Mapping genomic loci prioritises genes and implicates synaptic biology in schizophrenia

Trubetskoy, Vassily, Pardinas, Antonio, Qi, Ting, Panagiotaropoulou, Georgia, Awasthi, Swapnil, Bigdeli, Tim B., Bryois, Julien, Chen, Chia-Yen, Dennison, Charlotte A., Hall, Lynsey, Lam, Max, Watanabe, Kyoto, Frei, Oleksandr, Ge, Tian, Harwood, Janet C., Koopmans, Frank, Magnusson, Sigurdur, Richards, Alexander L., Sidorenko, Julia, Wu, Yang, Zeng, Jian, Grove, Jakob, Kim, Minsoo, Li, Zhiqiang, Voloudakis, Georgios, Zhang, Wen, Adams, Mark, Agartz, Ingrid, Atkinson, Elizabeth G., Agerbo, Esben, Al Eissa, Mariam, Albus, Margot, Alexander, Madeline, Alizadeh, Behrooz Z., Alptekin, Köksal, Als, Thomas D., Amin, Farooq, Arolt, Volker, Arrojo, Manuel, Athanasiu, Lavinia, Azevedo, Maria Helena, Bacanu, Silviu A., Bass, Nicholas J., Begemann, Martin, Belliveau, Richard A., Bene, Judit, Benyamin, Beben, Bergen, Sarah E., Blasi, Giuseppe, Bobes, Julio, Bonassi, Stefano, Braun, Alice, Affonseca Bressan, Rodrigo, Bromet, Evelyn J., Bruggeman, Richard, Buckley, Peter F., Buckner, Randy L., Bybjerg-Grauholm, Jonas, Cahn, Wiepke, Cairns, Murray J., Calkins, Monica E., Carr, Vaughan J., Castle, David, Catts, Stanley V., Chambert, Kimberley D., Chan, Raymond C. K., Chaumette, Boris, Cheng, Wei, Cheung, Eric F. C., Chong, Siow Ann, Cohen, David, Consoli, Angele, Cordeiro, Quirino, Costas, Javier, Curtis, Charles, Davidson, Michael, Davis, Kenneth L., De Haan, Lieuwe, Degenhardt, Franziska, DeLisi, Lynn E., Demontis, Ditte, Dickerson, Faith, Dikeos, Dimitris, Dinan, Timothy, Djurovic, Srdjan, Duan, Jubao, Ducci, Giuseppe, Dudbridge, Frank, Eriksson, Johan G., Fananas, Lourdes, Faraone, Stephen V., Fiorentino, Alessia, Forstner, Andreas, Frank, Josef, Freimer, Nelson B., Fromer, Menachem, Frustaci, Alessandra, Gadelha, Ary, Genovese, Giulio, Gershon, Elliot S., Giannitelli, Marianna, Giegling, Ina, Giusti-Rodríguez, Paola, Godard, Stephanie, Goldstein, Jacqueline I., González Peñas, Javier, González-Pinto, Ana, Gopa, Srihari, Gratten, Jacob, Green, Michael F., Greenwood, Tiffany A., Guillin, Olivier, Gülöksüz, Sinan, Gur, Raquel E., Gur, Ruben C., Gutiérrez, Blanca, Hahn, Eric, Hakonarson, Hakon, Haroutunian, Vahram, Hartmann, Annette M., Harvey, Carol, Hayward, Caroline, Henskens, Frans A., Herms, Stefan, Hoffmann, Per, Howrigan, Daniel P., Ikeda, Masashi, Iyegbe, Conrad, Joa, Inge, Julià, Antonio, Kähler, Anna K., Kam-Thong, Tony, Kamatani, Yoichiro, Karachanak-Yankova, Sena, Kebir, Oussama, Keller, Matthew C., Kelly, Brian J., Khrunin, Andrey, Kim, Sung-Wan, Klovins, Janis, Kondratiev, Nikolay, Konte, Bettina, Kraft, Julia, Kubo, Michiaki, Kučinskas, Vaidutis, Ausrele Kučinskiene, Zita, Kusumawardhani, Agung, Kuzelov a-Ptackova, Hana, Land, Stefano, Lazzeroni, Laura C., Lee, Phil H., Legge, Sophie E., Lehrer, Douglas S., Lencer, Rebecca, Lerer, Bernard, Li, Miaoxin, Lieberman, Jeffrey, Light, Gregory A., Limborska, Svetlana, Liu, Chih-Min, Lönnqvist, Jouko, Loughland, Carmel M., Lubiski, Jan, Luykx, Jurjen J., Lynham, Amy, Macel Jr., Milan, Mackinnon, Andrew, Magnusson, Patrik K. E., Maher, Brion S., Maier, Wolfgang, Malaspina, Dolores, Mallet, Jacques, Marder, Stephen R., Marsal, Sara, Martin, Alicia R., Martorell, Lourdes, Mattheisen, Manuel, McCarley, Robert W., McDonald, Colm, McGrath, John J., Medeiros, Helena, Meier, Sandra, Melegh, Bela, Melle, Ingrid, Mesholam-Gately, Raquelle I., Metspalu, Andres, Michie, Patricia T., Milani, Lili, Milanova, Vihara, Mitjans, Marina, Molden, Espen, Molina, Esther, Molto, María Dolores, Mondelli, Valeria, Moreno, Carmen, Morley, Christopher P., Muntané, Gerard, Murphy, Kieran C., Myin-Germeys, Inez, Nenadić, Igor, Nestadt, Gerald, Nikitina-Zake, Liene, Noto, Cristiano, Neuchterlein, Keith H., O'Brien, Niamh Louise, O'Neill, F. Anthony., Oh, Sang-Yun, Olincy, Ann, Ota, Vanessa Kiyomi, Pantelis, Christos, Papadimitrou, George N., Paredella, Mara, Paurio, Tiina, Pellegrino, Renata, Periyasamy, Sathish, Perkins, Diana O., Pfuhlmann, Bruno, Pietilainen, Olli, Pimm, Jonathan, Porteous, David, Powell, John, Quattrone, Diego, Quested, Digby, Radant, Allen D., Rampino, Antonio, Rapaport, Mark H., Rautanen, Anna, Reichenberg, Abraham, Roe, Cheryl, Roffman, Joshua L., Roth, Julian, Rothermundt, Matthias and Rutten, Bart P. F. 2022. Mapping genomic loci prioritises genes and implicates synaptic biology in schizophrenia. Nature 604 , pp. 502-508. 10.1038/s41586-022-04434-5 Item availability restricted.

