Study Report

Reference	Williams, N. M., 2006 PMID: 16585465
Citation	Williams, N. M., E. K. Green, et al. (2006). "Variation at the DAOA/G30 locus influences susceptibility to major mood episodes but not psychosis in schizophrenia and bipolar disorder." Arch Gen Psychiatry 63(4): 366-373.
Disease Type	Bipolar Disorder & Schizophrenia
Study Design	case-control
Study Type	Candidate-gene association study
Sample Size	706 bipolar cases, 709 schizophrenia cases and 1416 controls
SNP/Region/Marker Size	19 variants
Predominant Ethnicity	Caucasian
Population	British
Gender	37.4% male bipolar cases, 70.9% male schizophrenia cases
Age Group	adults : mean [SD] age at interview, 47.7 [13.1] years of bipolar cases, mean [SD] age at interview, 41.8 [13.5] years of schizophrenia cases, mean [SD] age, 42.4 [11.1] years of controls

Sample Diagnosis	DSM-IV
Sample Status	Cases were recruited through mental health services in England and Wales. Bipolar: mean [SD] age at first impairment from major mood disorder, 26.3 [10.2] years; family history of psychiatric illness in first- or seconddegree relative present in 59.6% of patients. Of our bipolar sample, 62.9% had a lifetime occurrence of 1 or more psychotic features. Schizophrenia: mean [SD] age at first psychiatric contact for the sample, 23.6 [7.7] years; mean [SD] age at interview, 41.8 [13.5] years; 15.7% met diagnostic criteria for at least 1 episode of major affective disorder [n=82 with depression only; n=18 with mania only; n=12 with both mania and depression] during their lifetime as coded on the OPCRIT checklist; family history of psychiatric illness in a first- or second-degree relative was present in 26.6% of patients.
Technique	genotyping
Statistical Method	Departure from Hardy-Weinberg equilibrium was tested using a chi square goodness-of-fit test. Tests for differences between cases and controls for allele and haplotype frequencies were performed using UNPHASED version 2.40 software. The effect of haplotypes or alleles was assumed to be additive. Haplotype analysis was performed using a sliding window, excluding rare haplotypes with frequencies less than 1%. Uncertain haplotypes were estimated using the expectation maximization algorithm within the UNPHASED software. Two-tailed P values were noted. Nominally significant asymptotic P values were confirmed by permuting the case-control status over 50 000 replicates and observing the maximum test statistic in each case. To evaluate the evidence for overall association in the context of testing multiple markers, we applied the product of the P-values method to the 9 SNP results. This is a 'gene-wide' test that takes testing multiple SNPs and their linkage disequilibrium relationships into account and produces a single significance level for evidence of overall association at the gene.
Result Summary	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). 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.