A recent study led by researchers from the VA Connecticut Healthcare Center and Yale has revealed that various ancestries worldwide share a common genetic architecture related to problematic alcohol use (PAU). PAU refers to heavy drinking habits that are accompanied by harmful consequences. Published in Nature Medicine, the study’s findings could enhance the understanding of the genetic basis of PAU, a leading cause of health issues and mortality in affected individuals.
This study, the largest to date on PAU, identified numerous new risk genes and uncovered substantial new knowledge about the biology underlying the condition. With a better understanding of the biology of PAU, scientists can explore new possibilities for developing effective treatments. Dr. Hang Zhou, the first author of the study and an Assistant Professor of Psychiatry and Biomedical Informatics & Data Science at Yale School of Medicine and VA Connecticut, emphasized the importance of investigating the molecular mechanism underlying PAU and identifying potential gene targets for future pharmacological studies.
The research team analyzed data from more than 1 million individuals with PAU, including people from various genetic ancestral groups, such as those with European, African, Latin American, East Asian, and South Asian ancestries. The study drew data from the Million Veteran Program (MVP) along with other sources to produce comprehensive analyses.
Compared to previous research, this study broadened the findings and demonstrated that the genetic architecture of PAU is shared to a significant extent across different populations, despite some variations. By utilizing cross-ancestry information, the researchers were able to enhance the power of gene discovery and identify 110 gene regions while fine-mapping potential causal variants in each region.
The team also employed various methods to prioritize multiple genes that exhibited convergent evidence linking them to PAU, particularly in terms of brain biology. These methods included conducting transcriptional-wide association studies in 13 brain tissues and analyzing chromatin interactions in the brain. These findings will serve as valuable resources for future functional analyses and drug development efforts.
Dr. Joel Gelernter, the senior author of the study and a Professor of Psychiatry, Genetics, and Neuroscience at Yale School of Medicine and VA Connecticut, highlighted the significance of the study’s results in terms of understanding the biology of PAU. The data provide insights that suggest certain already-approved drugs could be repurposed as potential tools for treating PAU in the future, pending further research. The researchers aim to share the produced data with the scientific community, which will greatly aid future research endeavors.
The study’s drug-repurposing analyses identified several existing medications that hold promise as potential treatments for PAU, as outlined in the published article. In addition, the study generated genome-wide association data that can be utilized to compute polygenic risk scores (PRS) for estimating an individual’s genetic risk of developing PAU.
While the researchers caution that the PRS is not currently suitable for clinical use, they tested its association with hundreds of medical traits across multiple biobanks. These analyses, which included the Vanderbilt University Medical Center’s Biobank, Mount Sinai’s BioMe, the Mass General Brigham Biobank, and the Penn Medicine Biobank, revealed genetic correlations between PAU and numerous mental and neurological disorders. These findings shed further light on the complex relationship between genetic factors and PAU, opening up potential avenues for future research and treatment strategies.
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1. Source: Coherent Market Insights, Public sources, Desk research
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