Human Genetics of Addiction: New Insights and Future Directions.
- Authors
- Hancock, Dana B; Markunas, Christina A; Bierut, Laura J; Johnson, Eric O
- Year
- 2018
- Journal
- Current psychiatry reports
- PMID
- 29504045
- DOI
- 10.1007/s11920-018-0873-3
- PMCID
- PMC5983372
PURPOSE OF REVIEW: With the advent of the genome-wide association study (GWAS), our understanding of the genetics of addiction has made significant strides forward. Here, we summarize genetic loci containing variants identified at genome-wide statistical significance (Pβ<β5βΓβ10) and independently replicated, review evidence of functional or regulatory effects for GWAS-identified variants, and outline multi-omics approaches to enhance discovery and characterize addiction loci. RECENT FINDINGS: Replicable GWAS findings span 11 genetic loci for smoking, eight loci for alcohol, and two loci for illicit drugs combined and include missense functional variants and noncoding variants with regulatory effects in human brain tissues traditionally viewed as addiction-relevant (e.g., prefrontal cortex [PFC]) and, more recently, tissues often overlooked (e.g., cerebellum). GWAS analyses have discovered several novel, replicable variants contributing to addiction. Using larger sample sizes from harmonized datasets and new approaches to integrate GWAS with multiple 'omics data across human brain tissues holds great promise to significantly advance our understanding of the biology underlying addiction.
Concurrent integrative analysis approach with multiple types of βomics data used to inform discovery or characterize top findings from large-scale addiction GWAS. Genomics encompasses SNP/indel genotypes, rare variants, and structural variants including copy number variants; epigenomics includes DNA methylation and histone modification; and transcriptomics refers to expression of all RNA types. βOmics data may pertain to endogenous factors along the flow of information according to the Central Dogma of Biology or exogenous factors such as environmental exposures.
LLM interpretation
This figure is a conceptual diagram illustrating a concurrent integrative analysis approach using multiple "omics" data types. A central Venn diagram shows the overlap of genomics, epigenomics, transcriptomics, proteomics, and metabolomics, all enclosed within a larger circle representing the "Ordered Flow of Genetic Information (Central Dogma of Biology)." This integrated system is linked via a double-sided arrow to "Large-scale GWAS of addiction biomarkers and phenotypes," with an outer arc indicating the influence of "Overarching exposomics and microbiomics."
| Name | Type |
|---|---|
| 1000 Genomes African ancestry reference panels local | cohort |
| 241 African Americans local | cohort |
| 383 opioid-dependent African Americans local | cohort |
| abstinence | phenotype |
| acetaldehyde | drug |
| acetic acid | drug |
| addiction | phenotype |
| addiction biomarkers local | phenotype |
| addiction phenotype local | phenotype |
| addiction phenotypes | phenotype |
| addiction to any illicit drug local | phenotype |
| ADH1B | gene |
| ADH cluster | gene |
| Adult U.S. smokers local | cohort |
| African American | cohort |
| African American ancestry participants local | cohort |
| airflow obstruction | phenotype |
| alcohol | phenotype |
| Alcohol biomarkers local | phenotype |
| alcohol drinking problems local | phenotype |
| alcohol flush reaction | phenotype |
| alcohol-related phenotypes | phenotype |
| alcohol sensitivity | phenotype |
| Alcohol Use Disorder | phenotype |
| ALDH2 | gene |
| allocortex | anatomy |
| amphetamine | drug |
| Amphetamine GWAS local | cohort |
| Asian | cohort |
| assessed controls local | cohort |
| AUTS2 | gene |
| basal ganglia | anatomy |
| Bdnf | gene |
