Mapping genomic loci implicates genes and synaptic biology in schizophrenia

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....

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Veröffentlicht in:	Nature (London) Jg. 604; H. 7906; S. 502 - 508
Hauptverfasser:	Trubetskoy, Vassily, Qi, Ting, Bryois, Julien, Chen, Chia-Yen, Magnusson, Sigurdur, Kim, Minsoo, Adams, Mark, Agartz, Ingrid, Agerbo, Esben, Athanasiu, Lavinia, Bacanu, Silviu A., Calkins, Monica E., Carr, Vaughan J., Consoli, Angèle, Costas, Javier, Davis, Kenneth L., Degenhardt, Franziska, Dickerson, Faith, Frustaci, Alessandra, Giegling, Ina, Goldstein, Jacqueline I., González Peñas, Javier, Hayward, Caroline, Howrigan, Daniel P., Ikeda, Masashi, Kam-Thong, Tony, Kamatani, Yoichiro, Khrunin, Andrey, Kim, Sung-Wan, Klovins, Janis, Kubo, Michiaki, Lazzeroni, Laura C., Lehrer, Douglas S., Li, Miaoxin, Liu, Chih-Min, Loughland, Carmel M., Mallet, Jacques, Mattheisen, Manuel, McCarley, Robert W., Meier, Sandra, Milani, Lili, Milanova, Vihra, Morley, Christopher P., Muntané, Gerard, Murphy, Kieran C., Olincy, Ann, Papadimitriou, George N., Parellada, Mara, Paunio, Tiina, Pellegrino, Renata, Radant, Allen D., Saker-Delye, Safaa, Sanjuan, Julio, Savitz, Adam, Seidman, Larry J., Sim, Kang, Stain, Helen J., Streit, Fabian, Strengman, Eric, Ta, Thi Minh Tam, Terao, Chikashi, Toncheva, Draga, Veijola, Juha, Waddington, John, Walter, Henrik, Webb, Bradley T., Wu, Jing Qin, Xu, Zhida, Ayub, Muhammad, Bertolino, Alessandro, Buccola, Nancy G., Byerley, William F., Hwu, Hai-Gwo, McCarroll, Steven A., Neil, Amanda L., Smoller, Jordan W., Vilella, Elisabet, Xu, Shuhua, Braff, David, Buxbaum, Joseph D., Cichon, Sven, Ehrenreich, Hannelore, Escott-Price, Valentina, Esko, Tõnu, Iwata, Nakao, Kirov, George, Lee, Jimmy, Li, Qingqin S., Malhotra, Anil K., Malhotra, Dheeraj, McQuillin, Andrew, Morgan, Vera A., Nöthen, Markus M., Saka, Meram C., Sanders, Alan R., Serretti, Alessandro, van Os, Jim, Yu, Xin, Neale, Benjamin M., Ripke, Stephan
Format:	Journal Article
Sprache:	Englisch
Veröffentlicht:	London Nature Publishing Group UK 21.04.2022 Nature Publishing Group
Schlagworte:	45/43 631/208/205/2138 631/378/1689 631/378/2583 692/699/476/1799 Alleles Biological activity Central nervous system Consortia Datasets Disorders Gender differences Gene loci Gene mapping Genes Genetic Predisposition to Disease - genetics Genome-wide association studies Genome-Wide Association Study Genomes Genomics Glutamate receptors Heritability Humanities and Social Sciences Humans Liability Life Sciences Mental disorders multidisciplinary Neural coding Neurodevelopmental disorders Ontology Pathophysiology Peptide mapping Polymorphism, Single Nucleotide - genetics Schizophrenia Schizophrenia - genetics Science Science (multidisciplinary) Synaptic transmission
ISSN:	0028-0836, 1476-4687, 1476-4687
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Zusammenfassung:	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. A genome-wide association study including over 76,000 individuals with schizophrenia and over 243,000 control individuals identifies common variant associations at 287 genomic loci, and further fine-mapping analyses highlight the importance of genes involved in synaptic processes.
Bibliographie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23 GWAS meta-analyses (SA, GP, SR, VT); Replication data (SMag, HS, KSt [deCODE]); African-American and Latino sample analyses (EGA, TB, GG, SR, VT); Bioinformatics (JBr, JCH, AFP, AJP, DPos, PFS, KW, SynGO consortium); Comparison of males and females (SR, JSi, VT, PMV); Heritability and Polygenic Prediction (OAA, OF, TG, HHu, BMN, MOD, AFP, ALR, SR, VT, JTRW, NRW, JZ); Phenotype stratification (CAD, EVa); Cellular and Tissue analysis (JBr, MOD, DPos, PFS, JTRW, KW); Gene Ontology (JCH, MOD, AFP, AJP, DPos, JTRW, KW); Fine-mapping (CB, MJD, HHu, MLa, MOD, GP, AFP, MP, SR, JTRW); SMR (LSH, MOD, TQ, NRW, YW, JY); Hi-C (DPos, ALR, PFS, JTRW, KW); Other TWAS (MJG, LSH, MKi, PR, GV, WZha); Integration of fine-mapping, gene expression, Hi-C informatics, rare variants (LSH, MOD, AFP, TQ, ALR, PFS, JTRW, NRW, YW, JY); SynGO (FK, MOD, AFP, ABS, MV, JTRW); Additional statistical advice (PAH). The remaining authors contributed to the recruitment, phenotyping, genotyping, or data processing for the contributing components of the meta-analysis, or provided other forms of functional annotation data. Primary drafting and editing of the manuscript was coordinated by SR, JTRW, and MOD. The primary draft sections were written by JBr, CYC, CAD, LSH, HHu, BMN, MOD, MJO, AFP, AJP, SR, ABS, PFS, VT, EVa, MV, JTRW, NRW, JY. Additional edits were from OAA, MJD, KSK. Numerous other authors provided edits, comments and suggestions, and all authors saw and approved the contents of the manuscript. The Chair of the Psychiatric Genomics Consortium is PFS and the Schizophrenia Working Group of the PGC is led MOD and JTRW. AUTHOR CONTRIBUTIONS The management group for this paper was led by MOD and JTRW with SR responsible for primary analytic matters supported by BMN and MJD. The management group was comprised of a subset of the PIs of the component studies, bioinformaticians, and analysts and were responsible for study design, conduct, management, primary and final interpretation and included OAA, BTB, SIB, ADB, DB, EB, SC, ACor, DCu, MJD, MDF, ED, HE, AHF, PVG, MGi, SJG, KSH, HHu, NI, RSK, KSK, JAK, JLe, TL, DFL, JLi, AMcI, AMcQ, VAM, DWM, BJM, BMN, MOD, RAO, MJO, AP, DPos, SQ, BPR, SR, DR, SGS, ASe, YS, EAS, PFS, MTT, MPV, JTRW, DRW, TW, NRW, XY, WY. These authors jointly supervised this work: Stephan Ripke, James T. R. Walters, Michael C. O‘Donovan Deceased: Robert W. McCarley
ISSN:	0028-0836 1476-4687 1476-4687
DOI:	10.1038/s41586-022-04434-5