Genetic and functional abnormalities of the melatonin biosynthesis pathway in patients with bipolar disorder
Abstract
Patients affected by bipolar disorder (BD) frequently report abnormalities in sleep/wake cycles. In addition, they showed abnormal oscillating melatonin secretion, a key regulator of circadian rhythms and sleep patterns. The acetylserotonin O-methyltransferase (ASMT) is a key enzyme of the melatonin biosynthesis and has recently been associated with psychiatric disorders such as autism spectrum disorders and depression. In this paper, we analysed rare and common variants of ASMT in patients with BD and unaffected control subjects and performed functional analysis of these variants by assaying the ASMT activity in their B-lymphoblastoid cell lines. We sequenced the coding and the regulatory regions of the gene in a discovery sample of 345 patients with BD and 220 controls. We performed an association study on this discovery sample using common variants located in the promoter region and showed that rs4446909 was significantly associated with BD (P= 0.01) and associated with a lower mRNA level (P< 10(-4)) 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= 0.002). These results correlate with the general lower ASMT enzymatic activity observed in patients with BD (P= 0.001) compared with controls. Finally, several deleterious ASMT mutations identified in patients were associated with low ASMT activity (P= 0.01). In this…
How strong is the evidence?
Evidence Hub reads this as a meta-analysis, done in people. Its evidence level is 1 of 5 (Highest · pooled evidence). Pooled evidence from several studies sits at the top of the evidence pyramid. Reported size: 480 participants or records.
Read the paper
Related studies
- A Systematic Review and Network Meta-Analysis of Randomized Controlled Trials Evaluating the Evidence Base of Melatonin, Light Exposure, Exercise, and Complementary and Alternative Medicine for Patients with Insomnia Disorder
- Use of Melatonin and/on Ramelteon for the Treatment of Insomnia in Older Adults: A Systematic Review and Meta-Analysis
- Influence of evening light exposure on polysomnographically assessed night-time sleep: A systematic review with meta-analysis
- Use of melatonin in children and adolescents with idiopathic chronic insomnia: a systematic review, meta-analysis, and clinical recommendation
- Significant potential of melatonin therapy in Parkinson’s disease – a meta-analysis of randomized controlled trials
- Meta-Analysis: Melatonin for the Treatment of Primary Sleep Disorders
Go deeper in Evidence Hub
Evidence Hub adds a study data sheet (design, sample size, evidence level, key numbers), an AI summary and a chat grounded in the paper's text.