S.
Liu, C.-M.
Lönnqvist, J.
Loughland, C.M.
Lubinski, J.
Luykx, J.J.
Lynham, A.
Macek, M., Jr
Mackinnon, A.
Magnusson, P.K.E.
Maher, B.S.
Maier, W.
Malaspina, D.
Mallet, J.
Marder, S.R.
Marsal, S.
Martin, A.R.
Martorell, L.
Mattheisen, M.
McCarley, R.W.
McDonald, C.
McGrath, J.J.
Medeiros, H.
Meier, S.
Melegh, B.
Melle, I.
Mesholam-Gately, R.I.
Metspalu, A.
Michie, P.T.
Milani, L.
Milanova, V.
Mitjans, M.
Molden, E.
Molina, E.
Molto, M.D.
Mondelli, V.
Moreno, C.
Morley, C.P.
Muntané, G.
Murphy, K.C.
Myin-Germeys, I.
Nenadić, I.
Nestadt, G.
Nikitina-Zake, L.
Noto, C.
Nuechterlein, K.H.
O'Brien, N.L.
O'Neill, F.A.
Oh, S.-Y.
Olincy, A.
Ota, V.K.
Pantelis, C.
Papadimitriou, G.N.
Parellada, M.
Paunio, T.
Pellegrino, R.
Periyasamy, S.
Perkins, D.O.
Pfuhlmann, B.
Pietiläinen, O.
Pimm, J.
Porteous, D.
Powell, J.
Quattrone, D.
Quested, D.
Radant, A.D.
Rampino, A.
Rapaport, M.H.
Rautanen, A.
Reichenberg, A.
Roe, C.
Roffman, J.L.
Roth, J.
Rothermundt, M.
Rutten, B.P.F.
Saker-Delye, S.
Salomaa, V.
Sanjuan, J.
Santoro, M.L.
Savitz, A.
Schall, U.
Scott, R.J.
Seidman, L.J.
Sharp, S.I.
Shi, J.
Siever, L.J.
Sigurdsson, E.
Sim, K.
Skarabis, N.
Slominsky, P.
So, H.-C.
Sobell, J.L.
Söderman, E.
Stain, H.J.
Steen, N.E.
Steixner-Kumar, A.A.
Stögmann, E.
Stone, W.S.
Straub, R.E.
Streit, F.
Strengman, E.
Stroup, T.S.
Subramaniam, M.
Sugar, C.A.
Suvisaari, J.
Svrakic, D.M.
Swerdlow, N.R.
Szatkiewicz, J.P.
Ta, T.M.T.
Takahashi, A.
Terao, C.
Thibaut, F.
Toncheva, D.
Tooney, P.A.
Torretta, S.
Tosato, S.
Tura, G.B.
Turetsky, B.I.
Üçok, A.
Vaaler, A.
van Amelsvoort, T.
van Winkel, R.
Veijola, J.
Waddington, J.
Walter, H.
Waterreus, A.
Webb, B.T.
Weiser, M.
Williams, N.M.
Witt, S.H.
Wormley, B.K.
Wu, J.Q.
Xu, Z.
Yolken, R.
Zai, C.C.
Zhou, W.
Zhu, F.
Zimprich, F.
Atbaşoğlu, E.C.
Ayub, M.
Benner, C.
Bertolino, A.
Black, D.W.
Bray, N.J.
Breen, G.
Buccola, N.G.
Byerley, W.F.
Chen, W.J.
Cloninger, C.R.
Crespo-Facorro, B.
Donohoe, G.
Freedman, R.
Galletly, C.
Gandal, M.J.
Gennarelli, M.
Hougaard, D.M.
Hwu, H.-G.
Jablensky, A.V.
McCarroll, S.A.
Moran, J.L.
Mors, O.
Mortensen, P.B.
Müller-Myhsok, B.
Neil, A.L.
Nordentoft, M.
Pato, M.T.
Petryshen, T.L.
Pirinen, M.
Pulver, A.E.
Schulze, T.G.
Silverman, J.M.
Smoller, J.W.
Stahl, E.A.
Tsuang, D.W.
Vilella, E.
Wang, S.-H.
Xu, S.
Adolfsson, R.
Arango, C.
Baune, B.T.
Belangero, S.I.
Børglum, A.D.
Braff, D.
Bramon, E.
Buxbaum, J.D.
Campion, D.
Cervilla, J.A.
Cichon, S.
Collier, D.A.
Corvin, A.
Curtis, D.
Forti, M.D.
Domenici, E.
Ehrenreich, H.
Escott-Price, V.
Esko, T.
Fanous, A.H.
Gareeva, A.
Gawlik, M.
Gejman, P.V.
Gill, M.
Glatt, S.J.
Golimbet, V.
Hong, K.S.
Hultman, C.M.
Hyman, S.E.
Iwata, N.
Jönsson, E.G.
Kahn, R.S.
Kennedy, J.L.
Khusnutdinova, E.
Kirov, G.
Knowles, J.A.
Krebs, M.-O.
Laurent-Levinson, C.
Lee, J.
Lencz, T.
Levinson, D.F.
Li, Q.S.
Liu, J.
Malhotra, A.K.
Malhotra, D.
McIntosh, A.
McQuillin, A.
Menezes, P.R.
Morgan, V.A.
Morris, D.W.
Mowry, B.J.
Murray, R.M.
Nimgaonkar, V.
Nöthen, M.M.
Ophoff, R.A.
Paciga, S.A.
Palotie, A.
Pato, C.N.
Qin, S.
Rietschel, M.
Riley, B.P.
Rivera, M.
Rujescu, D.
Saka, M.C.
Sanders, A.R.
Schwab, S.G.
Serretti, A.
Sham, P.C.
Shi, Y.
St Clair, D.
Stefánsson, H.
Stefansson, K.
Tsuang, M.T.
van Os, J.
Vawter, M.P.
Weinberger, D.R.
Werge, T.
Wildenauer, D.B.
Yu, X.
Yue, W.
Holmans, P.A.
Pocklington, A.J.
Roussos, P.
Vassos, E.
Verhage, M.
Visscher, P.M.
Yang, J.
Posthuma, D.
Andreassen, O.A.
Kendler, K.S.
Owen, M.J.
Wray, N.R.
Daly, M.J.
Huang, H.
Neale, B.M.
Sullivan, P.F.
Ripke, S.
Walters, J.T.R.
O'Donovan, M.C.
Indonesia Schizophrenia Consortium
PsychENCODE
Psychosis Endophenotypes International Consortium
SynGO Consortium
Schizophrenia Working Group of the Psychiatric Genomics Consortium
Journal:
Nature Metabolism
Publisher:
NLM (Medline)
Volume:
604
Number:
7906
Pages:
502-508
Keywords:
allele; genetic predisposition; genetics; genome-wide association study; genomics; human; schizophrenia; single nucleotide polymorphism, Alleles; Genetic Predisposition to Disease; Genome-Wide Association Study; Genomics; Humans; Polymorphism, Single Nucleotide; Schizophrenia
Official URL (Publisher):
DOI:
10.1038/s41586-022-04434-5
The digital material of the item is not available.