Neurotransmission pathways/systems have been proposed to be involved in the pathophysiology and treatment of bipolar disorder for over 40 years. In order to test the hypothesis that common variants of genes in one or more of five neurotransmission systems confer risk for bipolar disorder, we analyzed 1,005 tag single nucleotide polymorphisms in 90 genes from dopaminergic, serotonergic, noradrenergic, GABAergic, and glutamatergic neurotransmitter systems in 101 trios and 203 quads from Caucasian bipolar families. Our sample has 80% power to detect ORs >or= 1.82 and >or=1.57 for minor allele frequencies of 0.1 and 0.5, respectively. Nominally significant allelic and haplotypic associations were found for genes from each neurotransmission system, with several reaching gene-wide significance (allelic: GRIA1, GRIN2D, and QDPR; haplotypic: GRIN2C, QDPR, and SLC6A3). However, none of these associations survived correction for multiple testing in an individual system, or in all systems considered together. Significant single nucleotide polymorphism associations were not found with sub-phenotypes (alcoholism, psychosis, substance abuse, and suicide attempts) or significant gene-gene interactions. These results suggest that, within the detectable odds ratios of this study, common variants of the selected genes in the five neurotransmission systems do not play major roles in influencing the risk for bipolar disorder or comorbid sub-phenotypes.