Parsing genetically influenced risk pathways: genetic loci impact problematic alcohol use via externalizing and specific risk.
- Authors
- Barr, Peter B; Mallard, Travis T; Sanchez-Roige, Sandra; Poore, Holly E; Linnér, Richard Karlsson; COGA Collaborators; Waldman, Irwin D; Palmer, Abraham A; Harden, K Paige; Dick, Danielle M
- Year
- 2022
- Journal
- Translational psychiatry
- PMID
- 36180423
- DOI
- 10.1038/s41398-022-02171-x
- PMCID
- PMC9525649
Genome-wide association studies (GWAS) identify genetic variants associated with a trait, regardless of how those variants are associated with the outcome. Characterizing whether variants for psychiatric outcomes operate via specific versus general pathways provides more informative measures of genetic risk. In the current analysis, we used multivariate GWAS to tease apart variants associated with problematic alcohol use (ALCP-total) through either a shared risk for externalizing (EXT) or a problematic alcohol use-specific risk (ALCP-specific). SNPs associated with ALCP-specific were primarily related to alcohol metabolism. Genetic correlations showed ALCP-specific was predominantly associated with alcohol use and other forms of psychopathology, but not other forms of substance use. Polygenic scores for ALCP-total were associated with multiple forms of substance use, but polygenic scores for ALCP-specific were only associated with alcohol phenotypes. Polygenic scores for both ALCP-specific and EXT show different patterns of associations with alcohol misuse across development. Our results demonstrate that focusing on both shared and specific risk can better characterize pathways of risk for substance use disorders. Parsing risk pathways will become increasingly relevant as genetic information is incorporated into clinical practice.
GWAS Models for Problematic Alcohol Use and Externalizing.Univariate (A) and multivariate (B) GWAS models for problematic alcohol use and externalizing. The SNP associations with the yellow box labeled ALCP are referred to herein as “ALCP-total” (original problematic alcohol use), the SNP associations with the purple circle are referred to herein as “EXT” (shared risk towards externalizing), and the SNP associations with the teal circle are referred to herein as “ALCP-specific” (problematic alcohol user-specific).
Values and differences in genetic correlations for ALCP-total and ALCP-specific.Panel (A) presents the genetic correlations (rg) and 95% CI between problematic alcohol use (ALCP-total, yellow dots), problematic alcohol use-specific (ALCP-specific, teal dots), and selected traits significantly correlated with ALCP-total (after correcting for an FDR of 5%, Supplementary Table 2 reports all preregistered genetic correlations). Asterisks (*) in Panel (A) represent genetic correlations for ALCP-specific that differ significantly from those with ALCP-total. Panel (B) presents changes in point estimates for genetic correlations from ALCP-total to ALCP-specific. In Panel (B), asterisks represent genetic correlations for ALCP-specific that are still significant (after correcting for an FDR of 5%).
Polygenic associations with substance use and substance use disorders.Bar charts illustrating the incremental proportion of variance (incremental R2, or ΔR2 above model with age, sex, PCs, and study-specific covariates) explained by the polygenic score in Add Health (N = 5107) and COGA (N = 7594). Association between polygenic scores and lifetime SUD criterion counts for alcohol, cannabis, nicotine, other illicit substances, and opioids (COGA only). Asterisks (*) represent polygenic scores that are significant after correcting for an FDR of 5%.
Longitudinal models of polygenic associations with alcohol use and misuse.Predicted values for alcohol use index (AUI) from ages 12 to 32 using linear mixed models in Add Health (N = 5107). Values for EXT and ALCP-specific polygenic scores set to ±1.5 SD. The shaded areas represent 95% confidence intervals. Confidence intervals estimated using percentile method bootstrapping over 1000 bootstrap samples. All other covariates set to mean values.
