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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 PapersComment 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 ScolnickComment 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 OwenComment 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

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 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: Large Family Study Links Genetics of Schizophrenia, Bipolar Disorder

Comment by:  Alastair Cardno
Submitted 7 April 2009
Posted 7 April 2009
  I recommend the Primary Papers

The results of the family/adoption study by Lichtenstein et al. (2009) and our twin study (Cardno et al., 2002) are remarkably similar. Using a non-hierarchical diagnostic approach, the genetic correlation between schizophrenia and bipolar/mania was 0.60 in the family/twin study and 0.68 in the twin study. The heritability estimates were somewhat lower in the family/adoption (~60 percent) than twin study (~80 percent), but can still be said to be substantial and similar for both disorders.

When we adopted a hierarchical approach, with schizophrenia above mania, we found no monozygotic twin pairs where one twin had schizophrenia and the other had bipolar/mania, but with their considerably larger sample, Lichtenstein et al. (2009) were able to confirm a significantly elevated risk for bipolar disorder in siblings of probands with schizophrenia (RR = 2.7), even when individuals with co-occurrence of both disorders were excluded.

I think there is a potentially interesting link between the family/adoption and twin studies focusing mainly on non-hierarchical diagnoses: Owen and Craddock’s (2009) commentary on the family/adoption study, where they advocate a dimensional approach, and Will Carpenter’s SRF comment regarding the value of domains of psychopathology. The non-hierarchical approach (where individuals can have a diagnosis of both schizophrenia and bipolar disorder during their lifetime) could be viewed as a form of dimensional/domains of psychopathology approach, with schizophrenia and bipolar disorder each having a dimension of liability, and there is now evidence from family, twin, and adoption analyses that these dimensions are correlated, i.e., that there is some overlap in etiological influences.

If schizophrenia and bipolar disorder share some causal factors in common, what might be the implications for the unresolved status of schizoaffective disorder? Our twin study suggested that the genetic (but not environmental) liability to schizoaffective disorder is entirely shared with schizophrenia and mania, defined non-hierarchically (Cardno et al., 2002). If so, and if schizophrenia and bipolar disorder share some genetic susceptibility loci in common, while other loci are not shared, then risk of schizoaffective disorder (or perhaps the bipolar subtype) could be elevated either by the coincidental co-occurrence of non-shared susceptibility loci, or by the occurrence of loci that are common to both disorders.

In this case, any loci that influence risk of schizoaffective disorder (bipolar subtype?) should also increase risk of schizophrenia and/or bipolar disorder, and this model would be refuted if any relatively specific susceptibility loci for schizoaffective disorder were confidently identified.

Some further outstanding issues:



References:

Cardno AG, Rijsdijk FV, Sham PC, Murray RM, McGuffin P. A twin study of genetic relationships between psychotic symptoms. American Journal of Psychiatry 2002;159:539-545. Abstract

Lichtenstein P, Yip BH, Björk C, Pawitan Y, Cannon TD, Sullivan PF, Hultman CM. Common genetic determinants of schizophrenia and bipolar disorder in Swedish families: a population-based study. Lancet 2009;373:234-9. Abstract

Owen MJ, Craddock N. Diagnosis of functional psychoses: time to face the future. Lancet 2009;373:190-191. Abstract

View all comments by Alastair Cardno