Maciukiewicz Malgorzata, Dmitrzak-Weglarz Monika, Pawlak Joanna, Leszczynska-Rodziewicz Anna, Zaremba Dorota, Skibinska Maria, Hauser Joanna
Laboratory of Psychiatric Genetics, Department of Psychiatry, Poznan University of Medical Sciences , Poznan , Poland.
Chronobiol Int. 2014 Jul;31(6):770-8. doi: 10.3109/07420528.2014.899244. Epub 2014 Mar 27.
Bipolar affective disorder (BD) is a severe psychiatric disorder characterized by periodic changes in mood from depression to mania. Disruptions of biological rhythms increase risk of mood disorders. Because clinical representation of disease is heterogeneous, homogenous sets of patients are suggested to use in the association analyses. In our study, we aimed to apply previously computed structure of bipolar disorder symptom dimension for analyses of genetic association. We based quantitative trait on: main depression, sleep disturbances, appetite disturbances, excitement and psychotic dimensions consisted of OPCRIT checklist items. We genotyped 42 polymorphisms from circadian clock genes: PER3, ARNTL, CLOCK and TIMELSSS from 511 patients BD (n = 292 women and n = 219 men). As quantitative trait we used clinical dimensions, described above. Genetic associations between alleles and quantitative trait were performed using applied regression models applied in PLINK. In addition, we used the Kruskal-Wallis test to look for associations between genotypes and quantitative trait. During second stage of our analyses, we used multidimensional scaling (multifactor dimensionality reduction) for quantitative trait to compute pairwise epistatic interactions between circadian gene variants. We found association between ARNTL variant rs11022778 main depression (p = 0.00047) and appetite disturbances (p = 0.004). In epistatic interaction analyses, we observed two locus interactions between sleep disturbances (p = 0.007; rs11824092 of ARNTL and rs11932595 of CLOCK) as well as interactions of subdimension in main depression and ARNTL variants (p = 0.0011; rs3789327, rs10766075) and appetite disturbances in depression and ARNTL polymorphism (p = 7 × 10(-4); rs11022778, rs156243).
双相情感障碍（BD）是一种严重的精神疾病，其特征是情绪从抑郁到躁狂的周期性变化。生物节律紊乱会增加情绪障碍的风险。由于该疾病的临床表现具有异质性，因此建议在关联分析中使用同质的患者群体。在我们的研究中，我们旨在应用先前计算的双相情感障碍症状维度结构进行遗传关联分析。我们基于以下定量特征：主要抑郁、睡眠障碍、食欲障碍、兴奋和由OPCRIT检查表项目组成的精神病维度。我们对511例双相情感障碍患者（n = 292名女性和n = 219名男性）的昼夜节律基因PER3、ARNTL、CLOCK和TIMELSSS中的42个多态性进行了基因分型。作为定量特征，我们使用了上述临床维度。使用PLINK中应用的回归模型对等位基因与定量特征之间的遗传关联进行了分析。此外，我们使用Kruskal-Wallis检验来寻找基因型与定量特征之间的关联。在我们分析的第二阶段，我们对定量特征使用多维标度法（多因素降维法）来计算昼夜节律基因变体之间的成对上位相互作用。我们发现ARNTL变体rs11022778与主要抑郁（p = 0.00047）和食欲障碍（p = 0.004）之间存在关联。在上位相互作用分析中，我们观察到睡眠障碍之间的两个基因座相互作用（p = 0.007；ARNTL的rs11824092和CLOCK的rs11932595），以及主要抑郁亚维度与ARNTL变体之间的相互作用（p = 0.0011；rs3789327，rs10766075），以及抑郁中的食欲障碍与ARNTL多态性之间的相互作用（p = 7×10(-4)；rs11022778，rs156243）。
