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

18 April 2006. More than 100 years ago, Emil Kraepelin first defined schizophrenia (dementia praecox) and bipolar disorder (manic depression) as distinct psychiatric diseases, despite the fact that both can feature psychosis and mood disturbances. Notwithstanding this overlap, the distinction has remained robust and useful for diagnosis—it is said that even a psychiatrist in training can quickly distinguish the two conditions in an initial interview. But more recent work, particularly in genetics, is revealing a biology that may be at odds with the widely accepted diagnostic boundaries that sprang from those early studies (for more background, see SRF Live Discussion on the Kraepelinian dichotomy).

In particular, evidence that some of the same genes determine susceptibility to both diseases argues that schizophrenia and bipolar disease are not distinct. For example, recent work links the G72/G30 (hereafter DAOA/G30) locus on chromosome 13 to both conditions. The gene for the D-amino acid oxidase activator (DAOA) is generally considered to be the target gene, and to be located at G72. However, multiple studies have yielded inconsistent associations with specific DAOA gene variants, so the question remains whether the same variants or different alleles are tied to each disease.

To try to bring some clarity to this area, the research group led by Nick Craddock, Mick O'Donovan, and Mike Owen at Cardiff University in Wales undertook a SNP analysis of a large group of well-characterized subjects diagnosed with schizophrenia or bipolar disorder. As reported in the April issue of Archives of General Psychiatry, their survey of SNPs spanning DAOA/G30, originally identified as a schizophrenia susceptibility locus (Chumakov et al., 2002), failed to find any variants associated with a classical diagnosis of schizophrenia. But then, rather than stick with the standard analysis, they held their population to a different standard, re-sorting subjects from both groups by the presence of mood disorders or psychosis. Using these nonclassical diagnostic categories, they found a strong association of four SNP variants with major mood disorder, while no variants were tied to psychosis.

The results suggest that DAOA/G30 may not be a schizophrenia gene or bipolar gene per se, but that variations in the locus confer susceptibility instead to mood instabilities across both disease categories. The results imply that sticking to traditional boundaries of diagnosis in genetic studies may obscure the biology of complex psychiatric diseases, and add support for the idea of superseding the classical diagnostic division of schizophrenia and bipolar disorder.

In the study, joint first authors Nigel Williams and Elaine Green analyzed a large and relatively homogenous group of United Kingdom residents, including 709 meeting the diagnostic criteria for schizophrenia, 706 with bipolar disorder, and 1,416 matched controls. "Our study is, in some respects, the largest to date and the most exhaustive examination of the locus, that is, the first to use the tag SNP approach," said Owen. The researchers chose nine SNPs that spanned the entire DAOA/G30 locus, including three that had previously been associated with schizophrenia. After sequencing the polymorphisms in all the individuals, the researchers looked for individual SNPs that tracked with the two diagnostic categories, and did a multi-SNP statistical analysis of gene-wide variation. They found that none of the genotypes showed a significant association with schizophrenia, and they observe significant association (p = .01-.047) of three polymorphisms (rs391695, or M12; rs1341402; and the novel DAOA_3'UTR_SNP12) and the whole gene variance with bipolar disorder.

In a second analysis of the SNP data, the researchers remixed the groups to focus on specific psychopathologies, dividing their test population into subsets of patients who had experienced hallucinations or delusions (n = 1,153) or who had at least one episode of depression or mania (n = 818). In this analysis, they found no association between any of the SNPs and psychosis, while there was an association with the three SNPs associated with bipolar disorder in the first analysis, plus an additional SNP variant (rs2391191, M15) with the occurrence of mood disorder (p = 0.002-.02). The association with mood disorder also held up for some SNPs when they examined only the patients diagnosed with schizophrenia: The subset of schizophrenia patients with mood disorders differed in their SNP pattern from either controls or the rest of the schizophrenia cases.

The effects of DAOA/G30 variants on mood manifested squarely within traditional diagnostic categories of schizophrenia and bipolar disorder, as the test population excluded the intermediate diagnosis of schizoaffective disorder. As the authors summarize: “This suggests that variation at the DAOA/G30 locus does not confer specific susceptibility to a set of cases that represent the middle ground of the mood-psychosis spectrum, where cases simultaneously have marked schizophrenia and bipolar features. Rather, our results are consistent with the notion that variation at DAOA/G30 influences susceptibility to episodes of mood disorder across the traditional bipolar and schizophrenia categories.”

How might DAOA/G30 locus variants spark mood disorder? In their seminal study of this locus, Chumakov and colleagues showed that the DAOA gene product could activate D-amino acid oxidase (DAO) in vitro (Chumakov et al., 2002). DAO, in turn, modulates the activity of NMDA glutamate receptors by regulating the levels of D-serine, which modulates NMDA receptors at the glycine modulatory site. By lowering serine levels, then, DAOA could interfere with activation of NMDA receptors. While problems of NMDA neurotransmission are more prominently hypothesized in schizophrenia, there are suggestions that depression is associated with enhanced glutaminergic function, so the prediction would be that variants associated with mood disorder would have a reduced serine oxidase activity.

The results of Williams, Green, and colleagues could help explain inconsistencies that have plagued studies of variants at this and other loci to schizophrenia. For example, in their recent meta-analysis of the DAOA/G30 locus in these disorders, Sevilla Detera-Wadleigh and Francis McMahon of the National Institute of Mental Health in Bethesda, Maryland, show that while strong associations with the locus are seen for schizophrenia and bipolar disorder, different markers are associated in different studies (Detera-Wadleigh and McMahon, 2006). They conclude that while the DAOA/G30 gene region appears to be a common locus for schizophrenia and bipolar disorder, there is not a consistent association with particular alleles. Part of the reason for this could be phenotypic variability—as the new work of Williams, Green, and colleagues shows, the strength of the apparent association, or the appearance of an association at all, of gene variants with schizophrenia in any group may depend on the prevalence of mood disorder in that group. The prevalence of mood disorder, in turn, is likely to vary among different study groups depending on methods of diagnosis, which require subjective assessments on the balance of mood versus schizophrenic pathologies.

This study highlights a major issue for gene association studies in psychiatric disorders—when is an existing diagnostic classification valid as a phenotype, and when is it necessary to discard a clinical diagnosis in favor of other categories that may more faithfully represent the underlying biological basis of the disease? With mounting pressure to revise the “Kraepelinian dichotomy”—the view that schizophrenia and bipolar disorder are different diseases with different etiologies—the findings here represent a step toward developing a new, and perhaps more useful diagnostic framework for gene-finding.—Pat McCaffrey.

Reference:
Williams NM, Green EK, Macgregor S, Dwyer S, Norton N, Williams H, Raybould R, Grozeva D, Hamshere M, Zammit S, Jones L, Cardno A, Kirov G, Jones I, O'Donovan MC, Owen MJ, Craddock N. Variation at the DAOA/G30 Locus Influences Susceptibility to Major Mood Episodes but Not Psychosis in Schizophrenia and Bipolar Disorder. Arch Gen Psychiatry. 2006 Apr ;63(4):366-73. Abstract

 
Comments on News and Primary Papers
Comment by:  Patricia Estani
Submitted 23 April 2006 Posted 23 April 2006
  I recommend the Primary Papers

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


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


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,...  Read more


View all comments by Daniel Weinberger
Comments on Related Papers
Related Paper: 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...  Read more


View all comments by Michael Owen
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