Researchers have previously shown that genetic variation in the NDE1 gene and the related DISC1 network increases risk for schizophrenia in a Finnish family cohort. Now the same family cohort with close to a thousand affected individuals has been studied further.
A team lead by researchers from the University of Helsinki took advantage of data on gene expression levels determined in 64 individuals. In addition, they analysed prescription medication information which has been collected over a ten-year period for all the affected individuals.
Based on these data, the multinational research team noticed that variants within the NDE1 gene both change the level of expression of a large number of genes, and correlate with the likelihood that a patient is to cease using specific psychoactive medications. The results of this study were recently published in the Royal Society journal Open Biology.
As a next step, the researchers wanted to discover the mechanisms behind these effects. Interestingly, the non-coding parts of the NDE1 gene were shown to contain sequence coding for a microRNA. MicroRNAs are short, noncoding RNAs that are known to regulate expression of many genes, though the existence and significance of miRNAs has been realised only recently.
Since a significant number of the genes with altered expression were shown to be predicted targets of this particular microRNA-484, the researchers concluded that the effects are driven through it. The same microRNA was further shown to alter the expression of the enzyme metabolizing many of the psychoactive medications, thus connecting the finding with the treatment response.
Our work identifies new biology underlying schizophrenia. The results demonstrate a means by which genetic variation in the DISC1 network can not only increase risk to major mental illnesses, but also how those same variants can alter treatment response to specific psychoactive medications through the regulation of their metabolizing enzyme, said William Hennah, a group leader at the Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki.
According to the researches, the role of the DISC1 network as a schizophrenia risk factor seems to be restricted to specific populations and families.
– Although the variants we studied are common to many populations, their specific biological consequences associated with schizophrenia and gene expression changes may be unique to this Finnish family cohort. However, other larger mutations (copy number variations) in this area have been found world-wide in people with schizophrenia, autism spectrum disorder and intellectual disability, implying a potential broader role for this micro-RNA, William Hennah explains.
Original publication: The NDE1 genomic locus can affect treatment of psychiatric illness through gene expression changes related to MicroRNA-484. Bradshaw N, Ukkola-Vuoti L, Pankakoski M, Zheutlin A, Ortega-Alonso A, Torniainen-Holm M, Sinha V, Therman S, Paunio T, Suvisaari J, Lönnqvist J, Cannon T, Haukka J, Hennah W. Open Biology 15.11.2017, DOI: 10.1098/rsob.170153
William Hennah, PhD
Institute for Molecular Medicine Finland (FIMM)
HiLIFE, University of Helsinki