Alternative titles; symbols
DO: 0070081;
Cytogenetic location: 6q13-q26 Genomic coordinates (GRCh38): 6:69,200,001-164,100,000
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 6q13-q26 | {Schizophrenia} | 181500 | Autosomal dominant | 2 |
For a phenotypic description and a discussion of genetic heterogeneity of schizophrenia, see 181500.
Cao et al. (1997) studied 2 independent datasets and reported evidence of a susceptibility locus for schizophrenia on 6q but could not confirm linkage to 6p They used a 2-stage approach and nonparametric linkage analysis: allele sharing identical by descent and multipoint maximum likelihood score (MLS) statistics. In the first dataset, they found excess allele sharing for markers on 6q13-q26; the greatest allele sharing was at 6q21-q22.3 at marker D6S416. The multipoint MLS values had a maximum value of 3.06 near D6S278 and of 3.05 at D6S454/D6S423. A second dataset also showed excess allele sharing for 6q13-q26.
Lindholm et al. (2001) performed a genome screen on a 12-generation Swedish family in which, among 210 individuals studied, 43 members were involved in an 'affecteds-only' analysis. The affected individuals included 29 patients with schizophrenia, 10 with schizoaffective disorders, and 4 with psychosis not otherwise specified. The pedigree was constructed on the basis of church records, old psychiatric records, national registers, and information from a postdoctoral thesis (Sjogren, 1935). All analyses pointed to the same region, 6q25. D6S264, located at 6q25.2, showed a maximum lod score of 3.45 when allele frequencies in the Swedish control population were used, compared with a maximum lod score of 2.59 when the pedigree's allele frequencies were used. Lindholm et al. (2001) analyzed additional markers in the 6q25 region and found a maximum lod score of 6.6 with marker D6S253, as well as a 6-cM haplotype that segregated, after 12 generations, with most of the affected individuals. Multipoint analysis with markers in the 6q25 region showed a maximum lod score of 7.7. To evaluate the significance of the genome scan, Lindholm et al. (2001) simulated the complete analysis under the assumption of no linkage. The results showed that a lod score greater than 2.2 should be considered as suggestive of linkage, whereas a lod score greater than 3.7 should be considered as significant. On the whole, these results suggested that a common ancestral region was inherited by the affected individuals in this large pedigree.
Lindholm et al. (2001) reviewed other reports of a schizophrenia-susceptibility locus on 6q. They concluded that 'the possibility remains that all the studies of the 6q region describe a single schizophrenia locus.'
By genomewide linkage analysis in 155 patients with schizophrenia from 21 Arab-Israeli families, Lerer et al. (2003) identified a 12-cM candidate disease locus at 6q23 between markers D6S1715 and D6S292 (nonparametric lod score of 4.29 for 'core' diagnostic category; parametric lod score of 4.16 under a dominant model). By typing additional microsatellite markers in the same patient sample used by Lerer et al. (2003), Levi et al. (2005) defined a 4.96-cM candidate disease region on 6q23 (maximum multipoint parametric lod score of 4.63 at D6S1626 and D6S292 for 'core' criteria and dominant model). The 'core' diagnostic category was defined as schizophrenia (52 cases), schizoaffective disorder, depressed and/or manic (14 cases total), and unspecified functional psychosis (2 cases).
Duan et al. (2004) reviewed the accumulated support for the reported linkage of schizophrenia to 6q13-q26 by Cao et al. (1997). They focused on the gene cluster on chromosome 6q23.2 which contains a number of prime candidate genes for schizophrenia and found a significant association with SNPs in the gene encoding trace amine receptor-4 (TRAR4, or TAAR6; 608923). Comparative genomic analyses suggested that the associated polymorphisms could potentially affect gene expression. Moreover, RT-PCR studies of various human tissues, including brain, confirmed that TRAR4 is preferentially expressed in those brain regions that have been implicated in the pathophysiology of schizophrenia.
Cao, Q., Martinez, M., Zhang, J., Sanders, A. R., Badner, J. A., Cravchik, A., Markey, C. J., Beshah, E., Guroff, J. J., Maxwell, M. E., Kazuba, D. M., Whiten, R., Goldin, L. R., Gershon, E. S., Gejman, P. V. Suggestive evidence for a schizophrenia susceptibility locus on chromosome 6q and a confirmation in an independent series of pedigrees. Genomics 43: 1-8, 1997. [PubMed: 9226366] [Full Text: https://doi.org/10.1006/geno.1997.4815]
Duan, J., Martinez, M., Sanders, A. R., Hou, C., Saitou, N., Kitano, T., Mowry, B. J., Crowe, R. R., Silverman, J. M., Levinson, D. F., Gejman, P. V. Polymorphisms in the trace amine receptor 4 (TRAR4) gene on chromosome 6q23.2 are associated with susceptibility to schizophrenia. Am. J. Hum. Genet. 75: 624-638, 2004. [PubMed: 15329799] [Full Text: https://doi.org/10.1086/424887]
Lerer, B., Segman, R. H., Hamdan, A., Kanyas, K., Karni, O., Kohn, Y., Korner, M., Lanktree, M., Kaadan, M., Turetsky, N., Yakir, A., Kerem, B., Macciardi, F. Genome scan of Arab Israeli families maps a schizophrenia susceptibility gene to chromosome 6q23 and supports a locus at chromosome 10q24. Molec. Psychiat. 8: 488-498, 2003. [PubMed: 12808429] [Full Text: https://doi.org/10.1038/sj.mp.4001322]
Levi, A., Kohn, Y., Kanyas, K., Amann, D., Pae, C.-U., Hamdan, A., Segman, R. H., Avidan, N., Karni, O., Korner, M., Jun, T.-Y., Beckmann, J. S., Macciardi, F., Lerer, B. Fine mapping of a schizophrenia susceptibility locus at chromosome 6q23: increased evidence for linkage and reduced linkage interval. Europ. J. Hum. Genet. 13: 763-771, 2005. [PubMed: 15812564] [Full Text: https://doi.org/10.1038/sj.ejhg.5201406]
Lindholm, E., Ekholm, B., Shaw, S., Jalonen, P., Johansson, G., Pettersson, U., Sherrington, R., Adolfsson, R., Jazin, E. A schizophrenia-susceptibility locus at 6q25, in one of the world's largest reported pedigrees. Am. J. Hum. Genet. 69: 96-105, 2001. [PubMed: 11389481] [Full Text: https://doi.org/10.1086/321288]
Sjogren, T. Investigations of the hereditary of psychoses and mental deficiency in two north Swedish parishes. Ann. Genet. 4: 253-318, 1935.