| Biomarkers of excessive alcohol intake local | phenotype |
| bipolar disorder | phenotype |
| blood | drug |
| blood pressure | phenotype |
| brain | anatomy |
| Brain eQTL Almanac local | cohort |
| cancer | phenotype |
| cannabis use | phenotype |
| cerebellum | anatomy |
| cessation treatment local | drug |
| CHRNA2 | gene |
| Chrna3 | gene |
| Chrna4 | gene |
| CHRNA5 | gene |
| Chrna6 | gene |
| Chrnb3 | gene |
| Chrnb4 | gene |
| cigarettes | phenotype |
| cis-eQTL SNP local | variant |
| cocaine | phenotype |
| Cocaine GWAS local | cohort |
| common variants | cohort |
| control population | cohort |
| COPD | phenotype |
| copy number variants | variant |
| coronary heart disease | phenotype |
| cotinine biomarker local | phenotype |
| CREBBP | gene |
| current smoking | phenotype |
| CYP2A6 | gene |
| CYP2B6 | gene |
| diverse ancestry groups local | cohort |
| DNA methylation | drug |
| Dnmt3b | gene |
| drug dependence | phenotype |
| drug-seeking behavior | phenotype |
| emphysema | phenotype |
| environmental exposures | drug |
| eQTLGen Consortium | cohort |
| European ancestry | cohort |
| European population | cohort |
| ever smoking | phenotype |
| extended amygdala | anatomy |
| Finnish participants local | cohort |
| former smokers | phenotype |
| frontal cortex | anatomy |
| functional missense SNPs local | variant |
| GCKR | gene |
| general substance dependence local | phenotype |
| general substance dependence liability local | phenotype |
| genetically correlated outcomes local | phenotype |
| genetic variants | cohort |
| GTEx | cohort |
| GWAS-identified variants local | variant |
| habenula | anatomy |
| healthy cohorts local | cohort |
| heavy drinking | phenotype |
| heavy smoking | phenotype |
| Hispanic | phenotype |
| illicit drugs | phenotype |
| illicit drug use | phenotype |
| indel | variant |
| insula | anatomy |
| intralobular white matter | anatomy |
| Japanese population | cohort |
| KAT2B | gene |
| kidney function | phenotype |
| Klb | gene |
| large GWAS meta-analysis (N=32,330 European ancestry) local | cohort |
| Large-scale biobanks local | cohort |
| Liver cirrhosis | phenotype |
| LOC151121 local | gene |
| lung cancer | phenotype |
| lung function | phenotype |
| meQTL local | variant |
| Methadone | drug |
| methadone dosing local | phenotype |
| methamphetamine | drug |
| Methamphetamine GWAS local | cohort |
| misuse | phenotype |
| morphine | drug |
| morphine dosing local | phenotype |
| Multiple ancestries cohort local | cohort |
| Multiple ancestries combined local | cohort |
| never smokers | phenotype |
| nicotine | drug |
| nicotine dependence | phenotype |
| nicotine metabolite ratio | phenotype |
| nicotine withdrawal | phenotype |
| noncoding SNP local | variant |
| nsSNP | variant |
| nucleus accumbens | anatomy |
| opioid | drug |
| opioid dependence | phenotype |
| opioid phenotypes local | phenotype |
| OPRM1 | cohort |
| other drugs | drug |
| people who inject drugs local | phenotype |
| peripheral arterial disease | phenotype |
| PFC | anatomy |
| pharmacologic treatment local | drug |
| postmortem human PFC local | anatomy |
| prefrontal cortex | anatomy |
| progression from misuse to later stages of addiction local | phenotype |
| psychiatric disorders | phenotype |
| RCF1 | gene |
| recent GWAS meta-analysis (N=14,754 European Americans and African Americans) local | cohort |
| reward system | anatomy |
| RNA expression local | drug |
| rs1051730 | variant |
| rs11636753 local | variant |
| rs117804171 local | variant |
| rs11940694 | variant |
| rs1229984 | variant |
| rs1229984-T local | variant |
| rs1344706 | variant |
| rs16969968 | variant |
| rs1799971 | variant |
| rs2273500 local | variant |
| rs2952561 local | variant |
| rs2952621 local | variant |
