The tryptophan hydroxylase gene influences risk for bipolar disorder but not major depressive disorder: results of meta-analyses

Objective: Tryptophan hydroxylase is the rate-limiting enzyme in the synthesis of serotonin, and thus its gene, TPH, has been extensively studied as a risk factor for both bipolar disorder and major depressive disorder. The purpose of the present report is to synthesize the available data on these putative associations and derive best estimates of the nature and magnitude of the influence of TPH on risk for mood disorders. Methods: We identified studies that examined the TPH A218C polymorphism in relation to major depressive disorder or bipolar disorder using the PubMed online search engine, ultimately including 10 case-control studies in two meta-analyses. Results: The AA genotype had a significant effect on risk for bipolar disorder in comparison to either the CC or AC genotypes, suggesting that the A allele may increase risk for bipolar disorder in a recessive manner. None of the three genotypes significantly increased risk for major depressive disorder relative to any of the other genotypes. Conclusion: The homozygous recessive genotype of the TPH A218C polymorphism has a significant effect on risk for bipolar disorder but not major depressive disorder. A possible explanation for these results is that the A allele influences mood by permitting or facilitating mania while having no effect on depression. Further replication of these findings in additional large case-control and family-based association is needed before TPH can be designated a risk gene for bipolar disorder.