| Name | Type |
|---|---|
| Add Health | cohort |
| ADH1B | gene |
| ADH1C | gene |
| age at first sexual intercourse | phenotype |
| age at smoking initiation | phenotype |
| alcohol | phenotype |
| alcohol metabolism | phenotype |
| Alcohol Problems | phenotype |
| alcohol-related phenotypes | phenotype |
| Alcohol Use Disorder | phenotype |
| alcohol use disorders | phenotype |
| Alcohol use index (AUI) local | phenotype |
| ALCP-specific local | cohort |
| ALCP-specific local | phenotype |
| ALCP-specific local | variant |
| ALCP-specific PGS local | drug |
| ALCP-specific PGS local | phenotype |
| ALCP-specific PGSs local | phenotype |
| ALCP-specific polygenic score local | phenotype |
| ALCP-total local | cohort |
| ALCP-total local | variant |
| ALCP-total PGS local | drug |
| ALCP-total PGS local | phenotype |
| antisocial personality disorder | phenotype |
| attention deficit hyperactivity disorder | phenotype |
| AUD | phenotype |
| AUI local | phenotype |
| bipolar disorder | phenotype |
| brain tissue | anatomy |
| Cadm2 | gene |
| cannabis use | phenotype |
| cocaine | phenotype |
| Collaborative Study on the Genetics of Alcoholism (COGA) | cohort |
| Composite alcohol use index local | phenotype |
| conduct disorder | phenotype |
| CUDsx | phenotype |
| DRD2 | gene |
| Drinking exposure local | phenotype |
| drinks per week | phenotype |
| drug exposure | phenotype |
| European ancestry | cohort |
| Ever use | phenotype |
| ever use of alcohol local | phenotype |
| ever using illicit substances (other than cannabis) local | phenotype |
| EXT | phenotype |
| externalizing behavior | phenotype |
| externalizing disorders | phenotype |
| externalizing liability | phenotype |
| EXT PGS local | drug |
| EXT PGS | phenotype |
| EXT polygenic score | cohort |
| FUMA | drug |
| gene | gene |
| genetic variants | cohort |
| H-MAGMA local | drug |
| impulsivity | phenotype |
| impulsivity and personality phenotypes local | phenotype |
| internalizing disorders | phenotype |
| iPSYCH cross-disorder local | cohort |
| Klb | gene |
| lack of perseverance | phenotype |
| Latent genetic factor EXT local | phenotype |
| lifetime cannabis use | phenotype |
| lifetime smoking | phenotype |
| MAGMA | drug |
| major depressive disorder | phenotype |
| Manic episode | phenotype |
| maternal smoking | phenotype |
| methamphetamine | drug |
| NCAM1 | gene |
| neuroticism | phenotype |
| nicotine | drug |
| nicotine dependence criteria local | phenotype |
| non-European ancestry | cohort |
| novelty seeking | phenotype |
| number of sexual partners | phenotype |
| opioid | drug |
| other substances | phenotype |
| personality traits | phenotype |
| polygenic risk score | cohort |
| positive urgency | phenotype |
| Post-Traumatic Stress Disorder | phenotype |
| preregistered phenotypes | phenotype |
| problematic alcohol use | phenotype |
| psychiatric disorders | phenotype |
| psychiatric traits | phenotype |
| psychosis | phenotype |
| psychotic conditions local | phenotype |
| risk-taking behavior | phenotype |
| risk tolerance | phenotype |
| RNU6-887P local | gene |
| RP11-696N14.3 local | gene |
| rs10511087 local | variant |
| rs11146609 local | variant |
| rs12299844 | variant |
| rs13135092 | variant |
| rs28712821 local | variant |
| rs31140454 local | variant |
| rs34333163 local | variant |
| rs35277073 local | variant |
| rs38118024 local | variant |
| rs46997434 local | variant |
| rs6842066 local | variant |
| rs9919558 local | variant |
| schizophrenia | phenotype |
| sedatives | drug |
| SLC39A8 | gene |
| smoking | phenotype |
| SNP | cohort |
| S-PrediXcan | drug |
| stimulants | drug |
| stress-related disorders | phenotype |
| substance use | phenotype |
| substance use phenotypes | phenotype |
| SUD criterion counts | phenotype |
| young adults | cohort |
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In this knowledge base
| Title | Year | PMID |
|---|---|---|
| Genomic risk for post-traumatic stress disorder in families densely affected with alcohol use disorders. | 2023 | 37344610 |
External
| Title | Authors | Journal | Year | Link |
|---|---|---|---|---|
| Characterizing the Pleiotropic Architecture of Impulsivity and Its Links to Psychopathology and Neurodevelopment. | Mallard TT et al. | — | 2026 | → |
| Trajectories of genetic risk across dimensions of alcohol use behaviors. | Savage JE et al. | — | 2026 | → |
| Transdiagnostic and Disorder-Level Genome-Wide Association Studies Enhance Precision of Substance Use and Psychiatric Genetic Risk Profiles in African and European Ancestries. | Khan Y et al. | — | 2026 | → |
| Associations among externalizing psychopathology, personality, and behavioral traits: Models of an externalizing spectrum in youth. | Poore HE 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 | → |
| Genetic, psychological, and environmental factors are uniquely associated with onset of alcohol use in the adolescent brain cognitive development (ABCD) study. | Choi 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 | → |
| A Developmentally-Informative Genome-wide Association Study of Alcohol Use Frequency. | Thomas NS et al. | — | 2024 | → |
| A multivariate approach to understanding the genetic overlap between externalizing phenotypes and substance use disorders. | Poore HE et al. | — | 2023 | → |
| Differences in genetic correlations between posttraumatic stress disorder and alcohol-related problems phenotypes compared to alcohol consumption-related phenotypes. | Bountress KE et al. | — | 2023 | → |
| Genetic Risk, Neighborhood Characteristics, and Behavioral Difficulties Among African American Adolescents Living in Very Low-Income Neighborhoods. | Sterrett-Hong EM 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 | → |
| Clinical, environmental, and genetic risk factors for substance use disorders: characterizing combined effects across multiple cohorts. | Barr PB et al. | — | 2022 | → |
| Dimensional Phenotypes in Psychiatric Genetics: Lessons from Genome-Wide Association Studies of Alcohol Use Phenotypes. | Mallard TT et al. | — | 2021 | → |