Genetic variations in tryptophan hydroxylase in suicidal behavior:: Analysis and meta-analysis

Background: Neurobiological studies implicate serotonergic dysfunction in suicidal behavior. Tryptophan hydroxylase (TPH), the rate-limiting enzyme in the biosynthesis of serotonin, plays a vital role in serotonin metabolism. Thus, variations in the TPH gene have been regarded as prime candidates in the susceptibility to suicidal behavior. The most widely studied genetic variations in the TPH gene, which are located in intron 7, yielded conflicting results in individual studies on suicide-related behavior. Methods: We performed a meta-analysis on a total of 898 patients and H 79 control subjects, in addition to our local association study in consecutively recruited suicide attempters (n = 147) and healthy control subjects of German descent (n = 326). Results: We observed a nonsignificant higher frequency of the TPH intron 7 A218 allele in our local group. The meta-analysis showed a weak yet highly significant increase in the frequency of the A218 allele (odds ratio [OR]: 1.33; 95% confidence interval [CI]: 1. 17-1.50; p = .00002) and an over-representation of A-carriers (OR: 1.48; 95% CI: 1.22-1.79; p = .00005) in Caucasian suicide attempters/victims. Conclusions: Our meta-analysis provides strong evidence for an association of suicide-related behavior with an A218 single-nucleotide polymorphism in the TPH gene in Caucasians. Because this variation do not seem to alter functional properties of the TPH gene or protein, functional variations remain to be identified and subsequently tested for association with suicide- related behavior. (C) 2003 Society of Biological Psychiatry.