Association between the DAOA/G72 gene and bipolar disorder and meta-analyses in bipolar disorder and schizophrenia

Abstract

Objective: The D-amino acid oxidase activator (DAOA, or G72) is involved in the oxidation of D-serine, an endogenous modulator of N-methyl-D-aspartate receptors and thus represents an important candidate in psychotic disorders. Several studies reported the DAOA/G72 gene to be associated with schizophrenia (SZ) and bipolar disorder (BD); however, the associated polymorphisms varied between SZ and BD. This study attempts to replicate the DAOA/G72 findings in BD and to conduct subgroup analyses based on the presence or absence of psychotic symptoms.

Methods: Five polymorphisms of the DAOA/G72 gene (rs1341402, rs1935062, rs2391191, rs947267, and rs778294) were analysed for association with BD in a family-based study design (303 core families including 916 individuals). We also conducted a meta-analysis of DAOA/G72 polymorphisms in BD and SZ.

Results: Marker rs1935062 was significantly associated with BD diagnosis in our sample (Z-score for C-allele= -2.33, p=0.02, uncorrected for genome-wide multiple comparisons). When we examined the subset of BD patients with psychotic symptoms (157 families), no significant results were obtained. Our meta-analysis yielded negative findings for DAOA/G72 markers in BD and positive findings for marker rs2391191 in SZ in East Asians. However, significant heterogeneity across studies limits interpretation.

Conclusions: Our results provide evidence that suggests a possible role of the DAOA/G72 gene in BD and SZ. Marker rs1935062 may be specifically associated with BD, while marker rs2391191 may be associated with SZ but not with BD. Together with previous studies, these findings suggest that the DAOA/G72 gene confers susceptibility to both BD and SZ, but that different polymorphisms may potentially differentiate between these two disorders.