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1.
Mol Psychiatry ; 23(4): 952-962, 2018 04.
Article in English | MEDLINE | ID: mdl-28924186

ABSTRACT

Recent genome-wide association studies identified over 100 genetic loci that significantly associate with schizophrenia (SZ). A top candidate gene, ZNF804A, was robustly replicated in different populations. However, its neural functions are largely unknown. Here we show in mouse that ZFP804A, the homolog of ZNF804A, is required for normal progenitor proliferation and neuronal migration. Using a yeast two-hybrid genome-wide screen, we identified novel interacting proteins of ZNF804A. Rather than transcriptional factors, genes involved in mRNA translation are highly represented in our interactome result. ZNF804A co-fractionates with translational machinery and modulates the translational efficiency as well as the mTOR pathway. The ribosomal protein RPSA interacts with ZNF804A and rescues the migration and translational defects caused by ZNF804A knockdown. RNA immunoprecipitation-RNAseq (RIP-Seq) identified transcripts bound to ZFP804A. Consistently, ZFP804A associates with many short transcripts involved in translational and mitochondrial regulation. Moreover, among the transcripts associated with ZFP804A, a SZ risk gene, neurogranin (NRGN), is one of ZFP804A targets. Interestingly, downregulation of ZFP804A decreases NRGN expression and overexpression of NRGN can ameliorate ZFP804A-mediated migration defect. To verify the downstream targets of ZNF804A, a Duolink in situ interaction assay confirmed genes from our RIP-Seq data as the ZNF804A targets. Thus, our work uncovered a novel mechanistic link of a SZ risk gene to neurodevelopment and translational control. The interactome-driven approach here is an effective way for translating genome-wide association findings into novel biological insights of human diseases.


Subject(s)
Central Nervous System/embryology , Central Nervous System/physiology , Kruppel-Like Transcription Factors/genetics , Kruppel-Like Transcription Factors/metabolism , Neurons/physiology , Stem Cells/physiology , Animals , Cell Line , Cell Movement/physiology , Central Nervous System/metabolism , Female , Genetic Predisposition to Disease , Genome-Wide Association Study , Humans , Male , Mice , Mice, Inbred C57BL , Neurogranin/genetics , Neurogranin/metabolism , Neurons/cytology , Neurons/metabolism , Polymorphism, Single Nucleotide , Protein Biosynthesis , Schizophrenia/genetics , Stem Cells/cytology , Stem Cells/metabolism
2.
Genes Brain Behav ; 16(5): 515-521, 2017 06.
Article in English | MEDLINE | ID: mdl-28188958

ABSTRACT

Patients with schizophrenia show decreased processing speed on neuropsychological testing and decreased white matter integrity as measured by diffusion tensor imaging, two traits shown to be both heritable and genetically associated indicating that there may be genes that influence both traits as well as schizophrenia disease risk. The potassium channel gene family is a reasonable candidate to harbor such a gene given the prominent role potassium channels play in the central nervous system in signal transduction, particularly in myelinated axons. We genotyped members of the large potassium channel gene family focusing on putatively functional single nucleotide polymorphisms (SNPs) in a population of 363 controls, 194 patients with schizophrenia spectrum disorder (SSD) and 28 patients with affective disorders with psychotic features who completed imaging and neuropsychological testing. We then performed three association analyses using three phenotypes - processing speed, whole-brain white matter fractional anisotropy (FA) and schizophrenia spectrum diagnosis. We extracted SNPs showing an association at a nominal P value of <0.05 with all three phenotypes in the expected direction: decreased processing speed, decreased FA and increased risk of SSD. A single SNP, rs8234, in the 3' untranslated region of voltage-gated potassium channel subfamily Q member 1 (KCNQ1) was identified. Rs8234 has been shown to affect KCNQ1 expression levels, and KCNQ1 levels have been shown to affect neuronal action potentials. This exploratory analysis provides preliminary data suggesting that KCNQ1 may contribute to the shared risk for diminished processing speed, diminished white mater integrity and increased risk of schizophrenia.


Subject(s)
KCNQ1 Potassium Channel/genetics , Polymorphism, Single Nucleotide , Schizophrenia/genetics , White Matter/metabolism , 3' Untranslated Regions , Action Potentials , Adult , Case-Control Studies , Female , Humans , Male , Middle Aged , Reaction Time , Schizophrenia/physiopathology , White Matter/physiopathology
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