| rs3778150 | variant |
| rs588765 | variant |
| rs6265 | variant |
| rs671 | variant |
| rs671-A local | variant |
| rs6943555 | variant |
| rs73568641 | variant |
| rs880395 local | variant |
| rs910083 local | variant |
| rs9829896 | variant |
| schizophrenia | phenotype |
| Self-reported phenotypes local | phenotype |
| SERPINC1 | gene |
| SGOL1 | gene |
| smoking | phenotype |
| smoking biomarkers local | phenotype |
| smoking phenotypes | phenotype |
| SNP | cohort |
| stimulants | drug |
| substance | phenotype |
| substance use | phenotype |
| susceptibility to addiction local | phenotype |
| TF | gene |
| UGT2A3 local | gene |
| UGT2B10 local | gene |
| UK Biobank | cohort |
| U.S. population (2015) local | cohort |
| variant | cohort |
| ventral tegmental area | anatomy |
| ZNF804A | gene |
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In this knowledge base
External
| Title | Authors | Journal | Year | Link |
|---|---|---|---|---|
| Addiction Susceptibility: Genetic Factors, Personality Traits, and Epigenetic Interactions with the Gut Microbiome. | Borrego-Ruiz A et al. | β | 2025 | β |
| Association of <i>DRD2</i> and <i>BDNF</i> Genetic Polymorphisms with Exercise Addiction. | da Silva IM et al. | β | 2025 | β |
| Indoor Tanning Addiction: Biological Mechanisms and Association with Other Disorders. | LaMonte OC et al. | β | 2025 | β |
| Neuroimaging correlates of psychological resilience: an Open Science systematic review and meta-analysis. | Kuehn A et al. | β | 2025 | β |
| An emerging multi-omic understanding of the genetics of opioid addiction. | Johnson EO et al. | β | 2024 | β |
| Deep sequencing of candidate genes identified 14 variants associated with smoking abstinence in an ethnically diverse sample. | Cinciripini PM et al. | β | 2024 | β |
| Enhanced Novel Object Recognition and Spatial Memory in Rats Selectively Bred for High Nicotine Preference. | Bekci E et al. | β | 2024 | β |
| Genes associated with cortical thickness alterations in behavioral addiction. | Xie H et al. | β | 2024 | β |
| Genetic control of DNA methylation is largely shared across European and East Asian populations. | Hatton AA et al. | β | 2024 | β |
| Integrating genetic and clinical data to predict lung cancer in patients with chronic obstructive pulmonary disease. | Gu Z et al. | β | 2024 | β |
| Multi-ancestry meta-analysis of tobacco use disorder identifies 461 potential risk genes and reveals associations with multiple health outcomes. | Toikumo S et al. | β | 2024 | β |
| Opioid trail: Tracking contributions to opioid use disorder from host genetics to the gut microbiome. | Duffy EP et al. | β | 2024 | β |
| Reducing maladaptive behavior in neuropsychiatric disorders using network modification. | Timme NM | β | 2024 | β |
| Sex- and Substance-Specific Associations of Circadian-Related Genes with Addiction in the UK Biobank Cohort Implicate Neuroplasticity Pathways. | Khan A et al. | β | 2024 | β |
| SNP-based and haplotype-based genome-wide association on drug dependence in Han Chinese. | Xu H et al. | β | 2024 | β |
| An in-depth association analysis of genetic variants within nicotine-related loci: Meeting in middle of GWAS and genetic fine-mapping. | Mo C et al. | β | 2023 | β |
| Conflicting theories on addiction aetiology and the strengths and limitations of substance use disorder disease modelling. | Greener MR et al. | β | 2023 | β |
| Dissecting the epigenomic differences between smoking and nicotine dependence in a veteran cohort. | Nagamatsu ST et al. | β | 2023 | β |
| Evaluating 17 methods incorporating biological function with GWAS summary statistics to accelerate discovery demonstrates a tradeoff between high sensitivity and high positive predictive value. | Moore A et al. | β | 2023 | β |
