genomic aspects of schizophrenia as a neurodegenerative disorder

schizophrenia (scz) is a common severe highly heritable psychiatric disorder affecting the youth in puberty and is manifested by impairments in cognition and emotion along with negative (ie, avolition, alogia, apathy, poor social functioning) and positive (presence of hallucinations, delusions) symptoms. the aim of this paper is to provide evidence for the neurodegenerative model of scz and its genomic aspects. although multiple theories have been put forth regarding the origin of scz, it can be hypothesized that scz is a common polygenic neurodegenerative disorder in distinct populations and is likely governed by a number of different risk factors. it is likely that due to the heterogeneous nature of scz, multiple factors interact to produce the disorder state such as disruptions in the dopaminergic, serotonergic, and glutamatergic systems as well as neurodegenerative changes. there is a long gap between neurodevelopmental insult and the development of symptoms, the progressive clinical deterioration observed in some patients, and evidence of progressive changes in certain ventricular and cortical brain structures. there is evidence of an increase in ventricular volume over a period of 2–4 years among first-episode patients. moreover, a decline in the frontal lobe volume and posterior superior temporal gray matter volume over a period of 4 years has been reported in patients with chronic scz. a mechanism to explain the progressive elements of scz is apoptosis, or programmed cell death, especially synaptic apoptosis in which apoptosis is localized to distal neurites without inducing immediate neuronal death. evidence shows reduced expression of bcl-2, a molecule that protects against apoptosis, in schizophrenic brains. further evidence shows that caspase molecule, that is most associated with apoptosis in the cns, is not up-regulated in temporal cortex of subjects with scz, suggesting that chronic apoptosis is not taking place in contrast to classic neurodegenerative disorders. the vulnerability of neurons to proapoptotic insults such as oxidative stress and glutamate excitotoxicity could lead to selective dendritic and synaptic losses observed in scz. however, longitudinal studies of cognitive function, which would serve as a measure of cortical neuronal system integrity, do not support a progression of loss of function as would be expected by the neurodegenerative hypothesis. the mode of transmission in scz is unknown and most likely complex and non-mendelian. linkage and association studies show many chromosomal regions including chromosomes 1q21–22, 1q42, 6p22, 7q22, 8p12–p21, 11q14.3, 12q24, 13q34, and 22q11 are involved in aetiology of scz. variations/polymorphisms in 9 specific genes are involved in the aetiology of scz, including neuregulin 1 (nrg1), dystrobrevin-binding protein 1 (dtnbp1), g72 and g30, regulator of g-protein signaling 4 (rgs4), catechol-o-methytransferase (comt), proline dehydrogenase (prodh), disc1 and disc2, serotonin 2a receptor, and dopamine receptor d3 (drd3). although a vast majority of evidence supports a neurodevelopmental model for scz genesis, there are alternative models, including the neurodegenerative model, that have been used to explain the aetiology of scz. evidence from genetic studies suggests a high degree of heritability for scz and points to a number of potential candidate genes that may be perturbed early in the development leading ultimately to the development of psychotic symptoms. genes involved in cell migration, cell proliferation, axonal outgrowth, myelination, synaptogenesis, and apoptosis are affected in subjects with scz. brain imaging studies have shown differences between the brains of subjects with scz and normal controls in a number of brain regions including the prefrontal cortex (pfc), cerebellum, hippocampus, and amygdala. there is strong evidence that viral infections during pregnancy increase the risk for scz in the offspring. the presence of neurological soft signs (nsss) in children who later develop scz also points to the neurodevelopmental aetiology for scz. all these brain imaging abnormalities and nsss are under the control of genes. in brief, whether scz is a degenerative disorder is a question that has been discussed for more than 100 years. determining whether scz is a neurodegenerative illness with progressive structural changes in the brain after debut of the illness or a neurodevelopmental disorder starting in early life is of significant importance for understanding the pathophysiology of the illness and its treatments. it seems that a combined neurodevelopmental and neurodegenerative model can explain the nature of pathophysiology and symptoms of scz.