RORB与双相情感障碍的基因关联证据。
Evidence for genetic association of RORB with bipolar disorder.
作者信息
McGrath Casey L, Glatt Stephen J, Sklar Pamela, Le-Niculescu Helen, Kuczenski Ronald, Doyle Alysa E, Biederman Joseph, Mick Eric, Faraone Stephen V, Niculescu Alexander B, Tsuang Ming T
机构信息
Department of Psychiatry, Laboratory of Neurophenomics, Indiana University School of Medicine, Indianapolis, IN, USA.
出版信息
BMC Psychiatry. 2009 Nov 12;9:70. doi: 10.1186/1471-244X-9-70.
BACKGROUND
Bipolar disorder, particularly in children, is characterized by rapid cycling and switching, making circadian clock genes plausible molecular underpinnings for bipolar disorder. We previously reported work establishing mice lacking the clock gene D-box binding protein (DBP) as a stress-reactive genetic animal model of bipolar disorder. Microarray studies revealed that expression of two closely related clock genes, RAR-related orphan receptors alpha (RORA) and beta (RORB), was altered in these mice. These retinoid-related receptors are involved in a number of pathways including neurogenesis, stress response, and modulation of circadian rhythms. Here we report association studies between bipolar disorder and single-nucleotide polymorphisms (SNPs) in RORA and RORB.
METHODS
We genotyped 355 RORA and RORB SNPs in a pediatric cohort consisting of a family-based sample of 153 trios and an independent, non-overlapping case-control sample of 152 cases and 140 controls. Bipolar disorder in children and adolescents is characterized by increased stress reactivity and frequent episodes of shorter duration; thus our cohort provides a potentially enriched sample for identifying genes involved in cycling and switching.
RESULTS
We report that four intronic RORB SNPs showed positive associations with the pediatric bipolar phenotype that survived Bonferroni correction for multiple comparisons in the case-control sample. Three RORB haplotype blocks implicating an additional 11 SNPs were also associated with the disease in the case-control sample. However, these significant associations were not replicated in the sample of trios. There was no evidence for association between pediatric bipolar disorder and any RORA SNPs or haplotype blocks after multiple-test correction. In addition, we found no strong evidence for association between the age-at-onset of bipolar disorder with any RORA or RORB SNPs.
CONCLUSION
Our findings suggest that clock genes in general and RORB in particular may be important candidates for further investigation in the search for the molecular basis of bipolar disorder.
背景
双相情感障碍，尤其是在儿童中，其特征为快速循环和转换，这使得昼夜节律时钟基因成为双相情感障碍可能的分子基础。我们之前报道了建立缺乏时钟基因D-盒结合蛋白（DBP）的小鼠作为双相情感障碍应激反应性遗传动物模型的工作。微阵列研究显示，在这些小鼠中，两个密切相关的时钟基因，视黄酸受体相关孤儿受体α（RORA）和β（RORB）的表达发生了改变。这些类视黄醇相关受体参与了包括神经发生、应激反应和昼夜节律调节在内的多种途径。在此，我们报告双相情感障碍与RORA和RORB中的单核苷酸多态性（SNP）之间的关联研究。
方法
我们对一个儿科队列中的355个RORA和RORB SNP进行了基因分型，该队列包括一个由153个三联体组成的基于家系的样本以及一个由152例病例和140例对照组成的独立、不重叠的病例对照样本。儿童和青少年双相情感障碍的特征是应激反应性增加和频繁发作且持续时间较短；因此，我们的队列提供了一个潜在的富集样本，用于识别参与循环和转换的基因。
结果
我们报告，四个内含子RORB SNP与儿科双相情感障碍表型呈正相关，在病例对照样本中经多重比较的Bonferroni校正后仍具有统计学意义。在病例对照样本中，三个涉及另外11个SNP的RORB单倍型模块也与该疾病相关。然而，这些显著关联在三联体样本中未得到重复验证。在多重检验校正后，没有证据表明儿科双相情感障碍与任何RORA SNP或单倍型模块之间存在关联。此外，我们没有发现双相情感障碍发病年龄与任何RORA或RORB SNP之间存在关联的有力证据。
结论
我们的研究结果表明，一般而言，时钟基因，特别是RORB，可能是在寻找双相情感障碍分子基础的进一步研究中的重要候选基因。
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