Schizophrenia 9

A number sign (#) is used with this entry because of evidence that susceptibility to schizophrenia-9 (SCZD9) is conferred by variation in the DISC1 gene (605210) on chromosome 1q42.

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

Mapping

Ekelund et al. (2001) used a large, population-based study sample (221 Finnish families, 557 affected individuals) to refine schizophrenia loci on chromosome 1q. The results were analyzed separately for families originating from an internal isolate of Finland and for families from the rest of Finland, as well as for all families jointly. Evidence for linkage was obtained for 1 locus in the combined sample (maximum lod = 2.71, D1S2709) and in the nuclear families from outside the internal isolate (maximum lod = 3.21, D1S2709). In the families from the internal isolate the strongest evidence for linkage was obtained with markers located 22 cM centromeric from this marker (maximum lod = 2.30, D1S245). The strongest evidence for linkage in the combined study sample was obtained for marker D1S2709, which is an intragenic marker of the DISC1 gene (605210), previously suggested as a susceptibility gene for schizophrenia.

Molecular Genetics

In a follow-up study to Ekelund et al. (2001), Ekelund et al. (2004) genotyped 300 polymorphic markers on chromosome 1 using a sample of 70 Finnish families with multiple individuals affected with schizophrenia or related conditions. They again found linkage on chromosome 1q42 maximizing within the DISC1 gene (rs1000731, lod of 2.70).

By analysis of SNPs and corresponding haplotypes across candidate genes in the 1q42 region identified by Ekelund et al. (2001) as being linked to schizophrenia in a Finnish sample, Hennah et al. (2003) identified a significant region of interest within the DISC1 gene. They identified a 2-SNP haplotype spanning from intron 1 to exon 2 of the DISC1 gene, designated HEP3 (605210.0001), and demonstrated that it was undertransmitted to affected women in the general Finnish population. The HEP3 haplotype also displayed sex differences in transmission distortion, the undertransmission being significant only in affected females.

Hennah et al. (2005) tested whether identified allelic haplotypes of TRAX (602964)/DISC were associated with visual or verbal memory dysfunction known to aggregate with schizophrenia in families. The HEP3 haplotype of DISC1 displayed association with poorer performance on tests assessing short-term visual memory and attention. Analysis of affected and unaffected offspring separately revealed that both samples contributed to the observed association in visual working memory. The results provided genetic support for the view that the DISC1 gene contributes to sensitivity to schizophrenia and affects short-term visual memory functions.

Hodgkinson et al. (2004) presented data from a case-control study of a North American white population, confirming the underrepresentation of the HEP3 haplotype in individuals with schizoaffective disorder. Multiple haplotypes contained within 4 haplotype blocks extending between exon 1 and exon 9 were associated with schizophrenia, schizoaffective disorder, and bipolar disorder. Hodgkinson et al. (2004) also found overrepresentation of a missense allele of the DISC1 gene, leu607 to pro, in schizoaffective disorder. These data supported the idea that these apparently distinct disorders have at least a partially convergent etiology and that variation at the DISC1 locus predisposes individuals to a variety of psychiatric disorders.

Cannon et al. (2005) conducted a population-based twin cohort study in Finland to examine the association of SNPs of DISC1 and TRAX with schizophrenia and several endophenotypic traits thought to be involved in the disease pathogenesis. Two hundred and thirty-six subjects consisting of 7 pairs concordant for schizophrenia (6 monozygotic, 1 dizygotic), 52 pairs discordant for schizophrenia (20 monozygotic, 32 dizygotic), and 59 demographically balanced normal pairs (28 monozygotic, 31 dizygotic) were drawn from a twin cohort consisting of all same-sex twins born in Finland from 1940 through 1957. Diagnosis was confirmed and performance measurements on neurocognitive tests of short- and long-term memory as well as gray matter volume measurements as assessed on MRI images were recorded. A common haplotype incorporating 3 SNPs near the translocation breakpoint of DISC1 (HEP1; odds ratio, 2.6; p = 0.02) and a rare haplotype incorporating 4 markers from the DISC1 and TRAX genes (combined HEP2/HEP3; odds ratio, 13.0; p = 0.001) were significantly overrepresented among individuals with schizophrenia. These haplotypes were also associated with several quantitative and endophenotypic traits including impairments in short- and long-term memory, functioning, and reduced gray matter density in the prefrontal cortex.

Song et al. (2008) analyzed the regions of likely functional significance in the DISC1 gene in 288 patients with schizophrenia and 288 controls. Six patients with schizophrenia were heterozygous for 'ultra-rare' missense variants (R37W, S90L, T603I, G14A, and R418H) not found in 288 controls (p = 0.015) and shown to be ultra-rare by their absence in a pool of 10,000 control alleles. Song et al. (2008) concluded that these variants in DISC1 are associated with an attributable risk of about 2% for schizophrenia. In addition, they replicated the finding that 2 common structural variants (Q264R and S704C) slightly elevate the risk for schizophrenia (OR, 1.3, 95% CI, 1.0-1.7).

Schumacher et al. (2009) reported a circumscribed interval in intron 9 of DISC1, which was significantly associated with schizophrenia in females (p = 4.0 x 10(-5)) and contributed most strongly to early-onset cases (p = 9.0 x 10(-5)) in a central European population of 1,621 individuals. The SNP interplay effect between rs1538979 and rs821633 significantly conferred disease risk in male patients with schizophrenia (p = 0.016; OR, 1.57). In a metaanalysis of 9 schizophrenia samples from different European populations covering 50 SNPs, the authors found evidence for a common schizophrenia risk interval within DISC1 introns 4 to 6 (p = 0.002; OR, 1.27). Schumacher et al. (2009) proposed a complex association between schizophrenia and DISC1, including the presence of different risk loci and SNP interplay effects.

Animal Model

Hikida et al. (2007) developed a transgenic mouse model expressing a dominant-negative truncated form of Disc1. In vivo brain MRI showed enlarged lateral ventricles particularly on the left side in juvenile mutant mice, similar to asymmetric brain changes observed in patients with schizophrenia. There was also selective reduction of immunoreactivity to parvalbumin (PVALB; 168890) in the cortex, marking a possible interneuron deficit. Mutant mice displayed several behavioral abnormalities, including hyperactivity, disturbances in sensorimotor gating and olfactory-associated behavior, and an anhedonia/depression-like deficit. Hikida et al. (2007) suggested that the dominant-negative Disc1 mouse could be an animal model for schizophrenia.