Department of Preventive Medicine, School of Medicine, Eulji University, Daejeon, Republic of Korea.
Department of Pharmacology, School of Medicine, Eulji University, Daejeon, Republic of Korea.
J Affect Disord. 2019 Oct 1;257:510-517. doi: 10.1016/j.jad.2019.06.056. Epub 2019 Jul 2.
The genetic interactions in the circadian rhythm biological system are promising as a source of pathophysiology in mood disorder. We examined the role of the gene-gene interactions of clock genes in mood disorder.
We included 413 patients with mood disorder and 1294 controls. The clock genes investigated were BHLHB2, CLOCK, CSNK1E, NR1D1, PER2, PER3, and TIMELESS. Allele, genotype, and haplotype associations were tested. Gene--gene interactions were analyzed using the non-parametric model-free multifactor-dimensionality reduction (MDR) method.
TIMELESS rs4630333 and CSNK1E rs135745 were significantly associated with both major depressive disorder and bipolar disorder. The CLOCK haplotype was also strongly associated. The genetic roles of these SNPs were consistent from the allele and genotypic associations to the MDR interaction results. In MDR analysis, the combination of TIMELESS rs4630333 and CSNK1E rs135745 exhibited the most significant association with mood disorders in the two-locus model. BHLHB2 rs2137947 for major depressive disorder and CLOCK rs12649507 for bipolar disorder were the most significant third loci in the three-locus combination model. The four-locus SNP combination model showed the best balanced accuracy (BA), but its cross-validation consistency (CVC) was unsatisfactory.
We included only 17 SNPs for seven circadian genes due to our limited resources; all subjects were ethnically Korean.
Our results suggest significant single-gene associations and gene-gene interactions of circadian genes with mood disorder. Gene-gene interactions play a crucial role in mood disorder, even when individual clock genes do not have significant roles.
生物钟生物系统中的遗传相互作用是心境障碍病理生理学的一个有前途的来源。我们研究了时钟基因的基因-基因相互作用在心境障碍中的作用。
我们纳入了 413 名心境障碍患者和 1294 名对照。研究的时钟基因包括 BHLHB2、CLOCK、CSNK1E、NR1D1、PER2、PER3 和 TIMELESS。检测了等位基因、基因型和单倍型关联。使用非参数模型自由多因子降维（MDR）方法分析基因-基因相互作用。
TIMELESS rs4630333 和 CSNK1E rs135745 与重性抑郁障碍和双相障碍均显著相关。CLOCK 单倍型也与这些疾病强烈相关。这些 SNP 的遗传作用从等位基因和基因型关联到 MDR 相互作用结果都是一致的。在 MDR 分析中，TIMELESS rs4630333 和 CSNK1E rs135745 的组合在双基因模型中与心境障碍最显著相关。BHLHB2 rs2137947 与重性抑郁障碍相关，CLOCK rs12649507 与双相障碍相关，是三基因组合模型中最显著的第三基因。四基因 SNP 组合模型表现出最佳的平衡准确性（BA），但其交叉验证一致性（CVC）不理想。
由于资源有限，我们仅对 7 个生物钟基因的 17 个 SNP 进行了分析；所有受试者均为韩国人。
我们的研究结果表明，生物钟基因与心境障碍存在显著的单基因关联和基因-基因相互作用。基因-基因相互作用在心境障碍中起着至关重要的作用，即使个别时钟基因没有显著作用。
