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Variation at the DAOA/G30 Locus Influences Susceptibility to Major Mood Episodes but Not Psychosis in Schizophrenia and Bipolar Disorder
Nigel M. Williams, PhD;
Elaine K. Green, PhD;
Stuart Macgregor, PhD;
Sarah Dwyer, BSc;
Nadine Norton, PhD;
Hywel Williams, PhD;
Rachel Raybould, BSc;
Detelina Grozeva, MSc;
Marian Hamshere, PhD;
Stanley Zammit, PhD, MRCPsych;
Lisa Jones, PhD;
Alastair Cardno, PhD, MRCPsych;
George Kirov, PhD, MRCPsych;
Ian Jones, PhD, MRCPsych;
Michael C. O’Donovan, PhD, FRCPsych;
Michael J. Owen, PhD, FRCPsych;
Nick Craddock, PhD, FRCPsych
Arch Gen Psychiatry. 2006;63:366-373.
Context Variation at the DAOA/G30 locus has been described to be associated with both schizophrenia and bipolar disorder, but there is little consistency between studies of the tested polymorphisms or variants showing association.
Objectives To obtain a stringent replication of association in large samples of both disorders using consistent clinical and laboratory methods, and to test the hypothesis that association at DAOA/G30 identifies an underlying domain of psychopathological abnormalities that cuts across traditional diagnostic categories.
Design A systematic study of polymorphisms at DAOA/G30 using genetic case-control association analysis.
Setting Subjects were unrelated and ascertained from general psychiatric inpatient and outpatient services.
Participants White persons from the United Kingdom meeting criteria for DSM-IV schizophrenia (n = 709) or bipolar I disorder (n = 706) and 1416 ethnically matched controls.
Methods Nine polymorphisms that tag common genetic variations at DAOA/G30 were genotyped in all of the individuals, and comparisons were made between affected and unaffected individuals.
Results We identified significant association (P = .01-.047) between 3 single-nucleotide polymorphisms and bipolar disorder but failed to find association with schizophrenia. Analyses across the traditional diagnostic categories revealed significant evidence (P = .002-.02) for association with 4 single-nucleotide polymorphisms in the subset of cases (n = 818) in which episodes of major mood disorder had occurred (gene-wide P = .009). We found a similar pattern of association in bipolar cases and in schizophrenia cases in which individuals had experienced major mood disorder. In contrast, we found no evidence for association in the subset of cases (n = 1153) in which psychotic features occurred (all P>.08).
Conclusions Despite being originally described as a schizophrenia susceptibility locus, our data suggest that variation at the DAOA/G30 locus does not primarily increase susceptibility for prototypical schizophrenia or psychosis. Instead, our results imply that variation at the DAOA/G30 locus influences susceptibility to episodes of mood disorder across the traditional bipolar and schizophrenia categories.
Author Affiliations: Department of Psychological Medicine (Drs N. M. Williams, Green, Norton, H. Williams, Zammit, Cardno, Kirov, I. Jones, O’Donovan, Owen, and Craddock and Mss Dwyer, Raybould, and Grozeva) and Biostatistics and Bioinformatics Unit (Drs Macgregor and Hamshere), Wales School of Medicine, Cardiff University, Cardiff, Wales; and Division of Neuroscience, Queen Elizabeth Psychiatric Hospital, University of Birmingham, Birmingham, England (Dr L. Jones).
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