PHENOTYPIC TRANSLATION OF THE DISC1 NETWORK HIGHLIGHTS THE ROLE OF THE NDE1 LOCUS, WITH PHARMACOLOGICAL IMPLICATIONS

Abstract Previous studies in a Finnish family cohort for schizophrenia have observed significant association with haplotypes and SNPs from five genes within the DISC1 network: DISC1, NDE1, NDEL1, PDE4B and PDE4D. Here, in sub-samples of these Finnish families, we utilize gene expression levels and psychoactive medication use, in order to translate the role of the DISC1 network into biological consequences and potential treatment implications. Genome wide gene expression levels were determined using the Illumina HumanHT-12 v4 Expression BeadChip, in 63 individuals from 18 families, whilst prescription medication information has been collected over a ten year period for all 931 affected individuals. Analysis of the gene expression data, demonstrated that the NDE1 SNP rs2242549 was associated, at the false discovery rate p-value threshold of 0.05, with changes in a large number of probes (n = 1,363). Notably, a significant number of the genes altered (268 out of 1,250) are also predicted to be targets of microRNA 484, which is located on a 5’ non-coding exon of NDE1. Variants within the NDE1 locus also displayed significant association to early cessation of psychoactive medications, specifically a genotype by gender interaction significantly associated with use of CYP2C19 metabolised medications. Furthermore, in a cell culture system, it could be demonstrated that miR-484 can affect the expression of CYP2C19. Together, these findings suggest that mutations at the NDE1 locus may alter risk to mental illness, at least in part through the functional modification of miR-484, and that such modification also alters treatment response to specific psychoactive medications, leading to the potential for the NDE1 locus to be used to assist in the targeting of treatment for psychiatric illness.