Alternative titles; symbols
DO: 0070084;
Cytogenetic location: 18p Genomic coordinates (GRCh38): 18:1-18,500,001
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 18p | {Schizophrenia} | 181500 | Autosomal dominant | 2 |
For a phenotypic description of schizophrenia and a discussion of genetic heterogeneity, see 181500.
In a linkage study of 59 German or Israeli families segregating schizophrenia or schizoaffective disorder, Wildenauer et al. (1996) found a lod score of 1.23 for linkage with the GNAL gene (139312), which encodes the alpha subunit of the G protein G-olf, on chromosome 18p. A 2-point lod score of 2.46 was found for the marker D18S53 using a narrow definition for schizophrenia, and a lod score of 2.65 using a broad definition that included schizoaffective disorder, bipolar disease, and major depression. The authors commented on the proximity of these markers to a susceptibility locus for bipolar disease on 18p reported by Berrettini et al. (1994) and Stine et al. (1995). Crow (1995) presented arguments suggesting that there is continuum of psychoses extending from schizophrenia to bipolar disease that share a common genetic etiology.
The action of antipsychotic drugs on dopamine receptors suggests that dopaminergic signal transduction may play a role in the development of schizophrenia. Schwab et al. (1998) tested 8 candidate genes (coding for dopamine receptors, the dopamine transporter, and G proteins) in 59 families segregating schizophrenia from Germany and Israel. A P value of 0.00055 (0.0044 when corrected for the number of markers tested) was obtained for the intronic CA-repeat marker of the GNAL gene, which, they stated, maps to 18p. Although the GNAL gene was first identified in the olfactory epithelium, it is also highly expressed in certain areas of the brain and appears to be coupled to the dopamine D1 receptor (DRD1; 126449) (Herve et al., 1993; Sakagami et al., 1995). Linkage analysis using SSLP markers densely spaced around GNAL yielded a maximum 2-point lod score of 3.1 for a marker 0.5 cM distal to GNAL. Multipoint analysis under the assumption of heterogeneity supported this linkage (whether the affected phenotype was defined narrowly or broadly) as did nonparametric linkage (NPL). In 12 families with exclusively maternal transmission of the disorder, the NPL value also supported linkage to this marker. To test for association/linkage disequilibrium in the presence of linkage, the sample was restricted to independent offspring. When this sample was combined with 65 additional simplex families (each of them comprising 1 schizophrenic offspring and his/her parents), the 124-bp allele of GNAL was transmitted 47 times and was not transmitted 21 times (P = 0.009). These results suggested the existence on 18p of a susceptibility locus for functional psychoses.
Corradi et al. (2005) noted that genetic studies implicating the 18p11.2 region in susceptibility to bipolar disorder and schizophrenia have observed parent-of-origin effects that may be explained by genomic imprinting. Corradi et al. (2005) identified a transcriptional variant of the GNAL gene in this region. The variant uses an alternate first exon that is 5-prime to the originally identified start site and encodes a longer functional variant of GNAL. The 2 GNAL isoforms displayed different expression patterns in the central nervous system and both functionally coupled to DRD1. In addition, there are CpG islands in the vicinity of both first exons that are differentially methylated. Corradi et al. (2005) suggested that GNAL and possibly other genes in the region are subject to epigenetic regulation of potential significance to the etiology of schizophrenia.
Berrettini, W. H., Ferraro, T. N., Goldin, L. R., Weeks, D. E., Detera-Wadleigh, S., Nurnberger, J. I., Jr., Gershon, E. S. Chromosome 18 DNA markers and manic-depressive illness: evidence for a susceptibility gene. Proc. Nat. Acad. Sci. 91: 5918-5921, 1994. [PubMed: 8016089] [Full Text: https://doi.org/10.1073/pnas.91.13.5918]
Corradi, J. P., Ravyn, V., Robbins, A. K., Hagan, K. W., Peters, M. F., Bostwick, R., Buono, R. J., Berrettini, W. H., Furlong, S. T. Alternative transcripts and evidence of imprinting of GNAL on 18p11.2. Molec. Psychiat. 10: 1017-1025, 2005. [PubMed: 16044173] [Full Text: https://doi.org/10.1038/sj.mp.4001713]
Crow, T. J. A continuum of psychosis, one human gene, and not much else--the case for homogeneity. Schizophr. Res. 17: 135-145, 1995. [PubMed: 8562488] [Full Text: https://doi.org/10.1016/0920-9964(95)00059-u]
Herve, D., Levi-Strauss, M., Marey-Semper, I., Verney, C., Tassin, J.-P., Glowinski, J., Girault, J.-A. G(olf) and Gs in rat basal ganglia: possible involvement of G(olf) in the coupling of dopamine D1 receptor with adenylyl cyclase. J. Neurosci. 13: 2237-2248, 1993. [PubMed: 8478697] [Full Text: https://doi.org/10.1523/JNEUROSCI.13-05-02237.1993]
Sakagami, H., Sawamura, Y., Kondo, H. Synchronous patchy pattern of gene expression for adenylyl cyclase and phosphodiesterase but discrete expression for G-protein in developing rat striatum. Brain Res. Molec. Brain Res. 33: 185-191, 1995. [PubMed: 8750876] [Full Text: https://doi.org/10.1016/0169-328x(95)00123-a]
Schwab, S. G., Hallmayer, J., Lerer, B., Albus, M., Borrmann, M., Honig, S., Strauss, M., Segman, R., Lichtermann, D., Knapp, M., Trixler, M., Maier, W., Wildenauer, D. B. Support for a chromosome 18p locus conferring susceptibility to functional psychoses in families with schizophrenia, by association and linkage analysis. Am. J. Hum. Genet. 63: 1139-1152, 1998. [PubMed: 9758604] [Full Text: https://doi.org/10.1086/302046]
Stine, O. C., Xu, J., Koskela, R., McMahon, F. J., Gschwend, M., Friddle, C., Clark, C. D., McInnis, M. G., Simpson, S. G., Breschel, T. S., Vishio, E., Riskin, K., Feilotter, H., Chen, E., Shen, S., Folstein, S., Meyers, D. A., Botstein, D., Marr, T. G., DePaulo, J. R. Evidence for linkage of bipolar disorder to chromosome 18 with a parent-of-origin effect. Am. J. Hum. Genet. 57: 1384-1394, 1995. [PubMed: 8533768]
Wildenauer, D. B., Hallmayer, J., Schwab, S. G., Albus, M., Eckstein, G. N., Zill, P., Honig, S., Strauss, M., Borrmann, M., Lichtermann, D., Ebstein, R. P., Lerer, B., Risch, N., Maier, W. Searching for susceptibility genes in schizophrenia by genetic linkage analysis. Cold Spring Harbor Symp. Quant. Biol. 61: 845-850, 1996. [PubMed: 9246509]