Genome-wide association studies of alcohol dependence, DSM-IV criterion count and individual criteria.
paper
Primary
Public
- Authors
- Lai, Dongbing; Wetherill, Leah; Bertelsen, Sarah; Carey, Caitlin E; Kamarajan, Chella; Kapoor, Manav; Meyers, Jacquelyn L; Anokhin, Andrey P; Bennett, David A; Bucholz, Kathleen K; Chang, Katharine K; De Jager, Philip L; Dick, Danielle M; Hesselbrock, Victor; Kramer, John; Kuperman, Samuel; Nurnberger, John I; Raj, Towfique; Schuckit, Marc; Scott, Denise M; Taylor, Robert E; Tischfield, Jay; Hariri, Ahmad R; Edenberg, Howard J; Agrawal, Arpana; Bogdan, Ryan; Porjesz, Bernice; Goate, Alison M; Foroud, Tatiana
- Year
- 2019
- Journal
- Genes, brain, and behavior
- PMID
- 31090166
- DOI
- 10.1111/gbb.12579
- PMCID
- PMC6612573
Genome-wide association studies (GWAS) of alcohol dependence (AD) have reliably identified variation within alcohol metabolizing genes (eg, ADH1B) but have inconsistently located other signals, which may be partially attributable to symptom heterogeneity underlying the disorder. We conducted GWAS of DSM-IV AD (primary analysis), DSM-IV AD criterion count (secondary analysis), and individual dependence criteria (tertiary analysis) among 7418 (1121 families) European American (EA) individuals from the Collaborative Study on the Genetics of Alcoholism (COGA). Trans-ancestral meta-analyses combined these results with data from 3175 (585 families) African-American (AA) individuals from COGA. In the EA GWAS, three loci were genome-wide significant: rs1229984 in ADH1B for AD criterion count (P = 4.16E-11) and Desire to cut drinking (P = 1.21E-11); rs188227250 (chromosome 8, Drinking more than intended, P = 6.72E-09); rs1912461 (chromosome 15, Time spent drinking, P = 1.77E-08). In the trans-ancestral meta-analysis, rs1229984 was associated with multiple phenotypes and two additional loci were genome-wide significant: rs61826952 (chromosome 1, DSM-IV AD, P = 8.42E-11); rs7597960 (chromosome 2, Time spent drinking, P = 1.22E-08). Associations with rs1229984 and rs18822750 were replicated in independent datasets. Polygenic risk scores derived from the EA GWAS of AD predicted AD in two EA datasets (P < .01; 0.61%-1.82% of variance). Identified novel variants (ie, rs1912461, rs61826952) were associated with differential central evoked theta power (loss - gain; P = .0037) and reward-related ventral striatum reactivity (P = .008), respectively. This study suggests that studying individual criteria may unveil new insights into the genetic etiology of AD liability.
flow chart of analyses.
