Unified approach to the analysis of genetic variation in serotonergic pathways

Serotonin is a key neurotransmitter in the central nervous system, and dysregulation of serotonergic pathways has been implicated in the pathogenesis of many complex psychiatric diseases. Polymorphisms of many of the genes involved in serotonin biosynthesis, catabolism, and response have been reported, suggesting that genetic variability may underlie the development of diseases such as schizophrenia, obsessive compulsive disorder, and suicide. A number of single-gene polymorphisms in serotonergic pathways have been examined in these and other diseases, but to date results from this candidate gene approach have been disappointing. Although this may be because the detection of a small effect may require the analysis of large numbers of patients and controls, an alternative explanation is that the clinical importance of a single subtle genetic variant may be overlooked unless other functionally related genes are studied in tandem. To facilitate an integrated analysis, we have developed a PCR-SSP-based assay that permits the simultaneous genotyping of 13 single nucleotide polymorphisms in 9 serotonergic genes under identical conditions. These genes include tryptophan hydroxylase, tryptophan dioxygenase, monoamine oxidase A, and the serotonin receptors 5HT1A, 5HT1D-alpha, 5HT1D-beta, 5HT2A, 5HT2C, and 5HT5A. Using this technology, we have genotyped 100 Caucasoid control individuals and demonstrate that this approach is reliable, quick, cheap, and easy to interpret. We anticipate that this will facilitate the analysis of the genetic basis of susceptibility and phenotypic variability of a number of complex psychiatric diseases. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 88:621-627, 1999.