| Evolutionary modeling suggests that addictions may be driven by competition-induced microbiome dysbiosis. | Lewin-Epstein O et al. | β | 2023 | β |
| Invited Expert Opinion- Bioinformatic and Limitation Directives to Help Adopt Genetic Addiction Risk Screening and Identify Preaddictive Reward Dysregulation: Required Analytic Evidence to Induce Dopamine Homeostatsis. | Blum K et al. | β | 2023 | β |
| Low Dopamine D2 Receptor Expression Drives Gene Networks Related to GABA, cAMP, Growth and Neuroinflammation in Striatal Indirect Pathway Neurons. | Guerri L et al. | β | 2023 | β |
| The pleiotropic contribution of genes in dopaminergic and serotonergic pathways to addiction and related behavioral traits. | AntΓ³n-Galindo E et al. | β | 2023 | β |
| Why do we climb mountains? An exploration of features of behavioural addiction in mountaineering and the association with stress-related psychiatric disorders. | Habelt L et al. | β | 2023 | β |
| Association of Predicted Expression and Multimodel Association Analysis of Substance Abuse Traits. | Bost DM et al. | β | 2022 | β |
| A Systematic Review of Genetic Polymorphisms Associated with Bipolar Disorder Comorbid to Substance Abuse. | de Marco A et al. | β | 2022 | β |
| Back-translating GWAS findings to animal models reveals a role for Hgfac and Slc39a8 in alcohol and nicotine consumption. | Banna FKE et al. | β | 2022 | β |
| Cocaine-Induced Locomotor Activation Differs Across Inbred Mouse Substrains. | Gaines CH et al. | β | 2022 | β |
| Convergence of case-specific epigenetic alterations identify a confluence of genetic vulnerabilities tied to opioid overdose. | Corradin O et al. | β | 2022 | β |
| Frequency of the Dopamine Receptor D3 (rs6280) vs. Opioid Receptor Β΅1 (rs1799971) Polymorphic Risk Alleles in Patients with Opioid Use Disorder: A Preponderance of Dopaminergic Mechanisms? | GondrΓ©-Lewis MC et al. | β | 2022 | β |
| Multi-trait genome-wide association study of opioid addiction: OPRM1 and beyond. | Gaddis N et al. | β | 2022 | β |
| Relentless Stigma: A Qualitative Analysis of a Substance Use Recovery Needs Assessment. | Medina S et al. | β | 2022 | β |
| Smoking As an Outcome Moderator In the Treatment of Alcohol Use Disorders. | van Amsterdam J et al. | β | 2022 | β |
| The Impaired Nurse. | Salani D et al. | β | 2022 | β |
| The Promise of Polygenic Risk Prediction in Smoking Cessation: Evidence From Two Treatment Trials. | Bray M et al. | β | 2022 | β |
| Bibliometric Insights in Genetic Factors of Substance-Related Disorders: Intellectual Developments, Turning Points, and Emerging Trends. | Wang K et al. | β | 2021 | β |
| Ferroptosis-Related Genes in Neurodevelopment and Central Nervous System. | Kim SW et al. | β | 2021 | β |
| From single flies to many genes: Using <i>Drosophila</i> to explore the genetics of psychostimulant consumption. | Titos I et al. | β | 2021 | β |
| Genetic impacts on DNA methylation: research findings and future perspectives. | VillicaΓ±a S et al. | β | 2021 | β |
| Genetics of substance use disorders: a review. | Deak JD et al. | β | 2021 | β |
| Genome-wide DNA methylation differences in nucleus accumbens of smokers vs. nonsmokers. | Markunas CA et al. | β | 2021 | β |
| Heritable variation in locomotion, reward sensitivity and impulsive behaviors in a genetically diverse inbred mouse panel. | Bailey LS et al. | β | 2021 | β |
| Integration of evidence across human and model organism studies: A meeting report. | Palmer RHC et al. | β | 2021 | β |
| Intracranial self-stimulation and concomitant behaviors following systemic methamphetamine administration in Hnrnph1 mutant mice. | Borrelli KN et al. | β | 2021 | β |
| Pharmacokinetic and pharmacodynamic analyses of cocaine and its metabolites in behaviorally divergent inbred mouse strains. | Zhu J et al. | β | 2021 | β |
