Abstract
Disruptions in circadian rhythms have been described in mood disorders (MD), but the involvement of genetic variation in genes pertaining to the molecular circadian machinery in the susceptibility to MD has not been conclusively determined. We examined 209 single-nucleotide polymorphisms (SNPs) covering 19 circadian genes (ADCYAP1, ARNTL, ARNTL2, BHLHB2, BHLHB3, CLOCK, CRY1, CRY2, CSNK1E, DBP, NPAS2, NR1D1, PER1, PER2, PER3, RORA, TIMELESS, VIP, and VIPR2) in a sample of 534 MD patients (335 with unipolar major mood depression (MDD) and 199 with bipolar disorder (BD)) and 440 community-based screened controls. Nominally, statistically significant associations were found in 15 circadian genes. The gene-wide test, corrected for the number of SNPs analyzed in each gene, identified significant associations in CRY1 (rs2287161), NPAS2 (rs11123857), and VIPR2 (rs885861) genes with the combined MD sample. In the MDD subsample, the same SNPs in CRY1 and NPAS2 of the combined sample remained associated, whereas in the BD subsample CLOCK (rs10462028) and VIP (rs17083008) were specifically associated. The association with an SNP located 3′ near CRY1 gene in MDD remained statistically significant after permutation correction at experiment level (p=0.007). Significant additive effects were found between the SNPs that were statistically significant at the gene-wide level. We also found evidence of associations between two-marker haplotypes in CRY1 and NPAS2 genes and MD. Our data support the contribution of the circadian system to the genetic susceptibility to MD and suggest that different circadian genes may have specific effects on MD polarity.
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Acknowledgements
We are very grateful to all the study participants and clinicians and nurses from the Psychiatry Department of the ‘Hospital Universitari de Bellvitge’ and ‘Hospital de la Santa Creu i Sant Pau’ who helped to collect the sample of this study. Also to technicians from the Biobanc IISPV of Reus and Center for Genomic Regulation (CRG). This research project was supported in part by the Spanish Ministry of Health, Instituto de Salud Carlos III (Centro de Investigación en Red de Salud Mental, CIBERSAM; Centro de Investigación en Red en Epidemiología y Salud Pública CIBERESP; PI050960; PI000954), the Ministerio de Ciencia y Innovación (SAF2008-00357), and Genome Spain to the Barcelona node of the Spanish National Genotyping Center (CEGEN).
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Related to this work: The authors have no biomedical financial interests or potential conflicts of interest regarding this work.
Related to other compensations: Over the past 3 years authors Crespo, Menchón, Pérez, Urretavizcaya, and Vallejo have received compensation for lectures, advisories, or non-restricted grants from Almirall, AstraZeneca, Boehringer, GlaxoSmithKline, Lilly, Lundbeck, Janssen-Cilag, and Wyeth.
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Soria, V., Martínez-Amorós, È., Escaramís, G. et al. Differential Association of Circadian Genes with Mood Disorders: CRY1 and NPAS2 are Associated with Unipolar Major Depression and CLOCK and VIP with Bipolar Disorder. Neuropsychopharmacol 35, 1279–1289 (2010). https://doi.org/10.1038/npp.2009.230
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