THE NDE1 GENOMIC LOCUS CAN AFFECT TREATMENT OF PSYCHIATRIC ILLNESS THROUGH GENE EXPRESSION CHANGES RELATED TO MICRORNA-484

Background 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. Methods 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. Results We demonstrate that the NDE1 SNP rs2242549 associates with significant changes in a large number of probes (n=2,908), of which 944 genes were replicable. A significant number of the total genes altered (347 out of 2,510, p=3.0×10-8) were predicted targets of microRNA-484, 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. Discussion Thus, mutations at the NDE1 locus may alter risk to mental illness, in part through modification of miR-484, and such modification alters treatment response to specific psychoactive medications, leading to the potential use of this locus in targeting treatment.