| Name | Type |
|---|---|
| 1000 Genomes Project | cohort |
| 1000 Genomes projects local | cohort |
| AA | cohort |
| AA sample | cohort |
| AD criterion count measure local | phenotype |
| AD diagnosis | phenotype |
| addiction | phenotype |
| ADH1B | gene |
| ADH1C | gene |
| ADH cluster | gene |
| ADHD | phenotype |
| ADHD symptoms | phenotype |
| ADH gene cluster | gene |
| AD severity | phenotype |
| African American | cohort |
| age | phenotype |
| alcohol | phenotype |
| alcohol dependence | phenotype |
| Alcohol dependence (DSM-IV AD) local | phenotype |
| Alcohol Dependence GWAS in European and African Americans (Yale-Penn) local | cohort |
| alcohol metabolizing process local | phenotype |
| alcohol-related phenotypes | phenotype |
| Alcohol Use Disorder | phenotype |
| alcohol use disorders | phenotype |
| ALDH2 | gene |
| Alzheimer's disease | phenotype |
| anterior region | anatomy |
| AUD | phenotype |
| AUDIT-C | phenotype |
| Australian Twin-family Study of Alcohol Use Disorder (OZALC) local | cohort |
| bipolar disorder | phenotype |
| birth cohort | cohort |
| brain | anatomy |
| BRINP1 local | gene |
| cannabis use | phenotype |
| central region | anatomy |
| cerebrospinal fluid biomarker level local | phenotype |
| chr15 locus local | variant |
| chr2 locus local | variant |
| chr8 locus local | variant |
| chromosome 15 region local | variant |
| chromosome 8 region local | variant |
| cocaine | phenotype |
| COGA AA local | cohort |
| COGA AA family data local | cohort |
| COGA AA GWAS local | cohort |
| COGA case/control data local | cohort |
| COGA discovery GWAS local | cohort |
| COGA EA GWAS local | cohort |
| COGA European American family data local | cohort |
| COGA Prospective participants local | cohort |
| COGA sample | cohort |
| cognition disorders local | phenotype |
| cognitive decline | phenotype |
| cognitive test scores local | phenotype |
| Collaborative Study on the Genetics of Alcoholism (COGA) | cohort |
| combined trans-ancestral sample local | cohort |
| current smoking | phenotype |
| dependence on alcohol or illicit drugs local | phenotype |
| Desire to cut back local | phenotype |
| Desire to cut drinking local | phenotype |
| dopamine | drug |
| Drinking despite problem local | phenotype |
| Drinking despite problems local | phenotype |
| drinking more than intended | phenotype |
| DSM-IV alcohol dependence | phenotype |
| DSM-IV criterion count local | phenotype |
| Duke Neurogenetics Study | cohort |
| EA | cohort |
| EA+AA local | cohort |
| EA+AA analysis local | cohort |
| EA+AA meta-analysis local | cohort |
| EA+AA trans-ancestral meta-analysis local | cohort |
| EA GWAS local | cohort |
| EA-only local | cohort |
| EA participants | cohort |
| European ancestry | cohort |
| European population | cohort |
| Ever drinking local | phenotype |
| excessive alcohol consumption | phenotype |
| Excessive consumption despite negative consequences local | phenotype |
| FAM84B local | gene |
| frontal cortex | anatomy |
| frontal evoked theta power local | phenotype |
| frontal theta response local | phenotype |
| Giving up activities | phenotype |
| High Density Alcohol Dependent Families local | cohort |
| High genetic risk local | phenotype |
| High-risk AD latent class local | phenotype |
| identical phenotype local | phenotype |
| illicit drug dependence | phenotype |
| illicit drug use | phenotype |
| Illumina 2.5M array | drug |
| Illumina Human1M array | drug |
| Illumina Human OmniExpress 12V1 array | drug |
| individual AD criteria local | phenotype |
| individual criteria local | phenotype |
| individual dependence criteria local | phenotype |
| Jewish descent cohort local | cohort |
| juvenile myoclonic epilepsy local | phenotype |
| KIAA0040 | gene |
| left reward-related ventral striatum activity local | phenotype |
| left ventral striatum local | anatomy |
| Loss of control over drinking local | phenotype |
| low-risk group | cohort |
| major depressive disorder | phenotype |
| marijuana | phenotype |
| migraine | phenotype |
| Million Veteran Program | cohort |
| moderate-risk group local | cohort |
