High Polygenic Risk Scores Are Associated With Early Age of Onset of Alcohol Use Disorder in Adolescents and Young Adults at Risk.
- Authors
- Nurnberger, John I; Wang, Yumin; Zang, Yong; Lai, Dongbing; Wetherill, Leah; Edenberg, Howard J; Aliev, Fazil; Plawecki, Martin H; Chorlian, David; Chan, Grace; Bucholz, Kathleen; Bauer, Lance; Kamarajan, Chella; Salvatore, Jessica E; Kapoor, Manav; Hesselbrock, Victor; Dick, Danielle; Bierut, Laura; McCutcheon, Vivia; Meyers, Jacquelyn L; Porjesz, Bernice; Kramer, John; Kuperman, Samuel; Kinreich, Sivan; Anokhin, Andrey P; Collaborative Study on the Genetics of Alcoholism
- Year
- 2022
- Journal
- Biological psychiatry global open science
- PMID
- 36324664
- DOI
- 10.1016/j.bpsgos.2021.10.007
- PMCID
- PMC9616304
BACKGROUND: Genome-wide association studies have been conducted in alcohol use disorder (AUD), and they permit the use of polygenic risk scores (PRSs), in combination with clinical variables, to predict the onset of AUD in vulnerable populations. METHODS: A total of 2794 adolescent/young adult subjects from the Collaborative Study on the Genetics of Alcoholism were followed, with clinical assessments every 2 years. Subjects were genotyped using a genome-wide chip. Separate PRS analyses were performed for subjects of European ancestry and African ancestry. Age of onset of DSM-5 AUD was evaluated using the Cox proportional hazard model. Predictive power was assessed using receiver operating characteristic curves and by analysis of the distribution of PRS. RESULTS: European ancestry subjects with higher than median PRSs were at greater risk for onset of AUD than subjects with lower than median PRSs ( = 3 × 10). Area under the curve for the receiver operating characteristic analysis peaked at 0.88 to 0.95 using PRS plus sex, family history, comorbid disorders, age at first drink, and peer drinking; predictive power was primarily driven by clinical variables. In this high-risk sample, European ancestry subjects with a PRS score in the highest quartile showed a 72% risk for developing AUD and a 35% risk of developing severe AUD (compared with risks of 54% and 16%, respectively, in the lowest quartile). CONCLUSIONS: Predictive power for PRSs in the extremes of the distribution suggests that these may have future clinical utility. Uncertainties in interpretation at the individual level still preclude current application.
Polygenic risk score distribution in subjects from European ancestry (EA) case families (blue) and comparison families (red). The polygenic risk score distribution is shifted to the right in the case families, adjusting for sex and principal component 1 through principal component 4. The shift is not significant in the thresholded analysis (shown here for consistency) but is significant when calculated by the PRS-CS method (48) (p = 2.89 × 10−6). EA_MAX_ALC.P1, PRS based on MAX_ALC in European ancestry subjects using the threshold p < .1.
Age of onset for first diagnosis of alcohol use disorder (AUD) in European ancestry subjects with high polygenic risk scores (using a median split) is lower than age of onset for AUD for subjects with low polygenic risk scores. The Cox model shows the p value incorporating sex and principal components for ancestry (p = 4.89 × 10−6). The log-rank test is not adjusted for covariates (p = 5.30 × 10−7). EA_MAX_ALC.P1, PRS based on MAX_ALC in European ancestry subjects using the threshold p < .1.
Kaplan-Meier curves (survival analysis) for age of first alcohol use disorder (AUD) diagnosis for European ancestry subjects in quartiles of the polygenic risk score distribution. Shaded areas around each curve represent 95% confidence intervals. The Cox model incorporates sex and ancestry principal components. The log-rank test does not incorporate covariates. EA_MAX_ALC.P1, PRS based on MAX_ALC in European ancestry subjects using the threshold p < .1.
Kaplan-Meier curves (survival analysis) for age of first severe alcohol use disorder (AUD) diagnosis for European ancestry subjects in quartiles of the polygenic risk score distribution. Shaded areas around each curve represent 95% confidence intervals. The Cox model incorporates sex and ancestry principal components. The log-rank test does not incorporate covariates. EA_MAX_ALC.P1, PRS based on MAX_ALC in European ancestry subjects using the threshold p < .1.
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External
| Title | Authors | Journal | Year | Link |
|---|---|---|---|---|
| Genetic risk of chronic pain conditions associated with risk of suicide death through an integrative analysis of EHR and genomics data. | Han S et al. | — | 2026 | → |
| Polygenic risk moderation of stressful life events in alcohol use disorder severity. | Agabani Z et al. | — | 2026 | → |
| A comprehensive exploration of the impact and contribution of polygenic risk score on age at onset of 30 complex diseases. | Liu Y et al. | — | 2025 | → |
| Influence and role of polygenic risk score in the development of 32 complex diseases. | Liu Y et al. | — | 2025 | → |
| Interplay between polygenic risk and family processes in predicting trajectories of adolescent externalizing behaviors. | Su J et al. | — | 2025 | → |
| [Long-term courses of alcohol dependence]. | John U et al. | — | 2025 | → |
| Age at onset as an index of genetic heterogeneity in major psychiatric and substance use disorders. | Kendler KS 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 | → |
| Considerations for the application of polygenic scores to clinical care of individuals with substance use disorders. | Kember RL et al. | — | 2024 | → |
| Differing Effects of Alcohol Use on Epigenetic and Brain Age in Adult Children of Parents with Alcohol Use Disorder. | Scholl JL et al. | — | 2024 | → |
| Inverse relationship between polygenic risk burden and age of onset of autoimmune vitiligo. | Roberts GHL et al. | — | 2024 | → |
| Low-dose ondansetron: A candidate prospective precision medicine to treat alcohol use disorder endophenotypes. | Johnson B et al. | — | 2024 | → |
| A Phase 3 Randomized Precision Medicine Clinical Trial Using Low-Dose Ondansetron (a 5-HT3 Antagonist) to Treat Alcohol Use Disorder | Johnson B et al. | — | 2023 | — |
| Predicting Alcohol-Related Memory Problems in Older Adults: A Machine Learning Study with Multi-Domain Features. | Kamarajan C et al. | — | 2023 | → |
| The Collaborative Study on the Genetics of Alcoholism: Overview. | Agrawal A et al. | — | 2023 | → |
| The collaborative study on the genetics of alcoholism: Sample and clinical data. | Dick DM et al. | — | 2023 | → |