Sodium valproate rescues expression of TRANK1 in iPSC-derived neural cells that carry a genetic variant associated with serious mental illness View Full Text


Ontology type: schema:ScholarlyArticle     


Article Info

DATE

2019-04

AUTHORS

Xueying Jiang, Sevilla D. Detera-Wadleigh, Nirmala Akula, Barbara S. Mallon, Liping Hou, Tiaojiang Xiao, Gary Felsenfeld, Xinglong Gu, Francis J. McMahon

ABSTRACT

Biological characterization of genetic variants identified in genome-wide association studies (GWAS) remains a substantial challenge. Here we used human-induced pluripotent stem cells (iPSC) and their neural derivatives to characterize common variants on chromosome 3p22 that have been associated by GWAS with major mental illnesses. IPSC-derived neural progenitor cells carrying the risk allele of the single nucleotide polymorphism (SNP), rs9834970, displayed lower baseline TRANK1 expression that was rescued by chronic treatment with therapeutic dosages of valproic acid (VPA). VPA had the greatest effects on TRANK1 expression in iPSC, NPC, and astrocytes. Although rs9834970 has no known function, we demonstrated that a nearby SNP, rs906482, strongly affects binding by the transcription factor, CTCF, and that the high-affinity allele usually occurs on haplotypes carrying the rs9834970 risk allele. Decreased expression of TRANK1 perturbed expression of many genes involved in neural development and differentiation. These findings have important implications for the pathophysiology of major mental illnesses and the development of novel therapeutics. More... »

PAGES

613-624

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  • Identifiers

    URI

    http://scigraph.springernature.com/pub.10.1038/s41380-018-0207-1

    DOI

    http://dx.doi.org/10.1038/s41380-018-0207-1

    DIMENSIONS

    https://app.dimensions.ai/details/publication/pub.1106283476

    PUBMED

    https://www.ncbi.nlm.nih.gov/pubmed/30135510


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