Substance Use
Resilience to Alcohol Use Disorder Despite High Genetic Risk: Evidence from a Nationally Representative U.S. Sample Haitao Zhang* Haitao Zhang National Institute on Alcohol Abuse and Alcoholism, NIH
Background: Alcohol use disorder (AUD) is strongly influenced by genetic liability, yet many individuals at elevated genetic risk never develop the disorder. Identifying phenotypic characteristics associated with resilience under high genetic risk may clarify non-genetic factors that differentiate outcomes among vulnerable individuals.
Methods: Data were drawn from the National Epidemiologic Survey on Alcohol and Related Conditions–III (2012–2013). Analyses were restricted to genotyped current or former drinkers in the top quartile of AUD polygenic risk scores. Resilience was defined as absence of lifetime AUD within this high-risk group. Survey-weighted logistic regression models were estimated using SUDAAN with domain analysis to account for the complex sampling design. To reduce concerns about reverse causation, primary predictors were limited to early-life adversity, ages of substance initiation, and adult characteristics considered relatively stable or behaviorally anchored, including religious service attendance. Models adjusted for genetic ancestry principal components and key sociodemographic factors.
Results: Among 5,141 high–genetic-risk drinkers (weighted N ≈ 31.9 million), older age (per year: OR = 1.02, 95% CI 1.01–1.03) and female sex were consistently associated with higher odds of resilience. Greater childhood trauma (OR = 0.55) and earlier initiation of alcohol, tobacco, or other drugs were strongly associated with lower odds of remaining AUD-free. Religious or spiritual importance and binary indicators of religious service attendance were not independently associated with resilience. More frequent religious service attendance showed a modest positive association (OR = 1.22, 95% CI 1.00–1.49) with resilience in minimally adjusted models, but this association was attenuated after adjustment for sociodemographic characteristics. Several sociodemographic factors, including region of residence, were also associated with resilience.
Conclusions: In this nationally representative sample of individuals with high genetic liability for AUD, belief-based religiosity and some commonly studied early-life factors were insufficient to independently distinguish resilience. Earlier substance initiation and childhood trauma emerged as robust correlates of non-resilience, while regular participation in structured adult social contexts showed limited and context-dependent associations. These findings highlight the importance of developmentally anchored behavioral exposures over attitudinal characteristics in buffering genetic risk for AUD.