Using brain cell-type-specific protein interactomes to interpret neurodevelopmental genetic signals in schizophrenia.

Autor:	Hsu YH; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.; Novo Nordisk Foundation Center for Genomic Mechanisms of Disease, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.; Department of Surgery, Massachusetts General Hospital, Boston, MA 02114, USA., Pintacuda G; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.; Novo Nordisk Foundation Center for Genomic Mechanisms of Disease, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.; Harvard Stem Cell Institute and Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA., Liu R; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.; Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA., Nacu E; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.; Harvard Stem Cell Institute and Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA., Kim A; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.; Department of Computer Science, Johns Hopkins University, Baltimore, MD 21218, USA., Tsafou K; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA., Petrossian N; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA., Crotty W; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA., Suh JM; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA., Riseman J; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA., Martin JM; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA., Biagini JC; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA., Mena D; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA., Ching JKT; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA., Malolepsza E; Genomics Platform, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA., Li T; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA., Singh T; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.; Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA., Ge T; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.; Psychiatric and Neurodevelopmental Genetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA., Egri SB; Proteomics Platform, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA., Tanenbaum B; Proteomics Platform, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA., Stanclift CR; Proteomics Platform, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA., Apffel AM; Proteomics Platform, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA., Carr SA; Proteomics Platform, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA., Schenone M; Proteomics Platform, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA., Jaffe J; Proteomics Platform, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA., Fornelos N; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.; Novo Nordisk Foundation Center for Genomic Mechanisms of Disease, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.; Department of Surgery, Massachusetts General Hospital, Boston, MA 02114, USA., Huang H; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.; Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA., Eggan KC; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.; Harvard Stem Cell Institute and Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA., Lage K; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.; Novo Nordisk Foundation Center for Genomic Mechanisms of Disease, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.; Department of Surgery, Massachusetts General Hospital, Boston, MA 02114, USA.; Institute of Biological Psychiatry, Mental Health Centre Sct. Hans, Mental Health Services Copenhagen, 4000 Roskilde, Denmark.
Jazyk:	angličtina
Zdroj:	IScience [iScience] 2023 Apr 18; Vol. 26 (5), pp. 106701. Date of Electronic Publication: 2023 Apr 18 (Print Publication: 2023).
DOI:	10.1016/j.isci.2023.106701
Abstrakt:	Genetics have nominated many schizophrenia risk genes and identified convergent signals between schizophrenia and neurodevelopmental disorders. However, functional interpretation of the nominated genes in the relevant brain cell types is often lacking. We executed interaction proteomics for six schizophrenia risk genes that have also been implicated in neurodevelopment in human induced cortical neurons. The resulting protein network is enriched for common variant risk of schizophrenia in Europeans and East Asians, is down-regulated in layer 5/6 cortical neurons of individuals affected by schizophrenia, and can complement fine-mapping and eQTL data to prioritize additional genes in GWAS loci. A sub-network centered on HCN1 is enriched for common variant risk and contains proteins (HCN4 and AKAP11) enriched for rare protein-truncating mutations in individuals with schizophrenia and bipolar disorder. Our findings showcase brain cell-type-specific interactomes as an organizing framework to facilitate interpretation of genetic and transcriptomic data in schizophrenia and its related disorders. Competing Interests: K.C.E. is a co-founder of Q-State Biosciences, Quralis, and Enclear, and currently employed at BioMarin Pharmaceutical. Other authors declare no competing interests. (© 2023 The Authors.)
Databáze:	MEDLINE
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