Disrupted in schizophrenia 1 (DISC1): association with schizophrenia, schizoaffective disorder, and bipolar disorder

Abstract

Schizophrenia, schizoaffective disorder, and bipolar disorder are common psychiatric disorders with high heritabilities and variable phenotypes. The Disrupted in Schizophrenia 1 (DISC1) gene, on chromosome 1q42, was originally discovered and linked to schizophrenia in a Scottish kindred carrying a balanced translocation that disrupts DISC1 and DISC2. More recently, DISC1 was linked to schizophrenia, broadly defined, in the general Finnish population, through the undertransmission to affected women of a common haplotype from the region of intron 1/exon 2. We present data from a case-control study of a North American white population, confirming the underrepresentation of a common haplotype of the intron 1/exon 2 region in individuals with schizoaffective disorder. Multiple haplotypes contained within four haplotype blocks extending between exon 1 and exon 9 are associated with schizophrenia, schizoaffective disorder, and bipolar disorder. We also find overrepresentation of the exon 9 missense allele Phe607 in schizoaffective disorder. These data support 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.

Figure 1

A, Schematic of the DISC1 gene, showing the 13 exons and the relative positions of the 39 SNP markers and haplotype blocks. HEP1 and HEP3 are the haplotype blocks identified by Hennah et al. (2003). B, Haploview-generated LD map of the DISC1 gene in North American white controls. Regions of high LD (D′ = 1 and LOD>2) are shown in bright red. Markers with lower LD (D′ < 1 and LOD>2) are shown in red through pink (color intensity decreases with decreasing D′ value). Regions with high LD but low informativeness (D′ = 1 and LOD<2) are shown in blue. Regions of low LD and low LOD scores (D′ < 2 and LOD<2) are shown in white. Seven haplotype blocks are identified in which average D′ > 0.90.

Figure 2

Schematic of common haplotypes and of haplotypes showing significant association with disease, in haploblocks 1, 2, 3, and 4 (major alleles [unshaded] and minor alleles [shaded]). Haplotype frequencies for controls and for patients with schizophrenia (Sz), schizoaffective disorder (SA), and bipolar disorder (BP) are shown below the diagrams. Amino acid changes are shown within the given haplotypes for haploblock 1 (Gln264Arg) and haploblock 3 (Leu607Phe). *P<.05. **P<.01.