Park Mira, Kim Soon Ae, Shin Jieun, Joo Eun-Jeong
Department of Preventive Medicine, Eulji University School of Medicine, Daejeon 34824, Korea.
Department of Pharmacology, Eulji University School of Medicine, Daejeon 34824, Korea.
Genomics Inform. 2020 Dec;18(4):e38. doi: 10.5808/GI.2020.18.4.e38. Epub 2020 Dec 9.
Chronotype is an important moderator of psychiatric illnesses, which seems to be controlled in some part by genetic factors. Clock genes are the most relevant genes for chronotype. In addition to the roles of individual genes, gene-gene interactions of clock genes substantially contribute to chronotype. We investigated genetic associations and gene-gene interactions of the clock genes BHLHB2, CLOCK, CSNK1E, NR1D1, PER1, PER2, PER3, and TIMELESS for chronotype in 1293 healthy Korean individuals. Regression analysis was conducted to find associations between single nucleotide polymorphism (SNP) and chronotype. For gene-gene interaction analyses, the quantitative multifactor dimensionality reduction (QMDR) method, a nonparametric model-free method for quantitative phenotypes, were performed. No individual SNP or haplotype showed a significant association with chronotype by both regression analysis and single-locus model of QMDR. QMDR analysis identified NR1D1 rs2314339 and TIMELESS rs4630333 as the best SNP pairs among two-locus interaction models associated with chronotype (cross-validation consistency [CVC] = 8/10, p = 0.041). For the three-locus interaction model, the SNP combination of NR1D1 rs2314339, TIMELESS rs4630333, and PER3 rs228669 showed the best results (CVC = 4/10, p < 0.001). However, because the mean differences between genotype combinations were minor, the clinical roles of clock gene interactions are unlikely to be critical.
昼夜节律类型是精神疾病的一个重要调节因素，它似乎在某种程度上受遗传因素控制。生物钟基因是与昼夜节律类型最相关的基因。除了单个基因的作用外，生物钟基因之间的基因-基因相互作用对昼夜节律类型也有很大贡献。我们在1293名健康的韩国个体中研究了生物钟基因BHLHB2、CLOCK、CSNK1E、NR1D1、PER1、PER2、PER3和TIMELESS与昼夜节律类型的遗传关联及基因-基因相互作用。进行回归分析以寻找单核苷酸多态性（SNP）与昼夜节律类型之间的关联。对于基因-基因相互作用分析，采用了定量多因素降维（QMDR）方法，这是一种用于定量表型的非参数无模型方法。通过回归分析和QMDR的单基因座模型，没有单个SNP或单倍型与昼夜节律类型显示出显著关联。QMDR分析确定NR1D1 rs2314339和TIMELESS rs4630333是与昼夜节律类型相关的两位点相互作用模型中最佳的SNP对（交叉验证一致性 [CVC]=8/10，p = 0.041）。对于三位点相互作用模型，NR1D1 rs2314339、TIMELESS rs4630333和PER3 rs228669的SNP组合显示出最佳结果（CVC = 4/10，p < 0.001）。然而，由于基因型组合之间的平均差异较小，生物钟基因相互作用的临床作用不太可能至关重要。