| Smoking among inpatients in treatment for substance use disorders: prevalence and effect on mental health and quality of life. | Lien L et al. | β | 2021 | β |
| Studying the Utility of Using Genetics to Predict Smoking-Related Outcomes in a Population-Based Study and a Selected Cohort. | Bray MJ et al. | β | 2021 | β |
| The Gut Microbiome and Substance Use Disorder. | Russell JT et al. | β | 2021 | β |
| Understanding the genetics and neurobiological pathways behind addiction (Review). | Popescu A et al. | β | 2021 | β |
| Whole-Exome Sequencing to Identify Potential Genetic Risk in Substance Use Disorders: A Pilot Feasibility Study. | AshaRani PV et al. | β | 2021 | β |
| Dissecting the genetic overlap of smoking behaviors, lung cancer, and chronic obstructive pulmonary disease: A focus on nicotinic receptors and nicotine metabolizing enzyme. | Bray MJ et al. | β | 2020 | β |
| Effect of short-term prescription opioids on DNA methylation of the OPRM1 promoter. | Sandoval-Sierra JV et al. | β | 2020 | β |
| Expanding the genetic architecture of nicotine dependence and its shared genetics with multiple traits. | Quach BC et al. | β | 2020 | β |
| Expanding the Genetic Architecture of Nicotine Dependence and its Shared Genetics with Multiple Traits: Findings from the Nicotine Dependence GenOmics (iNDiGO) Consortium | Quach BC et al. | β | 2020 | β |
| Genome-wide association study of smoking trajectory and meta-analysis of smoking status in 842,000 individuals. | Xu K et al. | β | 2020 | β |
| Genome-Wide DNA Methylation Analysis in Male Methamphetamine Users With Different Addiction Qualities. | Liu L et al. | β | 2020 | β |
| Heterogeneity and Polygenicity in Psychiatric Disorders: A Genome-Wide Perspective. | Wendt FR et al. | β | 2020 | β |
| Identifying Early Risk Factors for Addiction Later in Life: A Review of Prospective Longitudinal Studies. | Morales AM et al. | β | 2020 | β |
| Implementation and Evaluation of a Text Message-Based Addiction Counseling Program (Text4Hope-Addiction Support): Protocol for a Questionnaire Study. | Agyapong VIO et al. | β | 2020 | β |
| Prospects for finding the mechanisms of sex differences in addiction with human and model organism genetic analysis. | Datta U et al. | β | 2020 | β |
| Recent Efforts to Dissect the Genetic Basis of Alcohol Use and Abuse. | Sanchez-Roige S et al. | β | 2020 | β |
| Dorsal Striatal Circuits for Habits, Compulsions and Addictions. | Lipton DM et al. | β | 2019 | β |
| Electronic Health Records Are the Next Frontier for the Genetics of Substance Use Disorders. | Sanchez-Roige S et al. | β | 2019 | β |
| Genetics of alcohol use disorder: a review. | Deak JD et al. | β | 2019 | β |
| Insights from intoxicated Drosophila. | Petruccelli E et al. | β | 2019 | β |
| <i>OPRM1</i> A118G Polymorphisms and Its Role in Opioid Addiction: Implication on Severity and Treatment Approaches. | Taqi MM et al. | β | 2019 | β |
| Networking in Biology: The Hybrid Rat Diversity Panel. | Tabakoff B et al. | β | 2019 | β |
| [Prediction of binge drinking in young adults: a cohort study over nine years]. | Morgenstern M et al. | β | 2019 | β |
| The Neuroscience of Drug Reward and Addiction. | Volkow ND et al. | β | 2019 | β |
| Three-dimensional chromosome architecture and drug addiction. | Chitaman JM et al. | β | 2019 | β |
| Tobacco Genomics: Complexity and Translational Challenges. | Bergen AW et al. | β | 2019 | β |
| Is the FagerstrΓΆm test for nicotine dependence invariant across secular trends in smoking? A question for cross-birth cohort analysis of nicotine dependence. | Glasheen C et al. | β | 2018 | β |
| Understanding the implications of the biobehavioral basis of nicotine addiction and its impact on the efficacy of treatment. | Bozinoff N et al. | β | 2018 | β |