Genome-wide association study of problematic opioid prescription use in 132,113 23andMe research participants of European ancestry.
- Authors
- Sanchez-Roige, Sandra; Fontanillas, Pierre; Jennings, Mariela V; Bianchi, Sevim B; Huang, Yuye; Hatoum, Alexander S; Sealock, Julia; Davis, Lea K; Elson, Sarah L; 23andMe Research Team; Palmer, Abraham A
- Year
- 2021
- Journal
- Molecular psychiatry
- PMID
- 34728798
- DOI
- 10.1038/s41380-021-01335-3
- PMCID
- PMC8562028
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 = 0.64, 0.80, respectively). We also identified numerous additional genetic correlations with POU, including alcohol dependence (r = 0.74), smoking initiation (r = 0.63), pain relief medication intake (r = 0.49), major depressive disorder (r = 0.44), chronic pain (r = 0.42), insomnia (r = 0.39), and loneliness (r = 0.28). Although POU was positively genetically correlated with risk-taking (r = 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.
Genome-wide association analysis for problematic opioid use.The nearest genes are labeled for the 2 lead SNPs (rs3791033, rs640561). The x-axis shows chromosomal position and the y-axis shows significance on –log10 scale. The horizontal red line denotes genome-wide significance (p = 5.00E–08).
Chord diagram of genes significantly associated with POU at 10% FDR and the Anatomical Therapeutic Chemical classifications of drugs.The width of each line is determined by the number of drugs known to interact with each gene.
LDSC FDR-significant genetic correlations with POU.Traits with positive genetic correlation (rg) values are plotted above the line; traits with negative rg values are plotted below the line. All traits surpass 5% FDR correction for multiple testing.
Genetic correlations (rg) with POU before and after conditioning on risk-taking behavior.All FDR-significant results are plotted on the left panel, selected relevant traits are shown on the right panel (original rg in grey; corrected rg in red). The top 5 traits with biggest change in rg value are labelled (left).
Phenome-wide (top) and lab-wide (bottom) association studies of polygenic risk scores for POU against 1,338 diseases and 315 biomarkers (respectively) available from BioVU.The top and bottom red dashed lines indicate the threshold for Bonferroni correction (PheWAS p = 3.74E–05; LabWAS p = 1.59E–04). Only FDR significant results are presented. The sizes of the dots correspond to the magnitude of the effect. Y-axis represents the negative logarithm of the p-value for each trait multiplied by the sign of the effect.
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In this knowledge base
| Title | Year | PMID |
|---|---|---|
| Multi-trait genome-wide association study of opioid addiction: OPRM1 and beyond. | 2022 | 36207451 |
External
| Title | Authors | Journal | Year | Link |
|---|---|---|---|---|
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| Optimizing Control Definitions in Opioid Use Disorder Genetic Research Using Electronic Health Records | Niarchou M et al. | — | 2026 | → |
| 3D genomic features across >50 diverse cell types reveal insights into the genomic architecture of childhood obesity. | Trang KB et al. | — | 2025 | → |
| Association Between Self-Reported Opioid Use and Behavioral/Social Health Characteristics-Arizona, 2020. | Davidson S et al. | — | 2025 | → |
| Epigenome-wide association study of placental co-methylated regions in newborns for prenatal opioid exposure. | Meijer M et al. | — | 2025 | → |
| Exploration of Genetic Liability to Insomnia and Substance Use Disorders in Patients With Bipolar Disorder. | Melhuish Beaupre LM et al. | — | 2025 | → |
| Externalizing as a common genetic influence for a broad spectrum of substance use and behavioral conditions: A developmental perspective from the Avon Longitudinal Study of Parents and Children. | Deng WQ et al. | — | 2025 | → |
