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Mapping genomic loci implicates genes and synaptic biology in schizophrenia

文献类型:期刊论文

AuthorTrubetskoy, Vassily406; Pardinas, Antonio F.405; Qi, Ting403,404; Panagiotaropoulou, Georgia406; Awasthi, Swapnil406; Bigdeli, Tim B.400,401,402; Bryois, Julien399; Chen, Chia-Yen396,397,398; Dennison, Charlotte A.405; Hall, Lynsey S.405
SourceNATURE
Issued Date2022-04-21
Volume604Issue:7906Pages:502-+
ISSN0028-0836
DOI10.1038/s41586-022-04434-5
Corresponding AuthorWalter, Henrik(WaLtersJT@cardiff.ac.uk) ; Ripke, Stephan(sripke@broadinstitute.org) ; O'Donovan, Michael C.(ODonovanMC@cardiff.ac.uk)
English AbstractSchizophrenia 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 identify120 genes (106 protein-coding) that are likely to underpin associations at some of these loci, including16 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 factorSP4, 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.
Indexed TypeSCI
WOS KeywordASSOCIATION ; VARIANTS ; INTEGRATION ; DISEASE ; ARCHITECTURE ; INDIVIDUALS ; STATISTICS ; MUTATIONS ; PROFILE ; RISK
Funding ProjectNational Institute of Mental Health (USA)[U01MH109514] ; Medical Research Council Centre[MR/L010305/1] ; National Natural Science Foundation of China (NSFC)[31525014] ; National Natural Science Foundation of China (NSFC)[91731303] ; National Natural Science Foundation of China (NSFC)[31771388] ; National Natural Science Foundation of China (NSFC)[31961130380] ; National Natural Science Foundation of China (NSFC)[32041008] ; UK Royal Society-Newton Advanced Fellowship[NAF\R1\191094] ; Key Research Program of Frontier Sciences[QYZDJ-SSW-SYS009] ; Strategic Priority Research Program of the Chinese Academy of Sciences[XDB38000000] ; Shanghai Municipal Science and Technology Major Project[2017SHZDZX01] ; Research Council of Norway[283798] ; Research Council of Norway[262656] ; Research Council of Norway[248980] ; Research Council of Norway[273291] ; Research Council of Norway[248828] ; Research Council of Norway[248778] ; Research Council of Norway[223273] ; KG Jebsen Stiftelsen ; South-East Norway Health Authority ; EU H2020[847776] ; National Scientific Research Program (NKFIH)[K 138669] ; European Union[602805] ; European Union's Horizon 2020 research and innovation programme[667302] ; European Union's Horizon 2020 research and innovation programme[728018] ; NIMH[5R01MH101519] ; NIMH[U01 MH109536-01] ; NIMH[K01MH121659] ; FAPESP (Fundacao de Amparo a Pesquisa do Estado de Sao Paulo)[2010/08968-6] ; FAPESP (Fundacao de Amparo a Pesquisa do Estado de Sao Paulo)[2014/07280-1 2011/50740-5] ; National Medical Research Council Translational and Clinical Research Flagship Programme[NMRC/TCR/003/2008] ; Spanish Ministry of Science and Innovation, Instituto de Salud Carlos III[SAM16PE07CP1] ; Spanish Ministry of Science and Innovation, Instituto de Salud Carlos III[PI16/02012] ; Spanish Ministry of Science and Innovation, Instituto de Salud Carlos III[PI19/024] ; ERDF Funds from the European Commission , `A way of making Europe' ; CIBERSAM ; Madrid Regional Government[B2017/BMD-3740 AGES-CM-2] ; European Union Structural Funds ; European Union ; European Union H2020 Program under the Innovative Medicines Initiative 2 Joint Undertaking[115916] ; European Union H2020 Program under the Innovative Medicines Initiative 2 Joint Undertaking[777394] ; Fundacion Familia Alonso ; Fundacion Alicia Koplowitz ; National Institute of Health Research UK[NIHR200756] ; Mental Health Research UK John Grace QC Scholarship 2018 ; ESRC collaborative award 2020 ; BMA Margaret Temple Fellowship 2016 ; Medical Research Council New Investigator Award[G0901310] ; MRC Centenary Award[G1100583] ; MRC project grant[G1100583] ; National Institute of Health Research UK post-doctoral fellowship[PDA/02/06/016] ; NARSAD Young Investigator award 2005 ; Wellcome Trust Research Training Fellowship ; Wellcome Trust Case Control Consortium awards[085475/B/08/Z] ; Wellcome Trust Case Control Consortium awards[085475/Z/08/Z] ; European Commission Horizon 2020[747429] ; NIHR Biomedical Research Centre for Mental Health at the South London and Maudsley NHS Foundation Trust and King's College London ; NIHR Biomedical Research Centre at University College London Hospitals NHS Foundation Trust ; European Regional Development Fund (ERDF)-Valencian Community 2014-2020, Spain ; University College London (UCLH BRC -Mental Health Theme) ; [LM2018132] ; [CZ.02.1.01/0.0/0.0/18_046/0015515] ; [IP6003 -VZFNM00064203] ; [G0800509]
WOS Research AreaScience & Technology - Other Topics
Language英语
WOS IDWOS:000779867500004
PublisherNATURE PORTFOLIO
Funding OrganizationNational Institute of Mental Health (USA) ; Medical Research Council Centre ; National Natural Science Foundation of China (NSFC) ; UK Royal Society-Newton Advanced Fellowship ; Key Research Program of Frontier Sciences ; Strategic Priority Research Program of the Chinese Academy of Sciences ; Shanghai Municipal Science and Technology Major Project ; Research Council of Norway ; KG Jebsen Stiftelsen ; South-East Norway Health Authority ; EU H2020 ; National Scientific Research Program (NKFIH) ; European Union ; European Union's Horizon 2020 research and innovation programme ; NIMH ; FAPESP (Fundacao de Amparo a Pesquisa do Estado de Sao Paulo) ; National Medical Research Council Translational and Clinical Research Flagship Programme ; Spanish Ministry of Science and Innovation, Instituto de Salud Carlos III ; ERDF Funds from the European Commission , `A way of making Europe' ; CIBERSAM ; Madrid Regional Government ; European Union Structural Funds ; European Union ; European Union H2020 Program under the Innovative Medicines Initiative 2 Joint Undertaking ; Fundacion Familia Alonso ; Fundacion Alicia Koplowitz ; National Institute of Health Research UK ; Mental Health Research UK John Grace QC Scholarship 2018 ; ESRC collaborative award 2020 ; BMA Margaret Temple Fellowship 2016 ; Medical Research Council New Investigator Award ; MRC Centenary Award ; MRC project grant ; National Institute of Health Research UK post-doctoral fellowship ; NARSAD Young Investigator award 2005 ; Wellcome Trust Research Training Fellowship ; Wellcome Trust Case Control Consortium awards ; European Commission Horizon 2020 ; NIHR Biomedical Research Centre for Mental Health at the South London and Maudsley NHS Foundation Trust and King's College London ; NIHR Biomedical Research Centre at University College London Hospitals NHS Foundation Trust ; European Regional Development Fund (ERDF)-Valencian Community 2014-2020, Spain ; University College London (UCLH BRC -Mental Health Theme)