Table 1.
Examples of Schizophrenia Risk Genes and Their Proposed Mechanism of Action in the Disorder
| Coding Gene | Biological Mechanism | Functional Significance | Pathophysiologic Mechanism |
| NRG1 (8p12) | ErbB4 receptor is a postsynaptic target of NRG NRG1/erbB4 signaling perturbation | May directly affect neuronal communication and have downstream neurodevelopmental consequences through signaling variations | Interfering with activity-dependent maturation and plasticity of excitatory synaptic structure and function at glutamatergic synapses, it can lead to loss of synaptic NMDA currents and thus to glutamatergic hypofunction18 may affect disrupted neural communication in schizophrenia directly through axon guidance and myelination19 |
| DTNBP1 (6p22.3) | Protein expressed in the human central nervous system pre- and postsynaptic vesicles, likely affecting glutamatergic transmission vesicles, and in microtubules where it binds snapin20; disrupted DA/NMDA signaling21,22 | Individuals with schizophrenia express less of the protein in dorsolateral prefrontal cortex23 and in hippocampus24 | Through altered glutamate neurotransmission or through structural changes that may affect the organization of cerebral dendrite fields25 |
| COMT (22q11) | Enzyme involved in catecholamine metabolism results in a 4-fold increase (high activity) in the enzymatic breakdown of DA effectively translating to lower DA levels in COMT valine (val) carriers compared with methionine (met) allele carriers (low activity). | Particularly important in the prefrontal cortex where there are fewer DA transporters26,27 | Schizophrenia patients with the val/val genotype perform especially poorly on working memory tasks associated with abnormal cortical connectivity28a |
| CHRNA-7 (15q13-q14) | Alpha-7 subunit of the nicotinic acetylcholine receptor, associated with decreased function and/or expression of the nicotine alpha receptor gene29 | Predominantly through nicotine acetylcholine receptors improves cognition, visual attention, and memory30–32 | Schizophrenia patients may be self-medicating by using tobacco, whose nicotine content ameliorates specific cognitive and physiologic abnormalities in the disorder |
Note: NRG1, neuregulin 1; NMDA, N-methyl-D-aspartic acid; DA, dopamine; CHRNA-7, nicotinic cholinergic receptor, alpha polypeptide 7; COMT, catechol-O-methyltransferase; DTNBP1, dysbindin;
More recent evidence reviewed in 33 has indicated that the relationship between COMT, brain function, and pathogenesis of schizophrenia is complex, but still worthy of continued study as a schizophrenia susceptibility gene. Bilder et al. 34 have suggested that this complex relationship may be better understood by a tonic-phasic dopamine explanation where the met allele is associated with increased tonic and decreased phasic dopamine subcortically with increased D1 in cortical regions resulting in increased stability with decreased flexibility of neural systems supported by these networks and in executive function.