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Significant role of gene-gene interactions of clock genes in mood disorder.
J Affect Disord 2019; 257:510-517JA

Abstract

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.

Authors+Show Affiliations

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.Department of Physiology and Biophysics, School of Medicine, Eulji University, Daejeon, Republic of Korea.Department of Preventive Medicine, School of Medicine, Eulji University, Daejeon, Republic of Korea.Department of Neuropsychiatry, School of Medicine, Eulji University, Daejeon, Republic of Korea; Department of Psychiatry, Nowon Eulji Meical Center, Eulji University, Seoul, Republic of Korea.Department of Neuropsychiatry, School of Medicine, Eulji University, Daejeon, Republic of Korea; Department of Psychiatry, Nowon Eulji Meical Center, Eulji University, Seoul, Republic of Korea. Electronic address: jej1303@eulji.ac.kr.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31323592

Citation

Park, Mira, et al. "Significant Role of Gene-gene Interactions of Clock Genes in Mood Disorder." Journal of Affective Disorders, vol. 257, 2019, pp. 510-517.
Park M, Kim SA, Yee J, et al. Significant role of gene-gene interactions of clock genes in mood disorder. J Affect Disord. 2019;257:510-517.
Park, M., Kim, S. A., Yee, J., Shin, J., Lee, K. Y., & Joo, E. J. (2019). Significant role of gene-gene interactions of clock genes in mood disorder. Journal of Affective Disorders, 257, pp. 510-517. doi:10.1016/j.jad.2019.06.056.
Park M, et al. Significant Role of Gene-gene Interactions of Clock Genes in Mood Disorder. J Affect Disord. 2019 Jul 2;257:510-517. PubMed PMID: 31323592.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Significant role of gene-gene interactions of clock genes in mood disorder. AU - Park,Mira, AU - Kim,Soon Ae, AU - Yee,Jaeyong, AU - Shin,Jieun, AU - Lee,Kyu Young, AU - Joo,Eun-Jeong, Y1 - 2019/07/02/ PY - 2019/02/19/received PY - 2019/06/24/revised PY - 2019/06/30/accepted PY - 2019/7/20/pubmed PY - 2019/7/20/medline PY - 2019/7/20/entrez KW - Bipolar disorder KW - Clock genes KW - Gene–gene interaction KW - Major depressive disorder KW - Mood disorder SP - 510 EP - 517 JF - Journal of affective disorders JO - J Affect Disord VL - 257 N2 - 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. SN - 1573-2517 UR - https://www.unboundmedicine.com/medline/citation/31323592/Significant_role_of_gene-gene_interactions_of_clock_genes_in_mood_disorder L2 - https://linkinghub.elsevier.com/retrieve/pii/S0165-0327(19)30451-3 DB - PRIME DP - Unbound Medicine ER -