A promoter polymorphism in the Per3 gene is associated with alcohol and stress response

Abstract

The period homolog genes Per1, Per2 and Per3 are important components of the circadian clock system. In addition to their role in maintaining circadian rhythm, these genes have been linked to mood disorders, stress response and vulnerability to addiction and alcoholism. In this study, we combined high-resolution sequence analysis and quantitative trait locus (QTL) mapping of gene expression and behavioral traits to identify Per3 as a compelling candidate for the interaction between circadian rhythm, alcohol and stress response. In the BXD family of mouse strains, sequence variants in Per3 have marked effects on steady-state mRNA and protein levels. As a result, the transcript maps as a cis-acting expression QTL (eQTL). We found that an insertion/deletion (indel) variant in a putative stress response element in the promoter region of Per3 causes local control of transcript abundance. This indel results in differences in protein binding affinities between the two alleles through the Nrf2 transcriptional activator. Variation in Per3 is also associated with downstream differences in the expression of genes involved in circadian rhythm, alcohol, stress response and schizophrenia. We found that the Per3 locus is linked to stress/anxiety traits, and that the basal expression of Per3 is also correlated with several anxiety and addiction-related phenotypes. Treatment with alcohol results in increased expression of Per3 in the hippocampus, and this effect interacts with acute restraint stress. Our data provide strong evidence that variation in the Per3 transcript is causally associated with and also responsive to stress and alcohol.

Effects of Psychosocial Stress on the Gene Expression of the Clock Genes <i>hPER</i>1 and <i>hPER</i>2 in Humans

“…Similar results have been found in the gene expression of Per3 of stressed animals (Wang et al, 2012). Although reports on the interaction of chronic stress and cortisol are still conflicting (Kudielka et al, 2009), in our sample, high levels of chronic stress are unambiguously associated with lower basal cortisol.…”

“…This may imply an even stronger relationship between the circadian clock and glucocorticoids than hitherto assumed. Furthermore recent research could show a variation of gene expression in the hippocampus according to a promoter polymorphism in the Per3 gene and its association to the stress response in mice: there was a significantly higher Per3 expression in stressed animals compared to non stressed animals (Wang et al, 2012).…”

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

“…A central role for the circadian system in AUD is underscored by evidence linking most clock genes with AUD (Albrecht et al, 2001;Franken et al, 2000;Gamsby et al, 2013;Kovanen et al, 2010;Le-Niculescu et al, 2008;Lopez-Molina et al, 1997;Melendez et al, 2011;Perreau-Lenz et al, 2012;Spanagel et al, 2005;Steinlechner et al, 2002;Wang et al, 2012;Yang et al, 2012). In addition to ethanol (Melendez et al, 2011), morphine (Hood et al, 2011) and amphetamine (Wongchitrat et al, 2013) alter circadian variation in clock gene expression in the mesolimbic reward system during chronic use and/or withdrawal, which may contribute to addictive behavior and/or circadian misalignment.…”

Genetical Genomics of Behavior: A Novel Chicken Genomic Model for Anxiety Behavior

“…Successful examples of behavioral QTG identification are almost exclusively limited to mouse and rat models (Yalcin et al 2004;Chiavegatto et al 2008;Kim et al 2009;Tomida et al 2009;Gyetvai et al 2011;Wang et al 2012;Heyne et al 2014), Drosophila (Anholt and Mackay 2004;Mackay 2004;Fitzpatrick et al 2005), and the honeybee (Robinson et al , 2008. The ramifications for the identification of such behavioral genes are many and varied.…”