Significant role of gene–gene interactions of clock genes in mood disorder

Background 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. Methods 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. Results 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. Limitations We included only 17 SNPs for seven circadian genes due to our limited resources; all subjects were ethnically Korean. Conclusions 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.