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

PLoS One. 2019 Nov 5;14(11):e0224399. doi: 10.1371/journal.pone.0224399. eCollection 2019.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3' Untranslated Regions / genetics*
  • Basic Helix-Loop-Helix Transcription Factors / genetics
  • Circadian Rhythm / genetics
  • Genetic Predisposition to Disease
  • Humans
  • Opioid-Related Disorders / genetics*
  • Period Circadian Proteins / genetics*
  • Polymorphism, Single Nucleotide
  • Quantitative Trait Loci / genetics*
  • RNA, Long Noncoding / genetics*
  • Receptors, Vasoactive Intestinal Peptide, Type II / genetics
  • Repressor Proteins / genetics
  • Reward


  • 3' Untranslated Regions
  • Basic Helix-Loop-Helix Transcription Factors
  • HES6 protein, human
  • PER2 protein, human
  • Period Circadian Proteins
  • RNA, Long Noncoding
  • Receptors, Vasoactive Intestinal Peptide, Type II
  • Repressor Proteins
  • VIPR2 protein, human