Nievergelt Caroline M, Kripke Daniel F, Barrett Thomas B, Burg Elyssa, Remick Ronald A, Sadovnick A Dessa, McElroy Susan L, Keck Paul E, Schork Nicholas J, Kelsoe John R
Department of Psychiatry, University of California, San Diego, La Jolla, California 92093-0603, USA.
Am J Med Genet B Neuropsychiatr Genet. 2006 Apr 5;141B(3):234-41. doi: 10.1002/ajmg.b.30252.
Bipolar affective disorder (BPAD) is suspected to arise in part from malfunctions of the circadian system, a system that enables adaptation to a daily and seasonally cycling environment. Genetic variations altering functions of genes involved with the input to the circadian clock, in the molecular feedback loops constituting the circadian oscillatory mechanism itself, or in the regulatory output systems could influence BPAD as a result. Several human circadian system genes have been identified and localized recently, and a comparison with linkage hotspots for BPAD has revealed some correspondences. We have assessed evidence for linkage and association involving polymorphisms in 10 circadian clock genes (ARNTL, CLOCK, CRY2, CSNK1epsilon, DBP, GSK3beta, NPAS2, PER1, PER2, and PER3) to BPAD. Linkage analysis in 52 affected families showed suggestive evidence for linkage to CSNK1epsilon. This finding was not substantiated in the association study. Fifty-two SNPs in 10 clock genes were genotyped in 185 parent proband triads. Single SNP TDT analyses showed no evidence for association to BPAD. However, more powerful haplotype analyses suggest two candidates deserving further studies. Haplotypes in ARNTL and PER3 were found to be significantly associated with BPAD via single-gene permutation tests (PG = 0.025 and 0.008, respectively). The most suggestive haplotypes in PER3 showed a Bonferroni-corrected P-value of PGC = 0.07. These two genes have previously been implicated in circadian rhythm sleep disorders and affective disorders. With correction for the number of genes considered and tests conducted, these data do not provide statistically significant evidence for association. However, the trends for ARNTL and PER3 are suggestive of their involvement in bipolar disorder and warrant further study in a larger sample.
双相情感障碍（BPAD）被怀疑部分源于昼夜节律系统的功能失调，该系统能使人适应日常和季节性循环的环境。改变参与昼夜节律时钟输入、构成昼夜节律振荡机制本身的分子反馈回路或调节输出系统的基因功能的基因变异，可能会因此影响BPAD。最近已经鉴定并定位了几种人类昼夜节律系统基因，与BPAD连锁热点的比较揭示了一些对应关系。我们评估了10个昼夜节律时钟基因（ARNTL、CLOCK、CRY2、CSNK1epsilon、DBP、GSK3beta、NPAS2、PER1、PER2和PER3）中的多态性与BPAD的连锁和关联证据。对52个患病家庭进行的连锁分析显示，与CSNK1epsilon存在连锁的提示性证据。这一发现并未在关联研究中得到证实。在185个父母-先证者三联体中对10个时钟基因中的52个单核苷酸多态性（SNP）进行了基因分型。单SNP传递不平衡检验（TDT）分析未显示与BPAD相关的证据。然而，更强大的单倍型分析表明有两个候选基因值得进一步研究。通过单基因置换检验发现，ARNTL和PER3中的单倍型与BPAD显著相关（PG分别为0.025和0.008）。PER3中最具提示性的单倍型经Bonferroni校正后的PGC值为0.07。此前这两个基因已被认为与昼夜节律睡眠障碍和情感障碍有关。校正所考虑的基因数量和进行的检验后，这些数据并未提供具有统计学意义的关联证据。然而，ARNTL和PER3的趋势表明它们可能参与双相情感障碍，值得在更大样本中进一步研究。
