A 3’ UTR SNP rs885863, a cis-eQTL for the circadian gene VIPR2 and lincRNA 689, is associated with opioid addiction

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.

Seaweed intake modulates the association between VIPR2 variants and the incidence of metabolic syndrome in middle-aged Koreans

“…49,50 VIPR2 is a circadian gene that helps maintain normal circadian rhythms and metabolic homeostasis. 23,51 This circadian rhythm is influenced by environmental cues, such as nutrient intake. Growing evidence suggests that MetS is associated with circadian rhythm disturbances.…”

“…49,50 VIPR2 is a circadian gene that helps maintain normal circadian rhythms and metabolic homeostasis. 23,51 This circadian rhythm is influenced by environmental cues, such as nutrient intake. Growing 54,55 The composition of fatty acids in the plasma membrane of Acetabularia algae cells is affected by circadian regulation, which has been reported to regulate membrane-bound cation-pumping ATPases and alter the physical properties of the membrane.…”

Influence of Cannabinoid Receptor 1 Genetic Variants on the Subjective Effects of Smoked Cannabis

“…Firstly, the sample size of this study was small. From the original CADRI trial, there were 52 active cannabis group participants that consented to the secondary genetic analysis, and while this is not a particularly small sample size for a clinical trial, it is certainly small for a genotyping study [ 57 , 58 , 59 , 60 , 61 ]. Considering the limited contribution single-nucleotide polymorphisms (SNPs) have on their resultant protein products, genotyping studies generally require large subject pools to observe significant differences in genotypic groups.…”

“…SNPs have relatively small influence on resultant protein products and the phenotypic characteristics they control. Recently published genotyping experiments studying SNPs in relation to reward processing and addictive behaviour have assembled samples ranging from 500 to nearly 25,000 subjects [ 57 , 58 , 59 , 60 , 61 ]. Future investigations into this topic should have a primary aim of studying the genetics behind the subjective effects of smoked cannabis, and as such, develop a sample size more appropriate for answering these experimental questions.…”

Epigenetic Modulation of Opioid Receptors by Drugs of Abuse

“…Genetic variants within ANRIL (antisense non-coding RNA in the INK4 locus) are associated with an increased risk of METH-dependence in humans [ 99 ]. A SNP in the 3′ untranslated region (3’ UTR) of the circadian Vasoactive Intestinal Peptide Receptor 2 (VIPR2) gene ( VIPR2 SNP rs885863) is significantly noted in a pool of patients suffering from opioid dependence [ 100 ]. This SNP is an expression quantitative trait locus for VIPR2 and a long intergenic non-coding RNA, lncRNA 689.…”