Association of CAG repeat loci on chromosome 22 with schizophrenia and bipolar disorder

Abstract

Chromosome 22 has been implicated in schizophrenia and bipolar disorder in a number of linkage, association and cytogenetic studies. Recent evidence has also implicated CAG repeat tract expansion in these diseases. In order to explore the involvement of CAG repeats on chromosome 22 in these diseases, we have created an integrated map of all CAG repeats Ն5 on this chromosome together with microsatellite markers associated with these diseases using the recently completed nucleotide sequence of chromosome 22. Of the 52 CAG repeat loci identified in this manner, four of the longest repeat stretches in regions previously implicated by linkage analyses were chosen for further study. Three of the four repeat containing loci, were found in the coding region with the CAG repeats coding for glutamine and were expressed in the brain. All the loci studied showed varying degrees of polymorphism with one of the loci exhibiting two alleles of 7 and 8 CAG repeats. The 8-repeat allele at this locus was significantly overrepresented in both schizophrenia and bipolar patient groups when compared to ethnically matched controls, while alleles at the other three loci did not show any such difference. The repeat lies within a gene which shows homology to an androgen receptor related apoptosis protein in rat. We have also identified other candidate genes in the vicinity of this locus. Our results suggest that the repeats within this gene or other genes in the vicinity of this locus are likely to be implicated in bipolar disorder and schizophrenia. Molecular Psychiatry (2001) 6, 694-700.

SYNGR1 is associated with schizophrenia and bipolar disorder in southern India

“…Among the various chromosomal regions that have shown evidence of linkage with these disorders, 22q11-13 is consistently one of the most extensively studied regions (Coon et al 1994;Pulver et al 1994;Gill et al 1996;Papolos et al 1996;Bassett and Chow 1999;Schwab and Wildenauer 1999;Kelsoe et al 2001;Jorgensen et al 2002). Our group has also reported association of a novel CAG repeat marker (22CH3) on 22q13.2 with both SCZ and BPAD in the southern Indian population (Saleem et al 2001). Taken together, these studies provide clues regarding the existence of potential susceptibility genes for SCZ and BPAD on 22q11-13.…”

Association analyses suggest GPR24 as a shared susceptibility gene for bipolar affective disorder and schizophrenia

“…However, we cannot completely exclude that the associations observed with GPR24 SNPs might be due to LD to a nearby gene. In this context, it is interesting that a CAG trinucleotide repeat in the hypothetical gene KIAA1093, located just proximal to ADSL, has been reported to associate with both BPD and SZ in an Indian sample [Saleem et al, 2001]. We have identified SNPs and several specific haplotypes straddling GPR24, which is associated with SZ and/or with BPD.…”

Exploring metabolic pathway disruption in the subchronic phencyclidine model of schizophrenia with the Generalized Singular Value Decomposition

“…In addition, a role for this metabolic pathway in cognition and schizophrenia is supported by the observation that inherited deficiency in the enzyme responsible for the breakdown of adenylosuccinate (ASL) results in mental retardation and autistic features [67,68]. Furthermore, the ASL gene maps to chromosome 22 q 13.1- q 13.2 in humans [69] and these chromosomal loci have been repeatedly linked to schizophrenia [70-72]. The disruption of this metabolic pathway may also contribute to the reduced rate of cerebral glucose metabolism in the PFC of PCP-treated animals [3,4] as ASL deficiency results in hypometabolism in frontal cortical structures [73].…”