Leveraging genome-wide data to investigate differences between opioid use vs. opioid dependence in 41,176 individuals from the Psychiatric Genomics Consortium

Abstract

To provide novel insights into the biology of opioid dependence (OD) and opioid use (i.e., exposure, OE), we completed a genome-wide analysis comparing up to 4,503 OD cases, 4,173 opioid-exposed controls, and 32,500 opioid-unexposed controls. Among the variants identified, rs9291211 was associated with OE (a comparison of exposed vs. unexposed controls; z=-5.39, p=7.2×10 -8 ). This variant regulates the transcriptomic profiles of SLC30A9 and BEND4 in multiple brain tissues and was previously associated with depression, alcohol consumption, and neuroticism. A phenome-wide scan of rs9291211 in the UK Biobank (N>360,000) found association of this variant with propensity to use dietary supplements (p=1.68×10 -8 ). With respect to the same OE phenotype in the gene-based analysis, we identified SDCCAG8 (z=4.69, p=10 -6 ), which was previously associated with educational attainment, risk-taking behaviors, and schizophrenia. In addition, rs201123820 showed a genome-wide significant difference between OD cases and unexposed controls (z=5.55, p=2.9×10 -8 ) and a significant association with musculoskeletal disorders in the UK Biobank (p=4.88×10 -7 ). A polygenic risk score (PRS) based on a GWAS of risk-tolerance (N=466,571) was positively associated with OD (OD cases vs. unexposed controls, p=8.1×10 -5 ; OD cases vs. exposed controls, p=0.054) and OE (exposed controls vs. unexposed controls, p=3.6×10 -5 ). A PRS based on a GWAS of neuroticism (N=390,278) was positively associated with OD (OD cases vs. unexposed controls, p=3.2×10 -5 ; OD cases vs. exposed controls, p=0.002) but not with OE (p=0.671). Our analyses highlight the difference between dependence and exposure and the importance of considering the definition of controls (exposed vs. unexposed) in studies of addiction.

Genetic variation regulates opioid-induced respiratory depression in mice

“…Several GWAS studies have evaluated opioid use disorder (OUD) and/or opioid dependence, and have identified a variety of loci including SNPs linked to OPRM1, KCNG2, CNIH3, LOC647946, LOC101927293, CREB1, PIK3C3, and RGMA 52 – 57 Additional human linkage studies have identified sex-specific traits 58 , epigenetic biomarkers 59 or copy number variations 60 for risk of OUD. Other studies have sought to separate opioid use from opioid dependence, and have thus far identified SNPs associated with SDCCAG8, SLC30A9, and BEND4 61 . Only one study has looked at human opioid overdose risk, specifically by scoring overdose status and determining the number of times that medical treatment was needed in European American populations 54 .…”

Genetic Variation Regulates Opioid-Induced Respiratory Depression in Mice

“…Additional human linkage studies have identified sex-specific traits 46 , epigenetic biomarkers 47 or copy number variations 48 for risk of OUD. Other studies have sought to separate opioid use from opioid dependence, and have thus far identified SNPs associated with SDCCAG8, SLC30A9, and BEND4 49 . Only one study has looked at human opioid overdose risk, specifically by scoring overdose status and determining the number of times that medical treatment was needed in European American populations 50 .…”

GeneCup: mine PubMed for gene relationships using custom ontology and deep learning

“…A GWAS on alcohol use disorder identified 18 genome-wide significant loci 2 . GWAS on opioid 3 or cocaine use disorders 4 have also been conducted or are ongoing.…”