Worldwide genetic variation in dopamine and serotonin pathway genes: implications for association studies.

The dopamine and serotonin systems are two of the most important neurotransmitter pathways in the human nervous system and their roles in controlling behavior and mental status are well accepted. Genes from both systems have been widely implicated in psychiatric and behavioral disorders, with numerous reports of associations and almost equally as numerous reports of the failure to replicate a previous finding of association. We investigate a set of 21 dopamine and serotonin genes commonly tested for association with psychiatric disease in a set of 39 worldwide populations representing global genetic diversity to see whether the failure to replicate findings of association may be explained by population based differences in allele frequencies and linkage disequilibrium (LD) in this gene set. We present results demonstrating a surprising homogeneity of the allele frequencies across worldwide populations in these genes. LD both for populations within continent groupings and across continental regions also showed a remarkable similarity. These findings taken together suggest that ethnic differences in these parameters are not major generators of artifacts in genetic association studies of psychiatric disorders with genes from this set. Therefore, factors other than ethnic differences in genetic variation may explain the discrepancies reported among genetic association studies with this set of genes to date. The transferability of tagSNPs defined in the HapMap populations to other worldwide populations was also investigated and found to be high. A list of tagSNPs per gene and continental region is proposed providing a guide for future association studies with these genes.