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.
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This study was supported by the Intramural Research Programs of the National Institute of Mental Health (NIMH; ZIA-MH00284311/NCT00001174), National Institute of Neurological Disease and Stroke (NINDS), and the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health. Dr. Kevin Chen, at the NINDS Stem Cell Unit helped with Flow Cytometry Analysis; Dr. Wei Lu at the Synapse and Neural Circuit Unit (NINDS) helped with electrophysiological recordings; Dr. Mahendra Rao, formerly of the Center for Regenerative medicine (CRM), provided 2 neural progenitor lines; Dr. Manfred Boehm (Laboratory of Cardiovascular Regenerative Medicine, NHLBI) provided 5 iPSC lines; Dr. Kory Johnson (NINDS) Microarray Core helped analyze the microarray gene expression data; Drs. Amalia Dutra and Evgenia Pak of the NHGRI Cytogenetics Core performed spectral karyotyping. GM05990, GM23240, and GM23476 were obtained from Coriell Cell Repositories (Camden, NJ). Line 10593 was obtained from the Rutgers University Cell and DNA Repository (Piscataway, NJ; catalog #10C117904). Special thanks to Ioline Henter (NIMH), who provided invaluable editorial assistance.
XJ and FJM conceived the project, designed the experiments, conducted data analyses, and wrote the manuscript. X.J. performed most of the experimental procedures. SDD-W generated the GM05990 iPSC line, NA carried out SNP genotyping, XG performed and analyzed the electrophysiological experiments, TX and GF helped to design CTCF and EMSA assays and provided reagents and technical assistance; BSM provided technical assistance and advice on culture and differentiation of iPSC lines; LH performed the conditional association analysis; CS assisted with laboratory assays and manuscript preparation. All co-authors reviewed the manuscript before submission.
Conflict of interest
The authors declare that they have no conflict of interest.
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Jiang, X., Detera-Wadleigh, S.D., Akula, N. et al. Sodium valproate rescues expression of TRANK1 in iPSC-derived neural cells that carry a genetic variant associated with serious mental illness. Mol Psychiatry 24, 613–624 (2019). https://doi.org/10.1038/s41380-018-0207-1
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