Gene Expression Elucidates Functional Impact of Polygenic Risk for Schizophrenia

By Menachem Fromer, P. Roussos, S. Sieberts, Jessica S. Johnson, D. Kavanagh, T. Perumal, D. Ruderfer, Edwin C. T. Oh, A. Topol, Hardik Shah and 48 more. Nature Neuroscience, 2016

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Over 100 genetic loci harbor schizophrenia-associated variants, yet how these variants confer liability is uncertain. The CommonMind Consortium sequenced RNA from dorsolateral prefrontal cortex of people with schizophrenia (N = 258) and control subjects (N = 279), creating a resource of gene expression and its genetic regulation. Using this resource, ∼20% of schizophrenia loci have variants that could contribute to altered gene expression and liability. In five loci, only a single gene was involved: FURIN, TSNARE1, CNTN4, CLCN3 or SNAP91. Altering expression of FURIN, TSNARE1 or CNTN4 changed neurodevelopment in zebrafish; knockdown of FURIN in human neural progenitor cells yielded abnormal migration. Of 693 genes showing significant case-versus-control differential expression, their fold changes were ≤ 1.33, and an independent cohort yielded similar results. Gene co-expression implicates a network relevant for schizophrenia. Our findings show that schizophrenia is polygenic and highlight the utility of this resource for mechanistic interpretations of genetic liability for brain diseases.

Subfields: Genetics, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/df26ac037f23bf86b0addf6308d26c68a87b0fb7

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Citations in the corpus

Genomic dissection of bipolar disorder and schizophrenia including 28 subphenotypes (2018, methodology): “, 2013), human dorsolateral prefrontal cortex (DLPFC) (Fromer et al., 2016) from the CommonMind Consortium, and 11 brain regions from the GTEx consortium (The GTEx Consortium, 2015).”
Genome-wide association analysis identifies 30 new susceptibility loci for schizophrenia (2017, neutral): “83 12 2322513, 91291; 1514912, 1998075; (3) (27) 84 12 29905251, 236548; 28929407, 1998727; (1) (8) 85 12 92067323, 318494; 91246989, 1998394; (1) (13) 86 12 110554818, 618705; 109723411, 1998846; (12) (32) 87 12 116721603, 1985864; 116708829, 1997390; (18) (19) 88 12 123632930, 114032; 123164062, 7”
Integrative omics for health and disease (2018, background): “Indeed, a recent study of 108 loci associated with schizophrenia provided evidence for 20 of these loci having changes in gene expression that could at least partially explain their associations 20 .”
Transcriptome-scale spatial gene expression in the human dorsolateral prefrontal cortex (2020, background): “The shift from homogenate sequencing studies of brain tissue (Collado-Torres et al., 2019; Fromer et al., 2016; Jaffe et al., 2018) to large-scale snRNA-seq has already begun, with increasing sample sizes and numbers of nuclei (Mathys et al.”
Psychiatric Genomics: An Update and an Agenda (2017, background): “, brain gene expression in brain regions (60), DNA-DNA looping (57), and epigenomics (61).”
Comprehensive functional genomic resource and integrative model for the human brain (2018, background): “This estimate identified substantially more eQTLs and associated eGenes than previous studies, reflecting our large sample size (8, 11, 21).”
Transcriptome-wide isoform-level dysregulation in ASD, schizophrenia, and bipolar disorder (2018, positive): “Multiple neuronal and synaptic signaling pathways have been previously shown to be downregulated in a diminishing gradient across ASD, SCZ, and BD brains without identification of clear disease-specific signals for these neuronalsynaptic gene sets (13, 15, 18, 19, 56, 57).”