Multi-ancestry study reveals common genetics of problematic alcohol use

A study by researchers at the VA Connecticut Healthcare Center/Yale reveals that ancestors around the world have a common genetic architecture for problematic alcohol use (PAU) – habitual excessive drinking, accompanied by adverse consequences.

The results, published in Natural medicine, could help scientists understand the genetic basis of PAU, a major cause of health problems in many age groups. It is one of the leading causes of death among those affected.

This study is the most important to date on PAU: it identified numerous new risk genes and discovered a large quantity of new biological elements. With a better understanding of the biology of UAP, scientists will have new opportunities to develop treatments.

Hang Zhou, Ph.D., assistant professor of psychiatry, biomedical informatics and data science at the Yale School of Medicine and VA Connecticut, and first author of the study, said: “Research focused primarily on understanding the molecular mechanism underlying PAU. and identification of target genes for possible pharmacological studies is extremely important for future treatments and could help mitigate the consequences of excessive alcohol consumption.

Researchers studied more than a million people with UAP and included as many ancestral genetic groups as possible, including people of European, African, Latin American, East Asian, and South Asian ancestry.

The Million Veteran Program (MVP) was a major data source for this study: MVP data was combined with data from many other sources to create the analyses.

Compared to previous research, this work expanded the results and demonstrated that the genetic architecture of PAU is significantly shared between these populations. There are genetic differences between different UAP populations, but the similarities are greater. Cross-referenced ancestry information has allowed researchers to improve the power of gene discovery.

“By leveraging multi-ancestry information, we identified 110 genetic regions and obtained improved fine mapping of potential causal variants in each region,” Zhou said.

Researchers also used various methods to prioritize multiple genes with converging evidence linking the association to PAU with brain biology through gene expression (transcriptional-wide association study in 13 brain tissues) and analyzes of chromatin interactions in the brain. This work will provide valuable resources and targets for future functional analyzes and drug development.

Joel Gelernter, MD, Foundations Fund professor of psychiatry and professor of genetics and neuroscience at the Yale School of Medicine and VA Connecticut, was lead author of the study.

“One of the most important products of this research is the information provided on genome-wide PAU risk,” Gelernter said. “The resulting data allowed us to better understand the biology of PAU, suggesting that some already approved drugs could become tools to treat PAU in the future, with additional research. The data we produced will be shared with the research community, and this will greatly assist the future research of other scientists.

Drug reuse analyzes identified several existing drugs as potential treatments for UAP, which are described in the published article.

One of the results of this study involves genome-wide association data, and this type of information can be used to calculate “polygenic risk scores,” or PRS, which can be used to estimate the genetic risk of an individual for PAU.

The researchers emphasized that the PRS they calculated is not yet ready for clinical use, but they also tested the association of the PRS for PAU with hundreds of medical characteristics in several biobanks, including the Biobank from Vanderbilt University Medical Center, the BioMe at Mount Sinai, the Mass. Brigham General Biobank and the Penn Medicine Biobank. This analysis identified genetic correlations between PAU and many other mental and neurological disorders.