Alcohol milestones and internalizing, externalizing, and executive function: longitudinal and polygenic score associations.
paper
Primary
Public
- Authors
- Paul, Sarah E; Baranger, David A A; Johnson, Emma C; Jackson, Joshua J; Gorelik, Aaron J; Miller, Alex P; Hatoum, Alexander S; Thompson, Wesley K; Strube, Michael; Dick, Danielle M; Kamarajan, Chella; Kramer, John R; Plawecki, Martin H; Chan, Grace; Anokhin, Andrey P; Chorlian, David B; Kinreich, Sivan; Meyers, Jacquelyn L; Porjesz, Bernice; Edenberg, Howard J; Agrawal, Arpana; Bucholz, Kathleen K; Bogdan, Ryan
- Year
- 2024
- Journal
- Psychological medicine
- PMID
- 38721768
- DOI
- 10.1017/S003329172400076X
- PMCID
- PMC11464200
BACKGROUND: Although the link between alcohol involvement and behavioral phenotypes (e.g. impulsivity, negative affect, executive function [EF]) is well-established, the directionality of these associations, specificity to stages of alcohol involvement, and extent of shared genetic liability remain unclear. We estimate longitudinal associations between transitions among alcohol milestones, behavioral phenotypes, and indices of genetic risk. METHODS: Data came from the Collaborative Study on the Genetics of Alcoholism ( = 3681; ages 11-36). Alcohol transitions (first: drink, intoxication, alcohol use disorder [AUD] symptom, AUD diagnosis), internalizing, and externalizing phenotypes came from the Semi-Structured Assessment for the Genetics of Alcoholism. EF was measured with the Tower of London and Visual Span Tasks. Polygenic scores (PGS) were computed for alcohol-related and behavioral phenotypes. Cox models estimated associations among PGS, behavior, and alcohol milestones. RESULTS: Externalizing phenotypes (e.g. conduct disorder symptoms) were associated with future initiation and drinking problems (hazard ratio (HR)β©Ύ1.16). Internalizing (e.g. social anxiety) was associated with hazards for progression from first drink to severe AUD (HRβ©Ύ1.55). Initiation and AUD were associated with increased hazards for later depressive symptoms and suicidal ideation (HRβ©Ύ1.38), and initiation was associated with increased hazards for future conduct symptoms (HR = 1.60). EF was not associated with alcohol transitions. Drinks per week PGS was linked with increased hazards for alcohol transitions (HRβ©Ύ1.06). Problematic alcohol use PGS increased hazards for suicidal ideation (HR = 1.20). CONCLUSIONS: Behavioral markers of addiction vulnerability precede and follow alcohol transitions, highlighting dynamic, bidirectional relationships between behavior and emerging addiction.
Associations between stage-based phenotypes and alcohol transitions. (a) Associations between internalizing and externalizing and hazards of alcohol transitions. Asterisks reflect estimates that survived FDR correction for all 20 tests for internalizing phenotypes, and separately, all 16 tests for externalizing phenotypes. Note three violations of the proportional hazards assumption for which time interactions were incorporated to resolve the violations: ADHD hyperactive symptoms in models of βFirst Drinkβ and βFirst Drink to First Intoxicationβ and ODD symptoms in the model of βFirst Drink to First Diagnosis.β For simplicity, those interactions are not depicted here. All predictors were entered into the models simultaneously, alongside covariates. (b) Associations between executive function and hazards of alcohol transitions. ToL, Tower of London Test; VST, Visual Span Test. Note that for the ToL, higher scores reflect worse executive functioning, whereas the opposite is true for the VST. Hazard ratios for ToL measures are hazards associated with a doubling of the ToL measures, which were log2 transformed (Supplemental Methods). Each EF predictor was entered into analyses separately, given varying sample sizes and correlations among EF phenotypes. For both figures, point estimates reflect hazard ratios, and error bars represent 95% confidence intervals.
Associations between alcohol milestones and stage-based symptom onsets. Associations between alcohol milestones and hazards of stage-based symptom onsets. Point estimates reflect hazard ratios, and error bars represent 95% confidence intervals. Asterisks reflect estimates that survived FDR correction for all (24) tests. MDE, Major Depressive Episode; Panic, Panic Disorder Symptoms; Conduct, Conduct Disorder Symptoms; Oppositional, Oppositional Defiant Disorder Symptoms.
Associations between stage-based polygenic scores and alcohol transitions. Associations between stage-based PGS and hazards of alcohol transitions. EUR, PCA-selected European ancestry; AFR, PCA-selected African ancestry. Point estimates reflect hazard ratios, and error bars represent 95% confidence intervals. AFR ancestry PGS associations are depicted with dotted lines. Alcohol PGS are included for comparison at the bottom of each plot.
Associations between alcohol polygenic scores and stage-based outcomes. Associations between alcohol PGS and hazards of stage-based outcomes. Point estimates reflect hazard ratios, and error bars represent 95% confidence intervals. Solid lines represent PGS in EUR ancestry, and dashed lines represent PGS in AFR ancestry Asterisks reflect estimates that survived FDR correction for all 12 tests (2 alcohol PGS Γ 6 outcomes) in EUR ancestry. Note that, among individuals of AFR ancestry, models predicting panic symptoms, social anxiety symptoms, and oppositional defiant symptoms did not converge, so estimates may be unreliable.
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