Alcohol use disorder (AUD) is a major global public health challenge, contributing to significant illness, social harm, and premature mortality. While it is well established that genetic, psychiatric, and environmental factors all play a role in AUD, and we know that genes account for about half of the risk, what we can detect about their relative influence today — and how these influences may vary across populations — remained unclear.
A new study led by researchers at the Yale School of Medicine and the VA Connecticut Healthcare System provides the most comprehensive analysis to date of genetic, psychiatric, and environmental factors that shape risk for AUD. The findings, published online September 24 in the American Journal of Psychiatry, are based on data from more than 11,000 participants of African and European ancestries who participated in the Yale-Penn study, a study of the genetics of alcohol and drug use disorders that was started more than two and a half decades ago by Drs. Joel Gelernter of Yale, senior author of the American Journal of Psychiatry study, and Henry R. Kranzler, of University of Pennsylvania, and also an author.
“While GWAS remains a powerful tool for understanding the biology underlying alcohol and substance use disorders, currently polygenic risk scores are not the best clinical indicators for the potential of developing problems related to substance use,” said Joseph Deak, PhD, assistant professor of psychiatry at Yale School of Medicine, and co-lead author of the study.
The research team examined polygenic risk scores (PRS) derived from large genome-wide association studies (GWAS), together with psychiatric conditions and environmental exposures, to assess both their independent and combined effects on AUD severity.
Key findings include:
Genetic risk: Polygenic risk scores for problematic alcohol use predicted AUD severity in both African- and European-ancestry participants, explaining 1.3% and 1.9% of the variance in this outcome, respectively. These polygenic risk scores are based on current knowledge – as increasingly-better studies of AUD genetics are completed, their predictive value will continue to increase.Psychiatric disorders: Among psychiatric disorders, posttraumatic stress disorder showed the strongest association with AUD severity, followed by anxiety and major depressive disorders.Environmental factors: Environmental influences—including education, early household substance exposure, income, and sex—explained a much larger proportion of risk, accounting for 73% of the variance in African-ancestry participants and 59% in European-ancestry participants.Protective role of education: In European-ancestry participants, higher educational attainment moderated genetic risk, suggesting that education may buffer genetic vulnerability to AUD.
“Our findings show that while genetics play an important role—accounting for an estimated 50-60% of alcohol use disorder (AUD) risk—psychiatric and environmental factors account for the majority of alcohol use disorder risk that we can detect in a clinical context today,” said Peter Jongho Na, MD, MPH, psychiatrist at the VA Connecticut Healthcare System, assistant professor of psychiatry at Yale School of Medicine, and co-lead author of the study. “This highlights opportunities for prevention through education, social policy, and targeted interventions.”
The study also highlights the role of social determinants of health, as African-ancestry participants in the sample were less likely to have higher education or household income, both of which were strongly linked to AUD risk. “Efforts to address these social determinants of health could have meaningful impacts on reducing the burden of AUD in diverse populations,” said Robert Pietrzak, PhD, MPH, director of the Translational Psychiatric Epidemiology Laboratory of the National Center for PTSD, professor of psychiatry and of public health at Yale School of Medicine, and co-author of the study.
The authors conclude that integrating genetic risk prediction with psychiatric and environmental risk factors provides a more complete understanding of the biopsychosocial origins of AUD. They emphasize that future prevention and treatment strategies must address both environmental and genetic determinants to be effective across populations.
“Alcohol use traits are influenced by both genetic and environmental factors,” said Joel Gelernter, MD, Foundations Fund Professor of Psychiatry at Yale. “Genetic risk is important, but we can’t yet account for enough of the genetic risk for useful personalization, for most people. Non-genetic factors that we can quantify now, account for more of the risk. We should therefore approach genetic risk prediction for these traits with great caution, while we wait for more and better data.”
Other study authors include Daniel Levey, PhD, assistant professor of psychiatry at Yale School of Medicine.