Evidence from family, twin, and adoption studies has strongly implicated genetic factors in the etiology of schizophrenia. Quantitative summaries of twin studies have consistently demonstrated the strong influence of genetic effects (7, 8) ; a recent meta-analysis of twelve twin studies estimates the heritability of the disease at 81% (p and M.D. Neale, unpublished results).
Although genetic influences on the etiology of schizophrenia are notably strong, identification of the underlying susceptibility loci has proven problematic (9). Schizophrenia is a prototypic complex trait, demonstrating non-Mendelian inheritance and important environmental influences that are reviewed in the following section. Unlike some complex traits (e.g., breast cancer or Alzheimer disease), no subtype of schizophrenia has been found to segregate in a Mendelian fashion. It is likely that there are multiple, potentially interacting genes with small effects and incomplete penetrance (10). Moreover, etiologic and locus heterogeneities are widely suspected.
The difficulty of identifying specific sources of genetic variation within broad genomic regions has been a key limitation to the molecular dissection of nearly all complex traits. In schizophrenia, the numerous genomic regions that have been implicated by genome scanning pose an enormous challenge, because they are inconsistent between studies and are usually broad, sometimes containing hundreds of potential candidate genes. Nevertheless, as for other complex traits, there has been considerable recent progress for schizophrenia.
Two genes identified in linkage disequilibrium–based fine-mapping work following genome scans appear to be promising candidate genes for schizophrenia. DTNBP1 (dystrobrevin-binding protein 1, or dysbindin) was identified in a study of 270 Irish high-density schizophrenia pedigrees (11–13). Dysbindin is a component of the dystrophin protein complex in postsynaptic densities in the brain and appears to play a role in synaptic plasticity and signal transduction. For example, the dystrophin protein complex regulates nicotinic receptor clustering and recruits specific signaling molecules, such as neuronal nitric oxide synthase, and also interacts with postsynaptic density proteins involved in N -methyl-D -aspartate (NMDA) receptor clustering (14). Thus, defects in dysbindin function could affect synaptic transmission and postsynaptic receptor regulation during development, adulthood, or both (11).
A second gene identified via follow-up of a genome scan is neuregulin 1 (NRG1), initially demonstrated in an Icelandic sample (15) and subsequently in a Scottish sample (16). Neuregulin 1 is an interesting albeit complex candidate gene for schizophrenia given its important roles in neuronal migration and brain development, and its close associations with several neurotransmitter systems [e.g., NMDA, glutamate, and -aminobutyrate (GABA) (15)].
The DISC-1 and DISC-2 (DISRUPTED IN SCHIZOPHRENIA) genes are additional candidates for susceptibility to schizophrenia. In a large Scottish pedigree with a high rate of schizophrenia (forty-seven percent) and related psychiatric disorders, a balanced 1:11 translocation disrupts DISC-1 and DISC-2, both genes residing at 1q42.1 (17). The functions of DISC-1 and DISC-2, however, remain elusive. In a study of Finnish families, Ekelund and colleagues presented evidence in support of the linkage of region 1q42 to schizophrenia (18), although no major locus could be identified on chromosome 1q in a large multicenter sample (19).
Several lines of research have also focused interest on chromosome 22q11. People with "22q11 deletion syndrome," also known as DiGeorge syndrome, or velocardiofacial syndrome, have very high rates of schizophrenia (twenty-five to thirty percent) (20). Although it has been difficult to determine which of the specific genes in this genomic region may mediate 22q11 deletion syndrome, there are several intriguing candidates, such as the gene encoding COMT, the postsynaptic enzyme that metabolizes released dopamine.
A simpler approach to investigating genetic variation in schizophrenia is to compare specific candidate genes from patients and well-matched control subjects. Although this approach is controversial (particularly in neuropsychiatry) for its capacity to yield false positive findings (21), hundreds of association studies have yielded support for at least three genes that increase risk for schizophrenia. Each of the three genes appears to confer a relatively small increase in risk, which necessitates large sample sizes in order for individual studies to attain sufficient statistical power. The gene that encodes the type 2A serotonin receptor (HTR2A) has been implicated in a meta-analysis of twenty-eight published reports; the type 3 dopamine receptor gene (DRD3) has been similarly implicated from forty-eight published reports (22). A third gene (COMT), encoding catechol-O -methyl transferase, although not significantly associated with schizophrenia in a meta-analysis (22), nevertheless stands out in recent reports as contributing to the etiology of schizophrenia (23, 34). The relevance of these genes to the etiology of schizophrenia is discussed below (see Neurotransmitter Hypothesis).
Microarray analysis to assess gene expression levels in the postmortem brains of schizophrenics may identify candidate genes without regard to preconceptions of disease mechanism. For example, Hakak and colleagues (25) found in the dorsolateral prefrontal cortex of twelve schizophrenics downregulation of the genes that encode MAL (myelin and lymphocyte protein), 2’,3’-cyclic nucleotide 3’-phosphodiesterase, myelin-associated glycoprotein, transferrin, gelsolin, and the neuregulin receptor Her3 (i.e., ErbB3), all of which are involved in myelination and/or oligodendrocyte function. In another microarray study of the schizophrenic prefrontal cortex, the expression of genes encoding proteins that regulate presynaptic secretory function was compromised; the affected gene products included N-ethylmaleimide-sensitive factor and synapsin II (26). Expression of the gene encoding G protein–signaling regulator 4 (RGS4), which can regulate the duration of G protein–mediated intracellular signaling, was also found to be reduced (27). Interestingly, RGS4 maps to 1q21-22, a chromosome region that has been implicated in schizophrenia by linkage (28).