Genetic and functional abnormalities of the melatonin biosynthesis pathway in patients with bipolar disorder

associated with BD (P 5 0.01) and associated with a lower mRNA level (P < 10 24 ) and a lower enzymatic activity (P < 0.05) of ASMT. A replication study and a meta-analysis using 480 independent patients with BD and 672 controls confirmed the significant association between rs4446909 and BD (P 5 0.002). These results correlate with the general lower ASMT enzymatic activity observed in patients with BD (P 5 0.001) compared with controls. Finally, several deleterious ASMT mutations identified in patients were associated with low ASMT activity (P 5 0.01). In this study, we determined how rare and common variations in ASMT might play a role in BD vulnerability and suggest a general role of melatonin as susceptibility factor for BD.