Family-based association study of lithium-related and other candidate genes in bipolar disorder

Context: Association studies in bipolar disorder have been focused on a relatively narrow pool of candidate genes based on a limited understanding of the underlying pathophysiologic features. Recent developments suggest that a broader pool of genes may be associated with this disorder. Objective: To examine the association between genes related to the lithium mechanism of action, as well as other positional and functional candidates, with bipolar I disorder. Design: We examined a dense set of haplotype-tagging single-nucleotide polymorphisms using a gene-based test of association. Participants: Three hundred seventy-nine parent-affected offspring trios. Results: No genes specifically chosen to probe the action of lithium were associated with bipolar disorder. However, gene-based analysis of sialyltransferase 4A (SIAT4A), tachykinin receptor 1 (TACR1), and gamma-aminobutyric acid(A) beta 2 receptor subunit (GABRB2) yielded evidence of association (empirical P value, < .005). Among 3 genes associated with schizophrenia or bipolar disorder in multiple previous studies, including dysbindin (DTNBP1), neuregulin (NRG1), and disrupted-in-schizophrenia 1 (DISC1), only DISC1 showed evidence of association in this cohort. In a secondary analysis of these 6 genes among parent-proband trios with a history of psychosis, evidence of the association with SIAT4A was strengthened. Conclusions: These results suggest novel candidates and 1 gene (DISC1) previously associated with schizophrenia that merit further study in bipolar disorder. However, polymorphisms in major lithium-signaling genes do not appear to contribute substantially to bipolar liability.