Psychiatrie Génétique, INSERM U 955, Créteil 94000, France.
Hum Mol Genet. 2012 Sep 15;21(18):4030-7. doi: 10.1093/hmg/dds227. Epub 2012 Jun 13.
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 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.
受双相情感障碍（BD）影响的患者常报告睡眠/觉醒周期异常。此外，他们还表现出褪黑素分泌的异常振荡，褪黑素是调节昼夜节律和睡眠模式的关键调节剂。乙酰血清素 O-甲基转移酶（ASMT）是褪黑素生物合成的关键酶，最近与自闭症谱系障碍和抑郁症等精神疾病有关。在本文中，我们分析了 BD 患者和未受影响的对照个体中 ASMT 的罕见和常见变异，并通过测定其 B 淋巴细胞系中的 ASMT 活性来对这些变异进行功能分析。我们在一个由 345 名 BD 患者和 220 名对照组成的发现样本中对基因的编码和调节区域进行了测序。我们在这个发现样本中进行了常见变异位于启动子区域的关联研究，结果表明 rs4446909 与 BD 显著相关（P=0.01），与较低的 mRNA 水平（P<10(-4)) 和较低的 ASMT 酶活性（P<0.05)相关。使用 480 名独立的 BD 患者和 672 名对照进行的复制研究和荟萃分析证实了 rs4446909 与 BD 之间的显著关联（P=0.002）。这些结果与 BD 患者中普遍较低的 ASMT 酶活性（P=0.001）相比，与 ASMT 之间存在相关性。最后，在患者中鉴定出的几种有害 ASMT 突变与低 ASMT 活性相关（P=0.01）。在这项研究中，我们确定了 ASMT 中的罕见和常见变异如何在 BD 易感性中发挥作用，并提出了褪黑素作为 BD 易感因素的一般作用。
