Abstract
There is a reciprocal relationship between the circadian and the reward systems. Polymorphisms in several circadian rhythm-related (clock) genes were associated with drug addiction. This study aims to search for associations between 895 variants in 39 circadian rhythm-related genes and opioid addiction (OUD). Genotyping was performed with the Smokescreen® array. Ancestry was verified by principal/MDS component analysis and the sample was limited to European Americans (EA) (OUD; n = 435, controls; n = 138). Nominally significant associations (p < 0.01) were detected for several variants in genes encoding vasoactive intestinal peptide receptor 2 (VIPR2), period circadian regulator 2 (PER2), casein kinase 1 epsilon (CSNK1E), and activator of transcription and developmental regulator (AUTS2), but no signal survived correction for multiple testing. There was intriguing association signal for the untranslated region (3’ UTR) variant rs885863 in VIPR2, (p = .0065; OR = 0.51; 95% CI 0.31–0.51). The result was corroborated in an independent EA OUD sample (n = 398, p = 0.0036; for the combined samples). Notably, this SNP is an expression quantitative trait locus (cis-eQTL) for VIPR2 and a long intergenic non-coding RNA, lincRNA 689, in a tissue-specific manner, based on the Genotype-Tissue Expression (GTEx) project. Vasoactive intestinal peptide (VIP) is an important peptide of light-activated suprachiasmatic nucleus cells. It regulates diverse physiological processes including circadian rhythms, learning and memory, and stress response. This is the first report of an association of a VIPR2 variant and OUD. Additionally, analysis of combinations of single nucleotide polymorphisms (SNPs) genotypes revealed an association of PER2 SNP rs80136044, and SNP rs4128839, located 41.6 kb downstream of neuropeptide Y receptor type 1 gene, NPY1R (p = 3.4 × 10−6, OR = 11.4, 95% CI 2.7–48.2). The study provides preliminary insight into the relationship between genetic variants in circadian rhythm genes and long non-coding RNA (lncRNAs) in their vicinity, and opioid addiction.
Highlights
The circadian clock has a bidirectional relationship with the reward system [1]
The present study includes a subsample of a cohort (n = 1810) that was shared by the Laboratory of the Biology of Addictive Diseases from the Rockefeller University with the National Institute on Drug Abuse (NIDA) Genetics Consortium
From the original single nucleotide polymorphisms (SNPs) set of these genes, 119 SNPs were excluded based on low frequency in the control sample (MAF < 0.05), six variants were removed due to missing genotype data (< 94%), and two SNPs were excluded based on Hardy-Weinberg equilibrium (HWE) (p < 2 x 10
Summary
Circadian rhythms are physical and behavioral changes that follow a daily cycle and respond primarily to light. Drug addiction is a chronic relapsing disease with a genetic and environmental contribution (e.g., stress), that is characterized by compulsive use and destructive consequences [2]. Internal circadian desynchrony can exacerbate or affect the development of a range of diseases including drug addiction. Exposure to drugs of abuse affects neuronal firing within the suprachiasmatic nucleus (SCN) and produces changes to circadian rhythms that persist even after exposure is stopped and may contribute to return to use [3]. Drugs of abuse modulate the expression of circadian rhythm-related genes in the brain and these genes regulate pathways and neurotransmitter systems that have a role in drug addiction [4,5,6,7]
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