Schizophrenia affects 1% of the world's population
independent of race, culture, or socio-economic status,
with enormous social and economic consequences. Depression
is even more common with an overall incidence of about
19%. The incidence of both disorders increases substantially
in close relatives reaching a concordance of at least
50% in monozygotic twins. This indicates a strong genetic
element but also the possibility that epigenetic factors
may also play a role. There is some evidence that these
factors may operate during brain development.
Neuropathological studies have ruled out the likelihood
of a progressive degeneration, an overt pathology of
a single cell type, and overt localization of pathology
to a single brain region. In schizophrenia dilatation
of the lateral ventricles and hypoactivity of the dorsolateral
prefrontal cortex suggest a defect of brain circuitry
that is supported by the loss of thalamocortical neurons
in the mediodorsal nucleus of the thalamus, by cellular
changes within the cortex itself, and by manifestations
of activity-dependent up and down regulation in genes
sensitive to changes in neural activity.
Linkage, association, and gene profiling studies have
identified numerous genes that may confer susceptibility
to schizophrenia and depressive illness. These affect
a wide variety of brain mechanisms including neural
transmission, myelination, and metabolic processes.
Of the first mentioned, the putatively involved genes
could operate at presynaptic, postsynaptic sites or
further downstream with influences upon neuronal signaling
and gene transcription. High throughput expression profiling
of large cohorts of human brain tissue in schizophrenia
and depression points to a wide variety of possible
susceptibility genes whose involvement remains to be
verified. The image of these diseases that is emerging
suggests the existence of genes that confer susceptibility
that are acted upon by epigenetic factors during development
and maturation of the nervous system and in which the
disease process, by engaging brain mechanisms of plasticity,
may itself play a role in establishing the definitive
neuronal phenotype of each disorder.
