Alternative titles; symbols
DO: 0070089;
Cytogenetic location: 15q13 Genomic coordinates (GRCh38): 15:27,800,001-33,400,000
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 15q13 | {Schizophrenia, susceptibility to, 13} | 613025 | 2 |
For a general phenotypic description and a discussion of genetic heterogeneity of schizophrenia, see 181500.
Various psychophysiologic studies of patients with schizophrenia have shown basic deficits in the regulation of response to sensory stimuli that may underlie symptoms such as hallucinations, delusions, or other extraneous stimuli. One trait can be measured by responses to stimuli occurring 50 ms after an auditory stimulus (P50). In 9 families with multiple cases of schizophrenia, Freedman et al. (1997) found decreased P50 inhibition in cases and unaffected relatives. In a genomewide linkage analysis, assuming autosomal dominant transmission, Freedman et al. (1997) found linkage of this trait to a dinucleotide polymorphism at 15q13-q14 (maximum lod score of 5.3), the site of the CHRNA7 gene (118511). It was considered relevant that many patients with schizophrenia are heavy smokers. The authors speculated that heavy use of nicotine and nicotine dependency may represent self-treatment for the defect at the alpha-7-nicotinic receptor.
Freedman et al. (2001) studied parent-child triads from families with schizophrenia and found significant genotype-wise disequilibrium for a marker within a 1-Mb region on chromosome 15 containing CHRNA7 and CHRFAM7A (609756). CHRFAM7A contains a partial duplication of exons 5 through 10 of CHRNA7.
Leonard and Freedman (2006) provided a detailed review of the genetics of chromosome 15q13-q14 in schizophrenia.
In a genomewide search for copy number variations (CNV) associated with schizophrenia (see 181500), Stefansson et al. (2008) identified deletion of 15q13.3 as significantly associated with schizophrenia and related psychoses in combined samples. A total of 7 of 4,213 cases (0.17%) carried the deletion and 8 of 39,800 controls carried the deletion (0.02%) (p = 5.3 x 10(-4); odds ratio, 11.54).
The International Schizophrenia Consortium (2008) identified 15q13.3 deletion in 9 of 3,391 patients with schizophrenia and in none of 3,181 ancestrally-matched controls (empirical p = 0.0029; genomewide corrected p = 0.046; odds ratio, 17.9). The International Schizophrenia Consortium (2008) noted that this region had not previously been implicated. Both Stefansson et al. (2008) and the International Schizophrenia Consortium (2008) suggested the CHRNA7 gene (118511) as a positional and functional candidate.
To investigate large copy number variants segregating at rare frequencies (0.1 to 1.0%) in the general population as candidate neurologic disease loci, Itsara et al. (2009) compared large CNVs found in their study of 2,500 individuals with published data from affected individuals in 9 genomewide studies of schizophrenia, autism, and mental retardation. They found evidence to support the association of deletion at chromosome 15q13.3 with schizophrenia (CNV p = 1.08 x 10(-5)). They identified 19 CNVs in this region, all of which were disease-associated.
Freedman, R., Coon, H., Myles-Worsley, M., Orr-Urtreger, A., Olincy, A., Davis, A., Polymeropoulos, M., Holik, J., Hopkins, J., Hoff, M., Rosenthal, J., Waldo, M. C., and 11 others. Linkage of a neurophysiological deficit in schizophrenia to a chromosome 15 locus. Proc. Nat. Acad. Sci. 94: 587-592, 1997. [PubMed: 9012828] [Full Text: https://doi.org/10.1073/pnas.94.2.587]
Freedman, R., Leonard, S., Gault, J. M., Hopkins, J., Cloninger, C. R., Kaufmann, C. A., Tsuang, M. T., Farone, S. V., Malaspina, D., Svrakic, D. M., Sanders, A., Gejman, P. Linkage disequilibrium for schizophrenia at the chromosome 15q13-14 locus of the alpha-7-nicotinic acetylcholine receptor subunit gene (CHRNA7). Am. J. Med. Genet. 105: 20-22, 2001. [PubMed: 11424985]
International Schizophrenia Consortium. Rare chromosomal deletions and duplications increase risk of schizophrenia. Nature 455: 237-241, 2008. [PubMed: 18668038] [Full Text: https://doi.org/10.1038/nature07239]
Itsara, A., Cooper, G. M., Baker, C., Girirajan, S., Li, J., Absher, D., Krauss, R. M., Myers, R. M., Ridker, P. M., Chasman, D. I., Mefford, H., Ying, P., Nickerson, D. A., Eichler, E. E. Population analysis of large copy number variants and hotspots of human genetic disease. Am. J. Hum. Genet. 84: 148-161, 2009. [PubMed: 19166990] [Full Text: https://doi.org/10.1016/j.ajhg.2008.12.014]
Leonard, S., Freedman, R. Genetics of chromosome 15q13-q14 in schizophrenia. Biol. Psychiat. 60: 115-122, 2006. [PubMed: 16843094] [Full Text: https://doi.org/10.1016/j.biopsych.2006.03.054]
Stefansson, H., Rujescu, D., Cichon, S., Pietilainen, O. P. H., Ingason, A., Steinberg, S., Fossdal, R., Sigurdsson, E., Sigmundsson, T., Buizer-Voskamp, J. E., Hansen, T., Jakobsen, K. D., and 64 others. Large recurrent microdeletions associated with schizophrenia. Nature 455: 232-236, 2008. [PubMed: 18668039] [Full Text: https://doi.org/10.1038/nature07229]