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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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG)
Additional Information:	Bray, Nicholas BrayN3@cardiff.ac.uk A2183033H Psychosis And MAJOR Affective Disorders - PSMAD Click here to remove this relation. The item itself will not be deleted. Dennison, Charlotte DennisonC1@cardiff.ac.uk A2339759H Neurodevelopment - NUDEV Click here to remove this relation. The item itself will not be deleted. Escott-Price, Valentina EscottPriceV@cardiff.ac.uk A015705M Bioinformatics And Biostatistics - BIOIS Click here to remove this relation. The item itself will not be deleted. Hall, Lynsey HallL10@cardiff.ac.uk A2358735U Psychosis And MAJOR Affective Disorders - PSMAD Click here to remove this relation. The item itself will not be deleted. Harwood, Janet HarwoodJC@cardiff.ac.uk A3372827 Neurodegeneration - NUDEG Click here to remove this relation. The item itself will not be deleted. Holmans, Peter HolmansPA@cardiff.ac.uk A0466487 Bioinformatics And Biostatistics - BIOIS Click here to remove this relation. The item itself will not be deleted. Kirov, George Kirov@cardiff.ac.uk A0312379 Psychosis And MAJOR Affective Disorders - PSMAD Click here to remove this relation. The item itself will not be deleted. Legge, Sophie LeggeSE8@cardiff.ac.uk A1443447 Psychosis And MAJOR Affective Disorders - PSMAD Click here to remove this relation. The item itself will not be deleted. Lynham, Amy LynhamAJ@cardiff.ac.uk A158739J Psychosis And MAJOR Affective Disorders - PSMAD Click here to remove this relation. The item itself will not be deleted. O'Donovan, Michael ODonovanMC@cardiff.ac.uk A038895E Psychosis And MAJOR Affective Disorders - PSMAD Click here to remove this relation. The item itself will not be deleted. Owen, Michael OwenMJ@cardiff.ac.uk A069868J Psychosis And MAJOR Affective Disorders - PSMAD Click here to remove this relation. The item itself will not be deleted. Pardinas, Antonio PardinasA@cardiff.ac.uk A1835567O Psychosis And MAJOR Affective Disorders - PSMAD Click here to remove this relation. The item itself will not be deleted. Pocklington, Andrew PocklingtonAJ@cardiff.ac.uk A164850I Bioinformatics And Biostatistics - BIOIS Click here to remove this relation. The item itself will not be deleted. Richards, Alexander RichardsAL1@cardiff.ac.uk A092272D Psychosis And MAJOR Affective Disorders - PSMAD Click here to remove this relation. The item itself will not be deleted. Walters, James WaltersJT@cardiff.ac.uk A0230062 Psychosis And MAJOR Affective Disorders - PSMAD Click here to remove this relation. The item itself will not be deleted. Williams, Nigel WilliamsNM@cardiff.ac.uk A0001924 Neurodegeneration - NUDEG
Publisher:	Nature Research
ISSN:	0028-0836
Date of First Compliant Deposit:	14 January 2022
Date of Acceptance:	10 January 2022
Last Modified:	04 Aug 2022 17:01
URI:	https://orca.cardiff.ac.uk/id/eprint/146689

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