Overview: A Rare Opportunity or Just One Less Reason to Be Depressed

A year ago, in this journal, Zhang and coworkers (Zhang et al., 2005) reported that the gene encoding the enzyme responsible for the synthesis of brain sero-tonin, tryptophan hydroxylase-2 (THP2), exhibited a functional variant associated with major (or unipolar) depression. The variant in question (G1463A) altered a critical amino acid (Arg441His) in the enzyme such that, at least in a transfected cell model, serotonin synthetic capacity was significantly attenuated. Even more striking, the frequency of the variant was increased in a cohort of depressed subjects, reinforcing a common suspicion that the availability of or response to seroto-nin is altered in depression. Although serotonin has been studied in the brain for decades, only in the past few years has the central role of TPH2 become clear. Like the sighting of a long-suspected but as yet uncharted island, the discovery of functional variation in human TPH2 associated with depression was heralded as a major opportunity to move from correlation to cau-sality and anchor a flag for the serotonin hypothesis of depression on terra firma. But the party was short lived. As noted by the letters that follow this overview, several groups with much larger samples simply haven't found the variant—at all—in their collections of depressed subjects, unipolar or bipolar. And not even in their controls. My own group also found an absence of the variant in our own depression cohort (unpublished data). In such circumstances , the possibility of an experimenter mistake looms large among possible explanations. However, by sharing their DNAs with several of the groups attempting replication, Caron and workers put this concern to rest. It is possible that replicates can fail simply because the sample sizes are too small. Here, however, we see nearly 5000 subjects sampled from multiple ethnic groups in the replicate attempts, making the findings of Zhang et al., as one correspondent infers, ''a million to one shot.'' Given that the results have been validated by other groups using the Zhang et al. samples (a good practice for those of us analyzing rare mutations), the findings point to something quite distinct and possibly very important apart from depression per se in the subjects studied by Zhang et al. that enriches for the TPH2 Arg441His variant. The subjects studied by Zhang et al. are elderly, and many are severely depressed. Rare al-leles in a number of genes, several now known to present with functional phenotypes (Halushka et …