Circadian polymorphisms associated with affective disorders.
Circadian polymorphisms associated with affective disorders.
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DOI：
10.1186/1740-3391-7-2
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发表时间：
2009-01-23
影响因子：
--
通讯作者：
Kelsoe JR
中科院分区：
文献类型：
--
作者：
Kripke DF;Nievergelt CM;Joo E;Shekhtman T;Kelsoe JR
情感障碍的临床症状、对光治疗的反应以及对其他昼夜节律干预措施的敏感性表明昼夜节律系统在情绪障碍中发挥着作用。该机制可能涉及昼夜节律和光周期机制。由于遗传易感性是情感障碍的重要组成部分，因此我们在四项补充研究中探讨了昼夜节律基因多态性是否与情感障碍相关。从多个来源招募了四组受试者：1）双相情感障碍先证者父母三人组或同胞对父母核心家庭，2）已完成 BALM 早晚问卷的无关双相情感障碍参与者，3）来自 GenRed 项目的同胞对，其中至少有一个患有早发性复发性单相抑郁症的同胞，以及 4）经常患有抑郁症的睡眠诊所患者组。主要使用 SNPlex 检测系统，对参与者组中与昼夜节律功能相关的基因中 2 至 198 个多态性进行了基因分型。使用 TDT 统计数据检查与情感障碍的关联，以进行家庭内比较。在不相关的样本中检查数量性状关联。在 NR1D1 中，rs2314339 与双相情感障碍相关（P = 0.0005）。在不相关的双相情感障碍参与者中，PER3 和 CSNK1E 中的 3 个 SNP 与 BALM 评分相关。 PPARGC1B 编码 SNP rs7732671 与情感障碍相关，在双相情感障碍家庭组中具有名义意义，而在单相情感障碍中则独立存在。在 TEF 中，rs738499 与单相抑郁症相关；在一项重复研究中，rs738499 还与睡眠诊所患者样本中的 QIDS-SR 抑郁量表相关。除了锂的抗躁狂作用和强光的抗抑郁作用之外，这些发现表明，昼夜节律基因网络在多个层面上的扰动可能会影响情绪障碍，也许最终是通过 MAOA 的调节及其对多巴胺传递的调节。昼夜节律多态性与情感症状的 23 种关联符合名义显着性标准 (P < 0.05)，而 15 种关联是偶然的，表明许多代表错误的发现（II 型错误）。已经收集了一些复制证据，但需要更多的研究来确定昼夜节律基因多态性是否会导致情感障碍的易感性。
Clinical symptoms of affective disorders, their response to light treatment, and sensitivity to other circadian interventions indicate that the circadian system has a role in mood disorders. Possibly the mechanisms involve circadian seasonal and photoperiodic mechanisms. Since genetic susceptibilities contribute a strong component to affective disorders, we explored whether circadian gene polymorphisms were associated with affective disorders in four complementary studies. Four groups of subjects were recruited from several sources: 1) bipolar proband-parent trios or sib-pair-parent nuclear families, 2) unrelated bipolar participants who had completed the BALM morningness-eveningness questionnaire, 3) sib pairs from the GenRed Project having at least one sib with early-onset recurrent unipolar depression, and 4) a sleep clinic patient group who frequently suffered from depression. Working mainly with the SNPlex assay system, from 2 to 198 polymorphisms in genes related to circadian function were genotyped in the participant groups. Associations with affective disorders were examined with TDT statistics for within-family comparisons. Quantitative trait associations were examined within the unrelated samples. In NR1D1, rs2314339 was associated with bipolar disorder (P = 0.0005). Among the unrelated bipolar participants, 3 SNPs in PER3 and CSNK1E were associated with the BALM score. A PPARGC1B coding SNP, rs7732671, was associated with affective disorder with nominal significance in bipolar family groups and independently in unipolar sib pairs. In TEF, rs738499 was associated with unipolar depression; in a replication study, rs738499 was also associated with the QIDS-SR depression scale in the sleep clinic patient sample. Along with anti-manic effects of lithium and the antidepressant effects of bright light, these findings suggest that perturbations of the circadian gene network at several levels may influence mood disorders, perhaps ultimately through regulation of MAOA and its modulation of dopamine transmission. Twenty-three associations of circadian polymorphisms with affective symptoms met nominal significance criteria (P < 0.05), whereas 15 would be expected by chance, indicating that many represented false discoveries (Type II errors). Some evidence of replication has been gathered, but more studies are needed to ascertain if circadian gene polymorphisms contribute to susceptibility to affective disorders.