Association study of the tryptophan hydroxylase gene and bipolar affective disorder using family-based internal controls

In search for genetic factors predisposing to bipolar disorder, the tryptophan hydroxylase (TPH) gene has to be considered a major candidate as TPH is the rate-limiting enzyme of 5-HT synthesis. Recently, Bellivier and colleagues [1998] reported a positive association between bipolar affective disorder and a biallelic silent polymorphism in the TPH gene in 152 bipolar patients and 94 controls from France. Allele 218A was found to increase the risk for bipolar disorder with an odds ratio of 3.96 in probands carrying the allele on both chromosomes. We tried to replicate this finding in a German sample of bipolar patients. To avoid spurious association due to stratification, we applied the transmission disequilibrium test. Ninety-five patients (54 males, 41 females) and their parents were included in the study. Our sample size yielded a power of greater than 90% for detecting an association with the 218A allele of the magnitude reported by the French group. The frequency of the 218A allele in patients (0.4) however, was similar to that reported in the French controls. Ninety-eight of 190 parents were heterozygous for the A218C polymorphism. Neither allele 218A nor allele 218C were preferentially transmitted from heterozygous parents to bipolar offspring (TDT = 0.04; P = 0.92). Our results, therefore, do not support the hypothesis that either of the two alleles increase the risk for bipolar disorder. Given our sample size, we should have detected the reported effect of the TPH gene if it was present in the German population.