Abstract
BackgroundGenetic and biological evidence supports a role for DISC1 across a spectrum of major mental illnesses, including schizophrenia and bipolar disorder. There is evidence for genetic interplay between variants in DISC1 and in biologically interacting loci in psychiatric illness. DISC1 also associates with normal variance in behavioral and brain imaging phenotypes.MethodologyHere, we analyze public domain datasets and demonstrate correlations between variants in the DISC1 pathway genes and levels of gene expression. Genetic variants of DISC1, NDE1, PDE4B and PDE4D regulate the expression of cytoskeletal, synaptogenic, neurodevelopmental and sensory perception proteins. Interestingly, these regulated genes include existing targets for drug development in depression and psychosis.ConclusionsOur systematic analysis provides further evidence for the relevance of the DISC1 pathway to major mental illness, identifies additional potential targets for therapeutic intervention and establishes a general strategy to mine public datasets for insights into disease pathways.
Highlights
A key challenge for human genomics is to provide insight into normal physiological processes and pathogenic mechanisms
Previous studies have shown that expression levels of full length DISC1 are reduced by half in lymphoblastoid cell lines derived from t(1;11) cases [14] and that S704C missense variants alter binding of NDEL1 [15], arguing that altering either the quality or the quantity of DISC1 can be pathognomonic But, as yet, there have been no studies to determine whether the cellular effects of these alternative genetic mechanisms are fundamentally similar or distinct
We examined the effect of a) six novel variants shown here to exert an effect in cis on DISC1 expression b) three common missense variants R264Q, L607F and S704C, c) the 3 SNPs, rs1538979, rs821577 and rs821633, reported to show interplay conferring ‘risk’, ‘neutral’ and ‘protective’ effects on schizophrenia and bipolar disorder [10] and d) variants previously reported as associated with schizophrenia or related psychotic traits in European cohorts for the DISC1 interactors NDE1, NDEL1, PDE4B and PDE4D
Summary
A key challenge for human genomics is to provide insight into normal physiological processes and pathogenic mechanisms. There is strong evidence for a major genetic component to schizophrenia and bipolar disorder, but, with some notable exceptions, few of the many proposed candidate genes have been consistently replicated [1,2]. The combination of high density SNP analysis with expression profiling provides a means to assess the genome wide control of gene expression [4]. This approach has been applied successfully to the analysis of EBV transformed lymphoblastoid cell lines and of human tissue [4]. Genetic and biological evidence supports a role for DISC1 across a spectrum of major mental illnesses, including schizophrenia and bipolar disorder. DISC1 associates with normal variance in behavioral and brain imaging phenotypes
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