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

A year ago, in this journal, Zhang and coworkers (Zhang et al., 2005xZhang, X., Gainetdinov, R.R., Beaulieu, J.-M., Sotnikova, T.D., Burch, L.H., Williams, R.B., Schwartz, D.A., Krishnan, K.R.R., and Caron, M.G. Neuron. 2005; 45: 11–16Abstract | Full Text | Full Text PDF | PubMed | Scopus (285)See all ReferencesZhang et al., 2005) reported that the gene encoding the enzyme responsible for the synthesis of brain serotonin, 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 serotonin 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 causality 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found an absence of the variant in our own depression cohort (H.C. Prasad, E. Sanders-Bush, R.C. Shelton, and R.D.B., unpublished data).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 alleles in a number of genes, several now known to present with functional phenotypes (Halushka et al., 1999xHalushka, M.K., Fan, J.B., Bentley, K., Hsie, L., Shen, N., Weder, A., Cooper, R., Lipshutz, R., and Chakravarti, A. Nat. Genet. 1999; 22: 239–247Crossref | PubMed | Scopus (800)See all References, Hahn et al., 2005xHahn, M.K., Mazei-Robison, M.S., and Blakely, R.D. Mol. Pharmacol. 2005; 68: 457–466Crossref | PubMed | Scopus (60)See all References), have been isolated by using blood pressure extremes to cull out contributors to hyper/hypotension. Perhaps the extremes of the depression spectrum have been sampled by Zhang et al., although this raises the question of how they could find it in their control samples (yet others do not see this either). A reasonable person could claim, today, that these variants track with something having nothing to do with depression, just a shared characteristic yet to be recognized and controlled for. While I doubt that this is likely to be the case, I admit that my view is only a hunch. The identification of multiple homozygotes carrying alleles that no one can find in single copy seems too low a probability not to point to a key depression trait enriched in the Zhang et al. samples. Clearly, we need to know more about the subjects of Zhang et al. Of course, having access to their brain serotonin levels would be helpful, though possibly CSF serotonin metabolites may be all that we can reasonably expect.In their response to the correspondents below, Caron and colleagues suggest a key trait linked to the Arg441His substitution may be severe depression that is refractory to conventional medications, necessitating ECT. Presumably what led to the initial findings was a shared trait linked both to serotonin and depression, but not depression itself. It would be ideal to track these traits, or endophenotypes, within the families of the Zhang et al., cohort, though the elderly nature of the cohort leaves open the possibility that these traits emerge only late in life, a depressing thought considering the finite lifetime of the funding that sustains such studies. In time, the sampling of additional collections bearing greater similarity to that of Zhang et al. in search of Arg441His may clarify the issue. Until then, we must conclude that this TPH2 allele (as well as any other TPH2 coding variant, based on resequencing efforts described below) is not a major determinant of genetic risk for major depression. Other alleles, for example in the TPH2 promoter, may still be worth exploring, as evidence suggests that some form of variation at or near the TPH2 locus associates more broadly with major depression (Zill et al., 2004xZill, P., Baghai, T.C., Zwanzger, P., Schule, C., Eser, D., Rupprecht, R., Moller, H.J., Bondy, B., and Ackenheil, M. Mol. Psychiatry. 2004; 9: 1030–1036Crossref | PubMed | Scopus (220)See all ReferencesZill et al., 2004). The rarity of the Arg441His mutation doesn't mean that it is a less valuable finding—it may be a single nugget that points to a rich vein that we can mine for other gold. Recall just how few people have α synuclein or presenillin mutations, relative to the numbers stricken with Parkinson's and Alzheimer's disease, respectively. Yet the study of the pathways influenced by these genes are now seen as being central to efforts to treat and one day eradicate these disorders.Under a common disease/rare variant framework, there may simply be no single gene variant imposing a major effect on population risk for depression. Given that more than 100 genes are likely to be involved in the birth, development, function, and plasticity of serotonergic neurons (there are more than a dozen serotonin receptors, and the serotonin transporter alone is now known to associate with more than half a dozen proteins), even a serotonin centrist should expect contributions from many points in the network for something as complex an endpoint as depression. Regardless, a flag has been planted, land claimed for the amine, land that was only suspected to be out there before. It is something of a brave new world for sure, and some yet do not believe it truly exists. What manner of discovery Arg441His truly is, only time will tell. I, for one, would gamble on treasures beyond the beachhead. But it may be a treasure of small gems, one that must be appreciated in the context of other jewels, mined elsewhere and assembled patiently over time, to be a crowning achievement.