Genetic Heterogeneity Across Dimensions of Alcohol Use Behaviors.
- Authors
- Savage, Jeanne E; Barr, Peter B; Phung, Tanya; Lee, Younga H; Zhang, Yingzhe; McCutcheon, Vivia V; COGA Investigators; Ge, Tian; Smoller, Jordan W; Davis, Lea K; Meyers, Jacquelyn; Porjesz, Bernice; Posthuma, Danielle; Mallard, Travis T; Sanchez-Roige, Sandra
- Year
- 2024
- Journal
- The American journal of psychiatry
- PMID
- 39380376
- DOI
- 10.1176/appi.ajp.20231055
OBJECTIVE: Increasingly large samples in genome-wide association studies (GWASs) for alcohol use behaviors (AUBs) have led to an influx of implicated genes, yet the clinical and functional understanding of these associations remains low, in part because most GWASs do not account for the complex and varied manifestations of AUBs. This study applied a multidimensional framework to investigate the latent genetic structure underlying heterogeneous dimensions of AUBs. METHODS: Multimodal assessments (self-report, interview, electronic health records) were obtained from approximately 400,000 UK Biobank participants. GWAS was conducted for 18 distinct AUBs, including consumption, drinking patterns, alcohol problems, and clinical sequelae. Latent genetic factors were identified and carried forward to GWAS using genomic structural equation modeling, followed by functional annotation, genetic correlation, and enrichment analyses to interpret the genetic associations. RESULTS: Four latent factors were identified: Problems, Consumption, BeerPref (declining alcohol consumption with a preference for drinking beer), and AtypicalPref (drinking fortified wine and spirits). The latent factors were moderately correlated (r values, 0.12-0.57) and had distinct patterns of associations, with BeerPref in particular implicating many novel genomic regions. Patterns of regional and cell type-specific gene expression in the brain also differed between the latent factors. CONCLUSIONS: Deep phenotyping is an important next step to improve understanding of the genetic etiology of AUBs, in addition to increasing sample size. Further effort is required to uncover the genetic heterogeneity underlying AUBs using methods that account for their complex, multidimensional nature.
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External
| Title | Authors | Journal | Year | Link |
|---|---|---|---|---|
| Genetic substructure in Latin American individuals reveals novel associations, mechanistic insights, and variable polygenic risk score transferability for alcohol traits | Montalvo-Ortiz J et al. | — | 2026 | — |
| Trajectories of genetic risk across dimensions of alcohol use behaviors. | Savage JE et al. | — | 2026 | → |
| Drinking motives and alcohol sensitivity mediate multidimensional genetic influences on alcohol use behaviors. | Savage JE 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 | → |
| Refining the scope of genetic influences on alcohol misuse through environmental stratification and gene-environment interaction. | Savage JE et al. | — | 2024 | → |
| Substance Use Disorders. | Kalin NH | — | 2024 | → |
| What Are the Genetic Building Blocks of Alcohol-Related Behaviors? | Gelernter J et al. | — | 2024 | → |