Abstract
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 use 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, while prescription medication information has been collected over a 10-year period for 931 affected individuals. We demonstrate that the NDE1 SNP rs2242549 associates with significant changes in gene expression for 2908 probes (2542 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.
Highlights
The identification of genes that predispose to complex psychiatric traits is an important aspect in studying these conditions, it is vital that this information is used to improve our biological understanding and the treatment procedures for the disorders
We have demonstrated that variations within the NDE1 locus, encoding a protein of the DISC1 network of protein interaction partners, can affect both gene expression levels and medication usage of psychoactive drugs used to treat major mental illnesses
Two SNPs in high linkage disequilibrium (LD) are associated with replicable expression changes in a large number of genes, and with early cessation of psychoactive medications metabolized by CYP2C19 in a gender-dependent manner
Summary
The identification of genes that predispose to complex psychiatric traits is an important aspect in studying these conditions, it is vital that this information is used to improve our biological understanding and the treatment procedures for the disorders. This can be achieved through genetic studies in which, instead of using an end state diagnosis, alternative traits are employed that can measure a biological or pharmacological aspect of the condition Polygenic disorders, such as schizophrenia, are influenced by numerous interacting genetic factors, identification of one candidate gene may aid in identification of others. Cohort, in which DISC1 (disrupted in schizophrenia 1) was previously associated with schizophrenia [1,2], and which led to observation of association with four other genes (NDE1, NDEL1, PDE4B and PDE4D) [3,4] that encode protein binding partners of the DISC1 protein [5,6,7,8] The idea that such protein interaction partners of DISC1 are encoded for by genes which show genetic interaction in mental illness is termed the DISC1 network hypothesis. Through further investigation of the roles of these variants in the DISC1 network, the NDE1 locus has been identified to increase risk of schizophrenia in this Finnish family cohort through interaction with high birth weight, a promising proxy measure for multiple pre- and/or perinatal environments [14]
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