BACKGROUND: Catechol-O-methyltransferase (COMT) polymorphisms play an essential role in dopamine availability in the brain. However, there has been no study investigating whether a functional four-SNP (rs6269-rs4633-rs4818-rs4680) haplotype is associated with affective symptoms over the life course. METHODS: We tested this using 2093 members of the Medical Research Council National Survey of Health and Development (MRC NSHD), who had been followed up since birth in 1946, and had data for COMT genotypes, adolescent emotional problems (age 13-15) and at least one measure of adult affective symptoms at ages 36, 43, 53, or 60-64 years. First, differences in the levels of affective symptoms by the functional haplotype using SNPs rs6269, rs4818, and rs4680 were tested in a structural equation model framework. Second, interactions between affective symptoms by COMT haplotype were tested under an additive model. Finally, a quadratic regressor (haplotype2) was used in a curvilinear model, to test for a possible inverted-U trend in affective symptoms according to COMT-related dopamine availability. RESULTS: Women had a significant interaction between COMT haplotypes and adolescent emotional problem on affective symptoms at age 53. Post hoc analysis showed a significant positive association between adolescent emotional problems and affective symptoms at age 53 years in the middle dopamine availability group (valA/valB or met/met; β = .11, p = .007). For men, no significant interactions were observed. CONCLUSIONS: Combination of the COMT functional haplotype model and inverted-U model may shed light on the effect of dopaminergic regulation on the trajectory of affective symptoms over the life course.