Schizophrenia Susceptibility Genes Although twin studies show that schizophrenia has a heritability of about 80%, the search for the genetic basis of this disease has been frustrating. Because schizophrenia has no distinguishing pathology or diagnostic criteria, it is difficult to relate gene changes to discrete physiological or biochemical changes associated with the disease. Schizophrenia fits the profile of a complex disorder in which multiple genes interact – along with environmental influences – to produce a range of phenotypes. In this model, each of a number of susceptibility genes will account for only a small part of the total disease risk. This is consistent with family and association studies that point to several handfuls of risk genes and no conclusive evidence of disease-causing polymorphisms. The proteins made by most of the strongest candidate genes are involved in dopamine or glutamate signaling, the two signaling systems that have been most implicated in schizophrenia. Others are growth factors that participate in nerve growth and development. NRG1: Neuregulin 1 (NRG1) is a growth factor that stimulates neuron development and differentiation. Originally identified as the proto-oncogene (tumor activator) Neu/ErbB2, NRG1 contains immunoglobulin and epidermal growth factor-like domains. NRG1 interacts with cells through the Neu/ErbB2 receptor, which is a member of the epidermal growth factor receptor family. Increased neuregulin signaling in schizophrenia may suppress the NMDA receptor, leading to lowered glutamate levels. NRG1 also regulates the postsynaptic density (PSD-95). Differential RNA splicing gives rise to a variety of isoforms that function as growth factors in different cell types. The beginning (5’ region) of the gene has been most implicated in schizophrenia; however no mutations have yet been identified in coding regions of the gene that are related to schizophrenia. DTNBP1: Dystrobrevin-binding Protein 1 (DTNBP1, dysbindin)) is widely distributed in muscle and brain tissue, and is involved in the biogenesis of lysosome-related organelles. The protein is part of the dystrophin-associated protein complex (DPC) involved in the development of muscular dystrophy. Dysbindin mutations are a cause of Hermansky-Pudlak syndrome, a rare form of albinism coupled with bleeding disorders, but having no neurological symptoms. Dysbandin expression is decreased in schizophrenia, and RNAi knockdown of DTNBP1 reduces glutamate levels in cultured cells. However, no mutations have yet been identified in coding regions of the gene that are related to schizophrenia. Differential processing of the mRNA produces several DTNBP isoforms. DAOA: D-Amino Acid Oxidase Activator (DAOA) is found in peroxisomes where it triggers the degradation of the gliotransmitter D-serine, which is a strong activator of NMDA-type glutamate receptors. Increased activity of DAOA could reduce D-serine and NMDA receptor functioning. DAOA itself is activated by the protein G72. Polymorphisms DAOA and G72 are associated with schizophrenia risk and diminished prefrontal and hippocampal function. COMT: Catechol-O-Methytransferase (COMT) catalyzes O-methylation, a major step in the degradation of catecholamines – including the neurotransmitters dopamine, epinephrine, and norepinephrin. Clearing dopamine from synapses is a major effect of COMT. Low activity of the COMT gene is associated with obsessive-compulsive disorder, as well as schizophrenia. COMT is the strongest schizophrenia candidate among approximately 27 genes in a 1.5-3 million nucleotide region of chromosome 22 that is deleted in velo-cardio-facial syndrome (VCFS). About 20% of VCFS patients have schizophrenia or psychosis. Deletion of the COMT gene on one chromosome may work in combination with valine substitution at amino acid position 158 of the gene that significantly lowers enzyme activity. The lack of dopamine transporters in the cortex may accentuate the effect of the valine polymorphism, with its diminished ability to clear dopamine. This may correlate with the diminished cortical processing common in schizophrenics. DISC1: Disrupted in Schizophrenia 1 (DISC1) is located at the breakpoint of a balanced translocation identified in a large Scottish family with schizophrenia, schizoaffective disorder, and other major mental illnesses. The locus has been linked to schizophrenia in other populations as well. DISC1 encodes a multifunctional protein that influences neuronal development and adult brain function, including neurite architecture, neuronal migration, intracellular transport and synaptic transmission. It associates with cytoskeletal proteins involved in centrosome and microtubule function. DISC1 interacts with phosphodiesterase 4B (PDE4B), which inactivates cyclic AMP, a second messenger implicated in learning, memory, and mood. Alternatively spliced isoforms have been identified. PPP1R1B: Protein Phosphatase 1, Regulatory Subunit 1B (PPP1R1B), also known as Dopamine- and Cyclic AMP-Regulated Phosphoprotein 32 kDa (DARPP-32), is an inhibitor of protein phosphatase-1(PP1) and protein kinase A (PKA). The addition of phosphate groups by kinases and their removal by phosphatases is an essential mechanism to regulate the activity of a signaling molecule – with the phophorylated state generally “on” and the dephosphorylated state generally “off.” Stimulation of dopamine D1 receptors increases DARP-32 phosphatase inhibition; while stimulation of NMDA receptors reduces phosphatase inhibition. In addition, DARPP-32 can decrease phosphorylation by directly inhibiting protein kinase A. Because it integrates signaling from several key pathways and broadly modulates phosphorylation, DARPP-32 mutations can interfere with normal dopamine signaling in midbrain neurons. DARPP-32 appears critical to motivated behavior, working memory, and reward-related learning, and has been has been implicated in schizophrenia, Parkinson disease, alcoholism, drug abuse, and pathological gambling. GRM3: Metabotropic Glutamate Receptor-3 (GRM3) is a G-protein coupled receptor for glutamate, a major excitatory neurotransmitter. GRM3 also modulates serotonin and dopamine transmission. Several association studies have linked GRM3 polymorphisms to schizophrenia, suggesting functional changes in glutamate transmission in the prefrontal cortex and hippocampus. RGS4: Regulator of G-Protein Signaling 4 (RGS4) negatively regulates signaling through G-proteins, so named because they bind the guanine nucleotides GDP and GTP. G-protein signaling activates “second messengers,” such as cyclic AMP, which in turn regulate many intracellular processes. RGS4 is involved in neuronal differentiation and is abundant in the cerebral cortex. RGS4 expression is reduced in brain tissue from schizophrenic patients, but no functional mutations have been identified.

schizophrenia, susceptibility genes, candidate genes, genes, loci, NRG1, Neuregulin, DTNBP1, dysbindin, DAOA, D-serine, COMT, O-methylation, methylation, DISC1, PDE4B, DARPP-32, PPP1R1B, GRM3, RGS4