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G72 (DAOA)/G30

This locus was first implicated in studies of schizophrenia by Chumakov and colleagues⁴¹ who undertook association mapping in the linkage region on chromosome 13q22-34. They found associations in French Canadian and Russian populations in markers around 2 novel, putative genes, G72 and G30, which are overlapping but transcribed in opposite directions. Both G72 and G30 are apparently transcribed in brain, but in vitro translation experiments only resulted in production of protein for G72. Yeast 2-hybrid analysis of experimentally produced protein provided evidence for physical interaction between G72 and D-amino acid oxidase (DAO). DAO is expressed in human brain where it oxidizes D-serine, a potent activator of N-methyl-D-aspartate glutamate receptor. Coincubation of G72 and DAO in vitro revealed a functional interaction with G72 enhancing the activity of DAO. Consequently, G72 has now been named D-amino acid oxidase activator (DAOA). However, it should be noted that the existence of native G72 protein has not been demonstrated and there have been, as yet, no reports replicating the physical interaction with DAO. Associations between schizophrenia and markers in and around DAOA have subsequently been reported by a number of groups and supported by recent meta-analysis,⁴² although once again there is no consensus concerning the specific risk alleles or haplotypes across studies. Moreover, unlike NRG1 and DTNBP1, this locus has been quite extensively studied in bipolar disorder, for which it is now arguably the best-supported locus. Support for association with bipolar disorder has been reported from at least 5 independent datasets, and, as for schizophrenia, the presence of association is supported by meta-analysis without clear implication of specific alleles or haplotypes.⁴² No pathologically relevant variant has yet been identified, and the biological mechanism remains to be elucidated.

The largest study to date, and the only one which has attempted to tag all common genetic variation at this locus, was published after the meta-analysis of Detera-Wadleigh and McMahon⁴² was completed. This included 2831 individuals of whom 709 had DSM-IV schizophrenia, 706 had bipolar I disorder, and 1416 were ethnically matched controls.⁴³ The authors identified significant association with bipolar disorder but failed to find association with schizophrenia. Analyses across the traditional diagnostic categories revealed significant evidence for association in the subset of cases (n = 818) in which episodes of major mood disorder had occurred. A similar pattern of association was observed in both bipolar cases and schizophrenia cases in which individuals had experienced major mood disorder. In contrast, there was no evidence for association in the subset of cases (n = 1153) in which psychotic features occurred. This finding requires replication, but the data as they stand suggest that, despite being originally reported as a schizophrenia susceptibility locus, variation in DAOA/G30 does not primarily increase susceptibility for prototypical schizophrenia or psychosis. Instead, it appears that variation in DAOA/G30 influences susceptibility to episodes of mood disorder across the traditional bipolar and schizophrenia categories. Importantly, these findings also imply that whether or not significant associations are seen in schizophrenia will depend upon the proportion of cases that have suffered from episodes of mood disorder and remind us of the potential importance of sample differences in determining the reproducibility of genetic association studies.

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