Schizophrenia 7

For a phenotypic description and a discussion of genetic heterogeneity of schizophrenia, see 181500.

Mapping

From a study of 13 families in which multiple members had schizophrenia, Lin et al. (1995) presented data suggesting linkage to markers on chromosome 13q.

Blouin et al. (1998) used the term 'schizophrenia susceptibility locus' (SSL) for loci identified in linkage studies of schizophrenia. They reviewed previous studies in which regions of chromosomes 3, 8, and 22 had been linked to schizophrenia susceptibility and presented a genomewide scan for schizophrenia susceptibility loci using 452 microsatellite markers on 54 multiplex pedigrees. Nonparametric linkage analysis provided significant evidence for an SSL on 13q32 and suggested evidence for another SSL on 8p22-p21 (603013). The same consortium (Pulver et al., 1996) had earlier reported evidence for SSLs on 13q and 8p as well as at 2 other loci. Using the Maryland Epidemiology Sample, sib-pair analysis showed linkage to D13S770 (p = 0.0002), a maximum lod score of 3.24 in that region under a dominant model for D13S128, and a maximum lod score of 2.53 under a recessive model for D13S779.

Shaw et al. (1998) conducted a genomewide search for evidence of loci linked to schizophrenia, using an independent sample of 48 pedigrees with 70 sib pairs. Allele sharing tests demonstrated that 12 chromosomes, including 13 and 8, showed at least 1 region with a nominal P value of less than 0.05, whereas only chromosomes 16 and 13 markers showed a nominal P value less than 0.01. Only 5 chromosomes, including 13, had markers that showed a lod score greater than 2.0.

Brzustowicz et al. (1999) analyzed 21 extended Canadian families with schizophrenia under autosomal dominant and recessive models with broad and narrow definitions of schizophrenia. All models produced positive lod scores with markers on 13q, with higher scores under the recessive models. The maximum 3-point lod scores were obtained under the recessive-broad model: 3.92 at theta = 0.1 with D13S793 under homogeneity and 4.42 with alpha = 0.65 and straight theta = 0 with D13S793 under heterogeneity. Brzustowicz et al. (2000) used multipoint analysis on chromosome 13 and found a maximum lod score of 3.81 with p = 0.02 under the recessive-broad model of schizophrenia at D13S793, with an estimated 65% of families linked to this region. The findings were consistent with those in their previous studies in the same families.

Within a 5-Mb segment on chromosome 13q34 linked to schizophrenia, Chumakov et al. (2002) identified a gene, G72 (607408), that is transcribed in brain. Hattori et al. (2003) found an association between the G72 gene and bipolar disorder (see 125480), and suggested that a shared susceptibility gene complex may be involved in both psychiatric disorders.

Korostishevsky et al. (2004) studied 11 SNPs encompassing the G72/G30 (607415) locus in 60 Ashkenazi Jewish schizophrenic patients and 130 matched control subjects. Case control comparisons were based on linkage disequilibrium and haplotype frequency estimates. Two main SNP blocks were identified, one of which, containing 3 SNPs external to the genes, demonstrated an association with schizophrenia (p of 0.006 +/- 0.003). Korostishevsky et al. (2004) performed gene expression analysis of G72 and G30 on 44 schizophrenic and 44 control postmortem dorsolateral prefrontal cortex samples and identified a tendency toward G72 overexpression in schizophrenic brain samples.

Williams et al. (2006) sought to replicate previously reported association of variations in the DAOA/G30 locus in both schizophrenia and bipolar disorder. They genotyped 709 individuals with schizophrenia, 706 individuals with bipolar disorder, and 1,416 ethnically matched controls for 9 polymorphisms that tag common genetic variations. They identified significant association (p = 0.01-0.047) between 3 single nucleotide polymorphisms and bipolar disorder but failed to find association with schizophrenia. Analyses across diagnostic categories revealed significant evidence (p = 0.002-0.02) for association with 3 SNPS (rs391695, M12; rs1341402; rs2391191, M15) in a subset of cases (n = 818) in which episodes of major depressive disorder had occurred (genomewide p = 0.009), leading the authors to posit that the DAOA/G30 locus does not primarily increase susceptibility for schizophrenia or psychosis but influences susceptibility to episodes of mood disorders across the traditional bipolar and schizophrenia categories.