The DISC1 pathway modulates expression of neurodevelopmental, synaptogenic and sensory perception genes.
BACKGROUND
Genetic 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.


METHODS
Here, 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.


CONCLUSIONS
Our 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.
Hennah
William
W
Medical Genetics Section, University of Edinburgh, Edinburgh, United Kingdom. william.hennah@ed.ac.uk
Porteous
David
D
D054684:Cyclic Nucleotide Phosphodiesterases, Type 3 / Q000235:genetics / Q000378:metabolism; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000235:genetics / Q000378:metabolism; D016208:Databases, Factual; D005786:Gene Expression Regulation; D053263:Gene Regulatory Networks; D020022:Genetic Predisposition to Disease; D006801:Humans; D001523:Mental Disorders / Q000235:genetics / Q000378:metabolism; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D010465:Perception / Q000502:physiology*; D013569:Synapses / Q000502:physiology*
C412476:DISC1 protein, human; D008869:Microtubule-Associated Proteins; C525094:Nde1 protein, human; D009419:Nerve Tissue Proteins; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; C517360:PDE4B protein, human; C517376:PDE4D protein, human