New research led by three Yale School of Medicine scientists aims to achieve better understanding of the molecular effects of alcohol use disorder (AUD) on certain regions of the brain.
The study, funded by a five-year, $2.3 million grant from the National Institute on Alcohol Abuse and Alcoholism (NIAAA), will be led by Matthew Girgenti, PhD, assistant professor of psychiatry; and co-investigators John H. Krystal, MD, Robert L. McNeil, Jr. Professor of Translational Research and professor of psychiatry, of neuroscience, and of psychology; and Hongyu Zhao, PhD, Ira V. Hiscock Professor of Biostatistics, professor of genetics, and professor of statistics and data science. Zhao’s primary appointment is with the Yale School of Public Health.
The researchers want to learn more about the neurobiological mechanisms affected by AUD so more effective interventions for addiction may be identified.
Alcohol use remains a leading cause of death in the United States and affects over 16 million adults, so understanding the molecular basis for why some people become addicted to alcohol could help identify more useful individualized therapeutics.
The researchers will combine AUD genome-wide association studies with gene expression and DNA methylation findings from discreet regions in the human brain. They expect their analysis will identify unknown AUD-associated genes and epigenetic marks, allowing identification of neurobiological mechanisms and therapeutic targets.
The research will include a postmortem analysis of brains from 341 subjects, including 100 with AUD, 132 with major depressive disorder, and 109 with no known disorders.
The scientists will determine differential DNA methylation and RNA expression across eight areas of the prefrontal cortex, amygdala, nucleus accumbens, and hippocampus. They will analyze RNA-sequencing to identify transcriptional changes in etiologically relevant AUD brain regions, then will identify gene regulatory mechanisms of AUD by integrating whole-genome bisulfite sequencing of matched donors and regions.
Finally, they will prioritize AUD genes and test whether genome-wide significant variants identified from genome-wide association studies of AUD and alcohol-related phenotypes are associated with gene expression or DNA methylation across brain regions.