| negative feedback | phenotype |
| neuroticism | phenotype |
| nicotine | drug |
| non-European ancestry samples local | cohort |
| non-Hispanic AA local | cohort |
| Non-problem alcohol intake local | phenotype |
| opioid | drug |
| Other | phenotype |
| OTOP1 local | gene |
| OZ-ALC local | cohort |
| OZALC | cohort |
| OZALC-EA local | cohort |
| parietal cortex | anatomy |
| Parkinson’s disease | phenotype |
| phenotypic criteria local | phenotype |
| physiological dependence | phenotype |
| positive feedback | phenotype |
| Positive Feedback > Negative Feedback contrast local | phenotype |
| prefrontal cortex | anatomy |
| primary AD phenotype local | phenotype |
| primary phenotype local | phenotype |
| problematic use | phenotype |
| PRS | drug |
| RABGAP1L local | gene |
| Remaining samples local | cohort |
| reward-related brain function local | phenotype |
| reward-related neural phenotype local | phenotype |
| reward-related neural phenotypes local | phenotype |
| reward-related theta ERO local | phenotype |
| reward-related theta power local | phenotype |
| reward system | anatomy |
| right reward-related ventral striatum activity local | phenotype |
| rs11035102 local | variant |
| rs1229984 | variant |
| rs12639940 local | variant |
| rs12903120 | variant |
| rs17484734 local | variant |
| rs188227250 local | variant |
| rs1890881 local | variant |
| rs1912461 local | variant |
| rs2066702 | variant |
| rs2418646 local | variant |
| rs2961816 local | variant |
| rs61826952 local | variant |
| rs7597960 local | variant |
| SAGE | cohort |
| SAGE-AA local | cohort |
| SAGE-EA local | cohort |
| schizophrenia | phenotype |
| secondary DSM-IV AD criterion count local | phenotype |
| secondary phenotype | phenotype |
| sedatives | drug |
| severe pathology and impairment local | phenotype |
| Smokescreen genotyping array | drug |
| stimulants | drug |
| striatum | anatomy |
| Study of Addiction: Genetics and Environment (SAGE) local | cohort |
| substance use | phenotype |
| tertiary phenotype local | phenotype |
| Tertiary phenotypes local | phenotype |
| theta activity | phenotype |
| theta ERO | phenotype |
| Time spent drinking | phenotype |
| tolerance | phenotype |
| trans-ancestral (EA+AA) meta-analysis local | cohort |
| trans-ancestral meta-analysis local | cohort |
| variant_set_47k local | variant |
| ventral striatum | anatomy |
| VS | anatomy |
| withdrawal | phenotype |
| Yale-Penn | cohort |
| Yale-Penn-AA local | cohort |
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In this knowledge base
External
| Title | Authors | Journal | Year | Link |
|---|---|---|---|---|
| Genome-wide association studies of lifetime and frequency of cannabis use in 131,895 individuals. | Thorpe HHA et al. | — | 2026 | → |
| Multivariate genetic analyses of 2.2 million individuals reveal broad and substance-specific pathways of addiction risk. | Poore HE et al. | — | 2026 | → |
| Perceived partner substance use, genetic predispositions, and their associations with problematic alcohol use, emotional well-being, and relationship quality. | Cooke ME et al. | — | 2026 | → |
| Genetic analysis of alcohol use disorder: GWAS of alcohol use disorders identification test (AUDIT) and polygenic risk scores in an east slavic population. | Trofimov M et al. | — | 2025 | → |
| Genetic risk for alcohol use disorder in relation to individual symptom criteria: Do polygenic indices provide unique information for understanding severity and heterogeneity? | Sarles YM et al. | — | 2025 | → |
| Next-generation biomarkers for alcohol consumption and alcohol use disorder diagnosis, prognosis, and treatment: A critical review. | Clark SL et al. | — | 2025 | → |
| Parental Remission From Alcohol Use Disorder Shows Limited Protective Effects on Offspring Alcohol Outcomes. | McCutcheon VV et al. | — | 2025 | → |
| The Impact of Polygenic Risk, Parental Separation, and Parental Relationship Discord on Heavy Episodic Drinking Across Adolescence and Young Adulthood in a High-Risk Sample. | Kuo SI et al. | — | 2025 | → |
| A Developmentally-Informative Genome-wide Association Study of Alcohol Use Frequency. | Thomas NS et al. | — | 2024 | → |
