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

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.

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.

We examined a dense set of haplotype-tagging single-nucleotide polymorphisms using a gene-based test of association.

Three hundred seventy-nine parent-affected offspring trios.

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) beta2 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.

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.