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The NDE1 genomic locus can affect treatment of psychiatric illness through gene expression changes related to MicroRNA-484

By Nicholas J Bradshaw, Liisa Ukkola-Vuoti, Maiju Pankakoski, Amanda Blue Zheutlin, Alfredo Ortega-Alonso, Minna Torniainen-Holm, Vishal Sinha, Sebastian Therman, T. Paunio, J. Suvisaari, Jouko Lönnqvist, Tyrone D. Cannon, Jari Haukka, William Hennah

Posted 10 Nov 2016
bioRxiv DOI: 10.1101/087007 (published DOI: 10.1098/rsob.170153)

Genetic studies of familial schizophrenia in Finland have observed significant associations with a group of biologically related genes, DISC1, NDE1, NDEL1, PDE4B and PDE4D, the DISC1 network. Here, we utilize gene expression and psychoactive medication use data to study their biological consequences and potential treatment implications. Gene expression levels were determined in 64 individuals from 18 families, whilst prescription medication information has been collected over a ten-year period for 931 affected individuals. We demonstrate that the NDE1 SNP rs2242549 associates with significant changes in gene expression for 2,908 probes (2,542 genes), of which 794 probes (719 genes) were replicable. A significant number of the genes altered were predicted targets of microRNA-484 (p=3.0 × 10-8), located on a non-coding exon of NDE1. Variants within the NDE1 locus also displayed significant genotype by gender interaction to early cessation of psychoactive medications metabolized by CYP2C19. Furthermore, we demonstrate that miR-484 can affect the expression of CYP2C19 in a cell culture system. Thus, variation at the NDE1 locus may alter risk of mental illness, in part through modification of miR-484, and such modification alters treatment response to specific psychoactive medications, leading to the potential for use of this locus in targeting treatment.

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