Tyrosine hydroxylase polymorphism and phenotypic heterogeneity in bipolar affective disorder: A multicenter association study

Introduction: Tyrosine hydroxylase (TH), the ratelimiting enzyme in the synthesis of catecholamines, may be considered a candidate gene in unipolar affective disorder (UPAD). Taken together, most results do not support a major gene effect for the TH gene in bipolar affective disorder (BPAD). Very few studies involve UPAD patients. For this reason it is of interest to further examine the relationship between UPAD patients and TH polymorphism. Method: One hundred fifty-three UPAD patients and 153 unrelated matched controls have been recruited within a European collaborative project (BIOMED1, European Community grant CT 92-1217) for a case-control association study with TH tetranucleotide polymorphism. Patients and controls have been carefully matched for geographical origin. Phenotypic heterogeneity has been considered and subgroup analyses have been performed with relevant variables : age at onset (≤25), family history, and diagnostic stability. Results: An association between TH tetranucleotide polymorphism and patients having a positive family history for affective disorders (n = 62) has been found (P = 0.011). A trend was observed (P = 0.04)for the 33 patients with a high degree of diagnostic stability (> = 90) and a positive family history for affective disorders. No association has been observed in the total sample (P = 0.076) as well as for the subgroup according to age at onset (n = 50). Conclusions: These data indicate that TH tetranucleotide polymorphism may be involved in a particular subset of BPAD patients having a positive family history of affective disorders. No association has been found in the overall sample of 153 patients.