Unified approach to the analysis of genetic variation in serotonergic pathways

Serotonin is a key neurotransmitter in the central nervous system, and dysr egulation of serotonergic pathways has been implicated in the pathogenesis of many complex psychiatric diseases. Polymorphisms of many of the genes in volved in serotonin biosynthesis, catabolism, and response have been report ed, suggesting that genetic variability may underlie the development of dis eases such as schizophrenia, obsessive compulsive disorder, and suicide. A number of single-gene polymorphisms in serotonergic pathways have been exam ined in these and other diseases, but to date results from this candidate g ene approach have been disappointing. Although this may be because the dete ction of a small effect may require the analysis of large numbers of patien ts and controls, an alternative explanation is that the clinical importance of a single subtle genetic variant may be overlooked unless other function ally related genes are studied in tandem. To facilitate an integrated analy sis, we have developed a PCR-SSP-based assay that permits the simultaneous genotyping of 13 single nucleotide polymorphisms in 9 serotonergic genes un der identical conditions. These genes include tryptophan hydroxylase, trypt ophan 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 t hat this will facilitate the analysis of the genetic basis of susceptibilit y and phenotypic variability of a number of complex psychiatric diseases. A m. J. Med. Genet. (Neuropsychiatr. Genet.) 88:621-627, 1999. (C) 1999 Wiley -Liss, Inc.