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Genome-wide association study of problematic opioid prescription use in 132,113 23andMe research participants of European ancestry.

ABSTRACT: The growing prevalence of opioid use disorder (OUD) constitutes an urgent health crisis. Ample evidence indicates that risk for OUD is heritable. As a surrogate (or proxy) for OUD, we explored the genetic basis of using prescription opioids 'not as prescribed'. We hypothesized that misuse of opiates might be a heritable risk factor for OUD. To test this hypothesis, we performed a genome-wide association study (GWAS) of problematic opioid use (POU) in 23andMe research participants of European ancestry (N = 132,113; 21% cases). We identified two genome-wide significant loci (rs3791033, an intronic variant of KDM4A; rs640561, an intergenic variant near LRRIQ3). POU showed positive genetic correlations with the two largest available GWAS of OUD and opioid dependence (r_g = 0.64, 0.80, respectively). We also identified numerous additional genetic correlations with POU, including alcohol dependence (r_g = 0.74), smoking initiation (r_g = 0.63), pain relief medication intake (r_g = 0.49), major depressive disorder (r_g = 0.44), chronic pain (r_g = 0.42), insomnia (r_g = 0.39), and loneliness (r_g = 0.28). Although POU was positively genetically correlated with risk-taking (r_g = 0.38), conditioning POU on risk-taking did not substantially alter the magnitude or direction of these genetic correlations, suggesting that POU does not simply reflect a genetic tendency towards risky behavior. Lastly, we performed phenome- and lab-wide association analyses, which uncovered additional phenotypes that were associated with POU, including respiratory failure, insomnia, ischemic heart disease, and metabolic and blood-related biomarkers. We conclude that opioid misuse can be measured in population-based cohorts and provides a cost-effective complementary strategy for understanding the genetic basis of OUD.

SUBMITTER: Sanchez-Roige S

PROVIDER: S-EPMC8562028 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:ImportanceBetween 1997 and 2017, the United States saw increases in nonmedical prescription opioid use and its consequences, as well as changes in marijuana policies. Ecological-level research hypothesized that medical marijuana legalization may reduce prescription opioid use by allowing medical marijuana as an alternative.ObjectivesTo investigate the association of state-level medical marijuana law enactment with individual-level nonmedical prescription opioid use and prescription opioid use disorder among prescription opioid users and to determine whether these outcomes varied by age and racial/ethnic groups.Design, setting, and participantsThis cross-sectional study used restricted data on 627 000 individuals aged 12 years and older from the 2004 to 2014 National Survey on Drug Use and Health, a population-based survey representative of the civilian population of the United States. Analyses were completed from March 2018 to May 2018.ExposuresTime-varying indicator of state-level medical marijuana law enactment (0 = never law enactment, 1 = before law enactment, and 2 = after law enactment).Main outcomes and measuresPast-year nonmedical prescription opioid use and prescription opioid use disorder among prescription opioid users. Odds ratios of nonmedical prescription opioid use and prescription opioid use disorder comparing the period before and after law enactment were presented overall, by age and racial/ethnic group, and adjusted for individual- and state-level confounders.ResultsThe study sample included 627 000 participants (51.51% female; 9.88% aged 12-17 years, 13.30% aged 18-25 years, 14.30% aged 26-34 years, 25.02% aged 35-49 years, and 37.50% aged ≥50 years; the racial/ethnic distribution was 66.97% non-Hispanic white, 11.83% non-Hispanic black, 14.47% Hispanic, and 6.73% other). Screening and interview response rates were 82% to 91% and 71% to 77%, respectively. Overall, there were small changes in nonmedical prescription opioid use prevalence after medical marijuana law enactment (4.32% to 4.86%; adjusted odds ratio, 1.13; 95% CI, 1.06-1.20). Prescription opioid use disorder prevalence among prescription opioid users decreased slightly after law enactment, but the change was not statistically significant (15.41% to 14.76%; adjusted odds ratio, 0.95; 95% CI, 0.81-1.11). Outcomes were similar when stratified by age and race/ethnicity.Conclusions and relevanceThis study found little evidence of an association between medical marijuana law enactment and nonmedical prescription opioid use or prescription opioid use disorder among prescription opioid users. Further research should disentangle the potential mechanisms through which medical marijuana laws may reduce opioid-related harm.

Project description:Despite the large toll of opioid use disorder (OUD), genome-wide association studies (GWAS) of OUD to date have yielded few susceptibility loci. We performed a large-scale GWAS of OUD in individuals of European (EUR) and African (AFR) ancestry, optimizing genetic informativeness by performing MTAG (Multi-trait analysis of GWAS) with genetically correlated substance use disorders (SUDs). Meta-analysis included seven cohorts: the Million Veteran Program, Psychiatric Genomics Consortium, iPSYCH, FinnGen, Partners Biobank, BioVU, and Yale-Penn 3, resulting in a total N = 639,063 (Ncases = 20,686;Neffective = 77,026) across ancestries. OUD cases were defined as having a lifetime OUD diagnosis, and controls as anyone not known to meet OUD criteria. We estimated SNP-heritability (h2SNP) and genetic correlations (rg). Based on genetic correlation, we performed MTAG on OUD, alcohol use disorder (AUD), and cannabis use disorder (CanUD). A leave-one-out polygenic risk score (PRS) analysis was performed to compare OUD and OUD-MTAG PRS as predictors of OUD case status in Yale-Penn 3. The EUR meta-analysis identified three genome-wide significant (GWS; p ≤ 5 × 10-8) lead SNPs-one at FURIN (rs11372849; p = 9.54 × 10-10) and two OPRM1 variants (rs1799971, p = 4.92 × 10-09; rs79704991, p = 1.11 × 10-08; r2 = 0.02). Rs1799971 (p = 4.91 × 10-08) and another OPRM1 variant (rs9478500; p = 1.95 × 10-08; r2 = 0.03) were identified in the cross-ancestry meta-analysis. Estimated h2SNP was 12.75%, with strong rg with CanUD (rg = 0.82; p = 1.14 × 10-47) and AUD (rg = 0.77; p = 6.36 × 10-78). The OUD-MTAG resulted in a GWAS Nequivalent = 128,748 and 18 independent GWS loci, some mapping to genes or gene regions that have previously been associated with psychiatric or addiction phenotypes. The OUD-MTAG PRS accounted for 3.81% of OUD variance (beta = 0.61;s.e. = 0.066; p = 2.00 × 10-16) compared to 2.41% (beta = 0.45; s.e. = 0.058; p = 2.90 × 10-13) explained by the OUD PRS. The current study identified OUD variant associations at OPRM1, single variant associations with FURIN, and 18 GWS associations in the OUD-MTAG. The genetic architecture of OUD is likely influenced by both OUD-specific loci and loci shared across SUDs.

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Genome-wide association study of problematic opioid prescription use in 132,113 23andMe research participants of European ancestry.

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