Genetic analysis of a functional GRIN2A promoter (GT)n repeat in bipolar disorder pedigrees in humans.

Hypofunction of glutamatergic neurotransmission has been hypothesized to underlie the pathophysiology of bipolar affective disorder, as well as schizophrenia. We examined the role of the N-methyl-D-aspartate receptor 2A subunit (GRIN2A) gene on 16p13.3, a region thought to be linked to bipolar disorder, (1) because in a prior study we identified a functional and polymorphic (GT)n repeat in the 5' regulatory region of the gene, with longer alleles showing lower transcriptional activity and an over representation in schizophrenia, and (2) because of the suggestion of a genetic overlap between affective disorder and schizophrenia. Family-based association tests detected a nominally significant preferential transmission of longer alleles in a panel of 96 multiplex bipolar pedigrees. These results support the hypothesis that a hypoglutamatergic state is involved in the pathogenesis of bipolar affective disorder.