The G72/G30 gene locus in psychiatric disorders: a challenge to diagnostic boundaries?

Abstract

In follow-up from evidence obtained in linkage studies, systematic linkage disequilibrium mapping within chromosomal region 13q33 has led to the identification of a schizophrenia susceptibility locus which harbors the genes G72 and G30. These association findings have been replicated in several independent schizophrenia samples. Association has also been found between genetic variants at the G72/G30 locus and bipolar affective disorder (BPAD), with replication in independent studies. Results from studies of more detailed psychiatric phenotypes show that association exists with symptom clusters that are common to several disorders as well as with specific psychiatric diagnoses. These findings may indicate that the association lies not with the diagnostic categories per se but with more specific aspects of the phenotype, such as affective symptoms and cognitive effects, which cross traditional psychiatric diagnostic boundaries. At the molecular level, the picture remains far from clear. No putative functional variants have been identified in the coding regions of G72 or G30, and it is therefore likely that disease susceptibility is caused by as yet unidentified variants which alter gene expression or splicing. A further complication is the fact that inconsistencies are evident in the risk alleles and haplotypes observed to be associated across different samples and studies, which may suggest the presence of multiple susceptibility variants at this locus. Functional analyses indicate that the G72 gene product plays a role in the activation of N-methyl-D-aspartate receptors, a molecular pathway implicated in both schizophrenia and BPAD, making it the most plausible candidate gene at this locus.

Fig. 1

Summary of Linkage Results on Chromosome 13. The included studies are those which showed genome-wide significance or evidence suggestive of linkage on chromosome 13.

Fig. 2

The G72/G30 Locus: Genotyped SNPs and Haplotype Block Structure. At the top of the figure are shown the positions of the SNPs in kb, the dbSNP IDs and, where available, the coding of Chumakov et al. The haplotype block structure is shown at the bottom of the figure, based on HapMap data derived from individuals of European descent (CEU) (release No. 20/phaseII Jan06) and presented using Haploview Version 3.2.