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| Prescription Opioid Medication Survey: A Tool to Collect Deep Phenotypic Data on the Multifactorial Pathways to Opioid Use Disorder in Clinical and Population-Based Cohorts. | Courchesne-Krak NS et al. | — | 2025 | → |
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| Transdiagnostic Polygenic Risk Models for Psychopathology and Comorbidity: Cross-Ancestry Analysis in the<i>All of Us</i>Research Program | Lee PH et al. | — | 2025 | — |
| Utility of Candidate Genes From an Algorithm Designed to Predict Genetic Risk for Opioid Use Disorder. | Davis CN et al. | — | 2025 | → |
| An emerging multi-omic understanding of the genetics of opioid addiction. | Johnson EO et al. | — | 2024 | → |
| Considerations for the application of polygenic scores to clinical care of individuals with substance use disorders. | Kember RL et al. | — | 2024 | → |
| Genetically Regulated Gene Expression in the Brain Associated With Chronic Pain: Relationships With Clinical Traits and Potential for Drug Repurposing. | Johnston KJA et al. | — | 2024 | → |
| Genetic contribution to the comorbidity between attention-deficit/hyperactivity disorder and substance use disorders. | Koller D et al. | — | 2024 | → |
| Medical and genetic correlates of long-term buprenorphine treatment in the electronic health records. | Niarchou M et al. | — | 2024 | → |
| Multi-ancestry meta-analysis of tobacco use disorder identifies 461 potential risk genes and reveals associations with multiple health outcomes. | Toikumo S et al. | — | 2024 | → |
| Opioid trail: Tracking contributions to opioid use disorder from host genetics to the gut microbiome. | Duffy EP et al. | — | 2024 | → |
| Opioid use disorder risk alleles in self-reported assigned African American/Afro-Caribbean and European biogeographical genetic ancestry groups and in males and females. | Sprague JE et al. | — | 2024 | → |
| Sex and genetic background influence intravenous oxycodone self-administration in the hybrid rat diversity panel. | Duffy EP et al. | — | 2024 | → |
| A review of the genomics of neonatal abstinence syndrome. | Yen E et al. | — | 2023 | → |
| A Shared Genetic Signature for Common Chronic Pain Conditions and its Impact on Biopsychosocial Traits. | Farrell SF et al. | — | 2023 | → |
| CADM2 is implicated in impulsive personality and numerous other traits by genome- and phenome-wide association studies in humans and mice. | Sanchez-Roige S et al. | — | 2023 | → |
| Endogenous opiates and behavior: 2021. | Bodnar RJ | — | 2023 | → |
| Genetic Variants Associated With Opioid Use Disorder. | Freiermuth CE et al. | — | 2023 | → |
| Neuroimaging of opioid exposure: a review of preclinical animal models to inform addiction research. | Kamens HM et al. | — | 2023 | → |
| Neuroimmune Mechanisms of Opioid Use Disorder and Recovery: Translatability to Human Studies, and Future Research Directions. | Butelman ER et al. | — | 2023 | → |
| Accelerating Opioid Use Disorders Research by Integrating Multiple Data Modalities. | Bianchi SB et al. | — | 2022 | → |
| Be in it for the Long Haul: A Commentary on Human Tissue Recovery Initiatives. | Iadarola MJ et al. | — | 2022 | → |
| Cross-ancestry meta-analysis of opioid use disorder uncovers novel loci with predominant effects in brain regions associated with addiction. | Kember RL et al. | — | 2022 | → |
| Genome-wide association study in individuals of European and African ancestry and multi-trait analysis of opioid use disorder identifies 19 independent genome-wide significant risk loci. | Deak JD et al. | — | 2022 | → |
| Multi-trait genome-wide association study of opioid addiction: OPRM1 and beyond. | Gaddis N et al. | — | 2022 | → |
| Substance use and common contributors to morbidity: A genetics perspective. | Sanchez-Roige S et al. | — | 2022 | → |
| Unique prediction of developmental psychopathology from genetic and familial risk. | Loughnan RJ et al. | — | 2022 | → |