| Alcohol milestones and internalizing, externalizing, and executive function: longitudinal and polygenic score associations. | Paul SE et al. | — | 2024 | → |
| A Mendelian randomization study of alcohol use and cardiometabolic disease risk in a multi-ancestry population from the Million Veteran Program. | Kember RL et al. | — | 2024 | → |
| A phenome-wide association and Mendelian randomisation study of alcohol use variants in a diverse cohort comprising over 3 million individuals. | Jennings MV et al. | — | 2024 | → |
| Associations between alcohol use disorder polygenic score and remission in participants from high-risk families and the Indiana Biobank. | Lai D et al. | — | 2024 | → |
| Examining associations between genetic and neural risk for externalizing behaviors in adolescence and early adulthood. | Brislin SJ et al. | — | 2024 | → |
| Generalized genetic liability to substance use disorders. | Miller AP et al. | — | 2024 | → |
| Multivariate genetic of 2.2 million individuals demonstrate genetic influences on substance use disorders operate via behavioral disinhibition and substance-specific risk | Poore HE et al. | — | 2024 | — |
| The genetic landscape of substance use disorders. | Gerring ZF et al. | — | 2024 | → |
| Alcohol use polygenic risk score, social support, and alcohol use among European American and African American adults. | Su J et al. | — | 2023 | → |
| Association of parental divorce, discord, and polygenic risk with children's alcohol initiation and lifetime risk for alcohol use disorder. | Kuo SI et al. | — | 2023 | → |
| Associations Between Cannabis Use, Polygenic Liability for Schizophrenia, and Cannabis-related Experiences in a Sample of Cannabis Users. | Johnson EC et al. | — | 2023 | → |
| Contagious Transmission in a Swedish National Sample of Alcohol Use Disorders as a Function of Geographical Proximity Among Siblings and Propinquity-of-Rearing Defined Acquaintances. | Kendler KS et al. | — | 2023 | → |
| COVID-19 pandemic stressors are associated with reported increases in frequency of drunkenness among individuals with a history of alcohol use disorder. | Meyers JL et al. | — | 2023 | → |
| Genetic nurture effects for alcohol use disorder. | Thomas NS et al. | — | 2023 | → |
| Genomic risk for post-traumatic stress disorder in families densely affected with alcohol use disorders. | Saenz de Viteri S et al. | — | 2023 | → |
| Polygenic Contributions to Suicidal Thoughts and Behaviors in a Sample Ascertained for Alcohol Use Disorders. | Colbert SMC et al. | — | 2023 | → |
| Predicting Alcohol-Related Memory Problems in Older Adults: A Machine Learning Study with Multi-Domain Features. | Kamarajan C et al. | — | 2023 | → |
| RNA alternative splicing impacts the risk for alcohol use disorder. | Li R et al. | — | 2023 | → |
| The collaborative study on the genetics of alcoholism: Genetics. | Johnson EC et al. | — | 2023 | → |
| A Genome-Wide Association Study Reveals a <i>BDNF</i>-Centered Molecular Network Associated with Alcohol Dependence and Related Clinical Measures. | Levchenko A et al. | — | 2022 | → |
| Alcohol-Induced Oxidative Stress and the Role of Antioxidants in Alcohol Use Disorder: A Systematic Review. | Tsermpini EE et al. | — | 2022 | → |
| Alcohol use and alcohol use disorder differ in their genetic relationships with PTSD: A genomic structural equation modelling approach. | Bountress KE et al. | — | 2022 | → |
| Alcohol use disorder, psychiatric comorbidities, marriage and divorce in a high-risk sample. | Thomas NS et al. | — | 2022 | → |
| Common and distinguishing genetic factors for substance use behavior and disorder: an integrated analysis of genomic and transcriptomic studies from both human and animal studies. | Chang XW et al. | — | 2022 | → |
| Evaluating risk for alcohol use disorder: Polygenic risk scores and family history. | Lai D et al. | — | 2022 | → |
| Gene-based polygenic risk scores analysis of alcohol use disorder in African Americans. | Lai D et al. | — | 2022 | → |
