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Detera-Wadleigh SD, McMahon FJ. G72/G30 in schizophrenia and bipolar disorder: review and meta-analysis. Biol Psychiatry. 2006 Jul 15 ; 60(2):106-14. Pubmed Abstract

Comments on News and Primary Papers

Primary Papers: G72/G30 in schizophrenia and bipolar disorder: review and meta-analysis.

Comment by:  Michael Owen, SRF Advisor
Submitted 19 April 2006
Posted 19 April 2006

This is an excellent article that contains a meta-analysis of the putative association between G72/G30 with schizophrenia (SZ) and bipolar disorder (BP), together with a review of the relevant data from linkage and biology that place the association findings in context. I think that the authors are correct to conclude that, while the association data certainly favor the view that variation at this locus confers risk for both BP and SZ, a number of nagging concerns remain. The lack of consistency between the associated alleles in different studies could reflect true heterogeneity, but there are a number of artifactual causes that need to be excluded. Second, some of the best associated SNPs actually map some distance from the gene and in a different LD block to other associated SNPs. If both these sets of findings are correct, this also suggests that whatever is going on at the level of the gene is more complex than a simple association with a single functional variant. Third, no one has yet succeeded in demonstrating expression of the G72 protein. This might be because it is expressed only fleetingly or at very low levels. Alternatively it might be a member of an increasingly recognized class of genes that encode RNA only. However, it should be recalled that G72 gains its biological plausibility as a candidate gene for SZ and BP from its putative impact on glutamatergic neurotransmission via interaction (of the protein!) with DAO.

In many ways, this is a model of the sort of skeptical and thoughtful review of candidate genes that the field needs. It makes it clear that we need larger and more comprehensive studies of this locus, and points out some of the difficulties in interpretation of the data we already have.

View all comments by Michael Owen

Comments on Related News

Related News: Genetic Studies of DAOA(G72)/G30 Bridge Kraepelinian Divide

Comment by:  Patricia Estani
Submitted 23 April 2006
Posted 23 April 2006
  I recommend the Primary Papers

Related News: Genetic Studies of DAOA(G72)/G30 Bridge Kraepelinian Divide

Comment by:  Edward Scolnick
Submitted 23 April 2006
Posted 23 April 2006

I would caution that G72 has not been shown to be an actual gene, and in the four years since Chumakov and colleagues' report, the biochemistry has not been reproduced.

View all comments by Edward Scolnick

Related News: Genetic Studies of DAOA(G72)/G30 Bridge Kraepelinian Divide

Comment by:  Nick CraddockMichael Owen (SRF Advisor)
Submitted 26 April 2006
Posted 26 April 2006

Reply to comment by Dr Scolnick
We agree that caution is required regarding the assumption that the genetic association at this locus is causally related to the DAOA "gene," and this is the reason that in the paper we have referred to the "DAOA/ G30 locus." Establishing robust genetic association in a restricted region of the genome is clearly the first step on a path to characterizing the biological and phenotypic relationships associated with the variation. It is entirely possible that pathologically relevant variation occurs at the DAOA/G30 locus that does not involve a protein product of the DAOA DNA sequence.

View all comments by Nick Craddock
View all comments by Michael Owen

Related News: Genetic Studies of DAOA(G72)/G30 Bridge Kraepelinian Divide

Comment by:  Daniel Weinberger, SRF Advisor
Submitted 10 May 2006
Posted 10 May 2006

The DAOA/G30 locus is a paradigm of association in psychiatric genetics, where positive reports are followed by both confirmation of association and failures to associate, with the observers of the glass being half-full commenting that it is unlikely that replication would occur spuriously multiple times, and those seeing the glass as half-empty (or three-quarters empty) emphasizing allelic inconsistencies, lack of identified causative SNPs, and in the case of DAOA/G30, lack of conclusive evidence of a gene expressed in brain. Clearly, we are just scratching the surface of understanding the reasons for any association signal in this region of the genome. It is important to remember that the DAOA/G30 locus was cloned from a region that has shown linkage in a number of studies, giving prior probability to association analyses, and that association has been reported in samples from a number of corners of the world. Expression may be restricted to discrete times in development and may not be present in abundance in middle-aged brains. It is also possible, as noted by Mike Owen, that the association signal reflects variation that impacts on a gene or genetic network not yet fully characterized.

This study by Craddock and colleagues makes the case for variation in the gene being related to nondiagnostic aspects of psychopathology, consistent with the reasonable expectation that genes for mental illness will not respect DSM-IV boundaries. Nevertheless, the confirmation of a role for this locus in the pathophysiology of psychiatric disorders will not be based on statistics but on evidence that genetic variation impacts on the biology of brain functions related to the psychopathology in question. We recently reported evidence that the SNP in the 2002 report by Chumakov et al., 2002 that showed association in both of their clinical samples—M10—is associated with cognitive function in a large family sample and with physiologic activation of the medial temporal lobe measured with fMRI even in normal subjects (Goldberg et al., 2006). These associations were not found for SNPs that were negative in the Chumakov et al. study, and the pattern of association with risk alleles was in the direction of abnormalities associated with schizophrenia and with pharmacological NMDA antagonism. In our view, there is dense smoke in the DAOA locus, though fire has yet to be conclusively observed.

View all comments by Daniel Weinberger