Genomics of Schizophrenia

CNS disorders represent the third problem of health in developed countries. Schizophrenia and psychotic disorders are prototypical paradigms of chronic disability, high cost, and social-family burden. Common features in CNS disorders include the following: (i) polygenic/ complex disorders in which genomic, epigenetic and environmental factors are involved; (ii) deterioration of higher activities of the CNS; (iii) multifactorial dysfunctions in several brain circuits; and (iv) accumulation of toxic proteins in the nervous tissue in cases of neurodegeneration. Several neurobiological hypotheses have been postulated as responsible for SCZ pathogenesis: polygenic/multifactorial genomic defects, intrauterine and perinatal environmentgenome interactions, neurodevelopmental defects, dopaminergic, cholinergic, serotonergic, GABAergic, neuropeptidergic and glutamatergic/ NMDA dysfunctions, seasonal infection, neuroimmune dysfunction, and epigenetic dysregulation.

Schizophrenia (SCZ) and related disorders are highly heritable (60-90%) but cannot be explained by currently known genetic risk factors. About 80% of functional genes in the human genome are expressed in the brain and over 1000 different genes have been associated with the pathogenesis of schizophrenia and psychotic disorders. Structural variation in the neuronal genome is likely to be a relevant feature of neuronal diversity and brain dysfunction. Both Mendelian and susceptibility events are present in the genomes of the psychotic population. Traditional cytogenetic approaches highlight the high frequency of large chromosomal abnormalities (3%-7%). Large-scale genomic variations due to loss or gain of whole chromosomes (aneuploidy) have been described in cells of the normal and diseased human brain, which are generated from neural stem cells during the intrauterine period of life. Over 100 genes associated with SCZ are linked to specific pathogenic events (neurotransmitter dysfunction, neurodevelopmental defects). Studies of genome- wide trinucleotide repeats using the repeat expansion detection technique suggested possible association of large CAG/CTG repeat tracts with SCZ and bipolar affective disorder.



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