| High Polygenic Risk Scores Are Associated With Early Age of Onset of Alcohol Use Disorder in Adolescents and Young Adults at Risk. | Nurnberger JI et al. | — | 2022 | → |
| Principal Component Analysis Reduces Collider Bias in Polygenic Score Effect Size Estimation. | Thomas NS et al. | — | 2022 | → |
| The role of adolescent social relationships in promoting alcohol resistance: Interrupting the intergenerational transmission of alcohol misuse. | Stephenson M et al. | — | 2022 | → |
| The role of parental genotype in the intergenerational transmission of externalizing behavior: Evidence for genetic nurturance. | Kuo SI et al. | — | 2022 | → |
| Associations between Suicidal Thoughts and Behaviors and Genetic Liability for Cognitive Performance, Depression, and Risk-Taking in a High-Risk Sample. | Johnson EC et al. | — | 2021 | → |
| Associations of CB1 cannabinoid receptor (CNR1) gene polymorphisms with risk for alcohol dependence: Evidence from meta-analyses of genetic and genome-wide association studies. | Pabalan N et al. | — | 2021 | → |
| Exploring the Role of Alcohol Metabolizing Genotypes in a 12-Week Clinical Trial of Naltrexone for Alcohol Use Disorder. | Castaldelli-Maia JM et al. | — | 2021 | → |
| Genome-wide admixture mapping of DSM-IV alcohol dependence, criterion count, and the self-rating of the effects of ethanol in African American populations. | Lai D et al. | — | 2021 | → |
| Genome-wide association study of stimulant dependence. | Cox J et al. | — | 2021 | → |
| Heritability of ethanol consumption and pharmacokinetics in a genetically diverse panel of collaborative cross mouse strains and their inbred founders. | Bagley JR et al. | — | 2021 | → |
| Integration of evidence across human and model organism studies: A meeting report. | Palmer RHC et al. | — | 2021 | → |
| Mapping Pathways by Which Genetic Risk Influences Adolescent Externalizing Behavior: The Interplay Between Externalizing Polygenic Risk Scores, Parental Knowledge, and Peer Substance Use. | Kuo SI et al. | — | 2021 | → |
| Mediational Pathways From Genetic Risk to Alcohol Use Disorder in Swedish Men and Women. | Kendler KS et al. | — | 2021 | → |
| Multi-omics integration analysis identifies novel genes for alcoholism with potential overlap with neurodegenerative diseases. | Kapoor M et al. | — | 2021 | → |
| Predicting risk for Alcohol Use Disorder using longitudinal data with multimodal biomarkers and family history: a machine learning study. | Kinreich S et al. | — | 2021 | → |
| The association of polygenic risk for schizophrenia, bipolar disorder, and depression with neural connectivity in adolescents and young adults: examining developmental and sex differences. | Meyers JL et al. | — | 2021 | → |
| The influence of regression models on genome-wide association studies of alcohol dependence: a comparison of binary and quantitative analyses. | Li W et al. | — | 2021 | → |
| Whole Genome Interpretation for a Family of Five. | Corpas M et al. | — | 2021 | → |
| Identification of Functional Genetic Variants Associated With Alcohol Dependence and Related Phenotypes Using a High-Throughput Assay. | Thapa KS et al. | — | 2020 | → |
| Leveraging genome-wide data to investigate differences between opioid use vs. opioid dependence in 41,176 individuals from the Psychiatric Genomics Consortium. | Polimanti R et al. | — | 2020 | → |
| Liver transplantation in patients with alcohol-related liver disease: current status and future directions. | Mathurin P et al. | — | 2020 | → |
| On the path towards personalized medicine: Implications of pharmacogenetic studies of alcohol use disorder medications. | Nieto SJ et al. | — | 2020 | → |
| Recent advances in genetic studies of alcohol use disorders. | Gupta I et al. | — | 2020 | → |
| Recent Efforts to Dissect the Genetic Basis of Alcohol Use and Abuse. | Sanchez-Roige S et al. | — | 2020 | → |
| Sibling comparisons elucidate the associations between educational attainment polygenic scores and alcohol, nicotine and cannabis. | Salvatore JE et al. | — | 2020 | → |
| Within-Family Transmission of Alcohol Use Disorder in Parent-Offspring, Sibling, and Cousin Pairs: A Contagion Model. | Kendler KS et al. | — | 2020 | → |