Differential Association of Circadian Genes with Mood Disorders: CRY1 and NPAS2 are Associated with Unipolar Major Depression and CLOCK and VIP with Bipolar Disorder

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 0 near CRY1 gene in MDD remained statistically significant after permutation correction at experiment level (p ¼ 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.

Agomelatine, melatonin and depressive disorder

“…On the other hand, two lines of evidence suggest a link: the association of polymorphisms of some circadian genes and features of depression (such as age at onset, diurnal activity pattern, insomnia) and the effects of antidepressant medications on circadian gene expression. A recent study suggested an association between haplotypes in the cry1 and npas2 genes and unipolar major depression [16]. This study provides some support for the involvement of the circadian system with depression, suggesting that variations may, at least, represent a vulnerability factor(s) for the disorder.…”

Adenosinergic Regulation of Striatal Clock Gene Expression and Ethanol Intake During Constant Light

“…Of note, adult ADHD is linked with blunted Per2 expression (Baird et al, 2012). It is also interesting that the other clock genes with altered circadian profiles in ENT1 KO mice, Clock and Dbp, are associated with ADHD (Kissling et al, 2008;Roybal et al, 2007;Xu et al, 2010), bipolar disorder (Le-Niculescu et al, 2008;Lee et al, 2010;Shi et al, 2008;Soria et al, 2010), anxiety (Le-Niculescu et al, 2011a), and AUD (Le-Niculescu et al, 2011b;Le-Niculescu et al, 2008). Interestingly, ENT1 KO mice display mania-like behavior (Ruby et al, 2011) similar to Dbp KO mice (Le-Niculescu et al, 2008).…”

Tipología circadiana y problemas de salud mental

“…Genes reloj que también se hallan implicados en diversos problemas de salud mental. En los trastornos depresivos existen asociaciones con polimorfismos en los genes Per2 (Lavebratt, Sjöholm, Partonen, Schalling y Forsell, 2010), Per3 (Nievergelt et al, 2006) y Clock (Benedetti et al, 2003), en el trastorno bipolar destacan los polimorfismos en los genes Per3 (Nievergelt et al, 2006) y Clock (Soria et al, 2010) , en el consumo de drogas se han hallado relaciones con los genes Per1 (Liu et al, 2007;McClung, 2007), Per2 (Perreau-Lenz, Zghould, de Fonseca, Spanagel y Bilbao, 2009) y Clock (McClung, Sidiripoulou, Vitaterna, Takahashi y White, 2005), y la esquizofrenia se ha visto asociada a polimorfismos de los genes Per3 (Mansour et al, 2006) y Clock (Zhang et al, 2011). Por último, los trastornos de sueño se anales de psicología, 2014, vol.…”