A new study involving over 1 million individuals from diverse genetic backgrounds has discovered a shared genetic architecture for problematic alcohol use (PAU). The research, led by VA Connecticut Healthcare Center/Yale researchers, expands our understanding of PAU's genetic basis and its consequences, highlighting its significant role as a leading cause of health problems and mortality.

Published in Nature Medicine, the study identifies 110 risk gene regions associated with PAU, providing valuable insights into the biological mechanisms underlying this behavior. The findings also offer potential drug targets for future treatments, opening doors to personalized risk assessments and innovative interventions.

The study focused on individuals with PAU, characterized by habitual heavy drinking and its harmful consequences. It aimed to understand the genetic basis of PAU, a pervasive issue that affects individuals across various age groups and ancestries.

Hang Zhou, Ph.D., an assistant professor of psychiatry and of biomedical informatics & data science at Yale School of Medicine and VA Connecticut, and first author of the study, emphasized the importance of exploring the molecular mechanisms and identifying gene targets for potential pharmacological studies. Such research, Zhou noted, is paramount in developing effective treatments and mitigating the adverse effects of excessive alcohol consumption.

To achieve a comprehensive analysis, researchers gathered data from diverse ancestral groups, including those with European, African, Latin American, East Asian, and South Asian ancestries. The study utilized the Million Veteran Program (MVP) as a significant source of data, combining it with information from other sources for robust analyses.

The findings build upon previous research, revealing substantial shared genetic architecture for PAU across these diverse populations. While genetic differences exist among various populations, the similarities in PAU's genetic foundation are more prominent. Leveraging cross-ancestry data enhanced the researchers' ability to identify 110 gene regions and conduct in-depth fine-mapping analyses.

Additionally, the researchers employed different methods to prioritize genes associated with PAU by investigating their links to brain biology through gene expression and chromatin interaction analyses. These prioritized genes not only provide valuable targets for future functional analyses but also serve as potential candidates for drug development.

Joel Gelernter, MD, Foundations Fund Professor of Psychiatry, and professor of genetics and of neuroscience at Yale School of Medicine and VA Connecticut, served as the study's senior author. Gelernter highlighted the significance of the study's genome-wide information concerning PAU risk, emphasizing the potential for future treatments using already-approved drugs.

The study's drug-repurposing analyses identified several existing medications that could potentially be used to treat PAU. Furthermore, the study generated genome-wide association data that can be utilized to compute polygenic risk scores (PRS) to estimate an individual's genetic risk for PAU. The researchers caution that PRS is not yet ready for clinical use; however, the analysis of hundreds of medical traits in multiple biobanks revealed genetic correlations between PAU and various mental and neurological disorders.

The researchers intend to share the data generated from this study with the research community, facilitating future investigations by scientists in the field. The comprehensive understanding of PAU's genetic basis obtained from this study will help pave the way for personalized interventions and targeted therapies, potentially reducing the burden of PAU-related health issues and mortality.

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