Scientists Discover How Genetic Risk for Alcoholism Changes Brain Cell Behavior

Rutgers Health researchers have discovered that brain immune cells from people with a high genetic risk for alcohol use disorder (AUD) behave differently than cells from low-risk people when exposed to alcohol.

Their study in Science Advances could help explain why some people are more susceptible to developing drinking problems and potentially lead to more personalized treatments.

“This is the first study to show how the genetic variations that increase the risk of AUD affect the behavior of some brain cells,” said Zhiping Pang, a professor of neuroscience and cell biology at Robert Wood Johnson Medical School and a resident scientist at the Child Health Institute of New Jersey and a core member at the Rutgers Brain Health Institute.

“We started with a simple model, but as the models get more complex, we’ll learn more about what’s happening in the brain,” said Pang, the senior author of the study. “Hopefully, our discoveries will suggest treatment approaches because we don’t currently have great treatments for AUD.”

According to the 2023 National Survey on Drug Use and Health, nearly 28.9 million people ages 12 and older in the United States struggle with alcohol use disorder. While scientists have known the condition runs in families – with genetic factors accounting for 40% to 60% of risk – the biological mechanisms behind this hereditary component have remained unclear.

The research team took blood samples from two groups of people: those with both high genetic risk for AUD and diagnosed alcohol problems and those with low genetic risk and no alcohol problems. They transformed these blood cells into stem cells and made them develop into a type of brain-based immune cell called microglia.

They then exposed these two groups of cells, one from the people with a high genetic risk for AUD and one from the people with a low risk of AUD, to alcohol levels that mimicked those seen in the blood following alcohol use.

“The microglia with the high genetic risk scores were far more active than the microglia with the low genetic risk scores after the alcohol exposure,” said Xindi Li, lead author of the study, a postdoctoral fellow at the Child Health Institute of New Jersey.

The highly active cells engaged in more “synaptic pruning” – removing connections between neurons in the brain. This increased pruning activity could have significant implications, the researchers said.

“After many years of drinking, people with these genetics may have a greater risk of dementia because the microglia pruned so many more connections,” Li said. “Their overactivity could make neurons less functional.”

The study drew on expertise throughout Rutgers University, involving scientists from multiple labs and departments, including Ronald Hart and Jay Tischfield. This interdisciplinary approach brings together experts in genetics, neuroscience, and addiction research to tackle the complex challenge of understanding how genetic risk factors influence alcohol use disorder at the cellular level. This has been the long-term theme of the Rutgers component of the long-term NIH-funded Collaborative Study on the Genetics of Alcoholism (COGA).

While previous studies have identified genetic variants associated with increased risk, it has been challenging to see how these differences affect brain cell function.

Although this study focused on a single type of brain cell in a flat environment, the team is developing more sophisticated models for their research.

“We’re going from the cell cultures in a 2D situation to the brain organoids,” Pang said. “So we can study something more like a mini brain-structure, to understand how the cells interact with alcohol, and then to see how the genetic risk factors play a role in that response.”

This work could eventually lead to better treatments for alcohol use disorder. The results suggest that if different genetic variations lead to different cell behavior in the brain, people with different genetic signatures may need different treatments, for example targeting the microglia in some people at high risk.

That said, the researchers stressed that much work remains to be done to translate these cellular findings into clinical applications.