People who carry a high genetic risk for alcohol use disorder may have brain immune cells that respond differently to alcohol exposure, according to new research published in Science Advances. Using human-derived cell models, researchers found that microglia—immune cells in the brain—exhibited exaggerated responses to alcohol in individuals with elevated genetic susceptibility, potentially shedding light on the biological roots of alcohol dependence.
Alcohol use disorder is influenced by both genetic and environmental factors, with genetic components accounting for roughly half of the variation in who develops problematic drinking behaviors. Scientists have long suspected that immune and inflammatory processes in the brain contribute to this risk, but the exact cellular mechanisms have remained unclear. One challenge has been the lack of human-specific models that can accurately reflect how genetic risk plays out in brain cells.
“Alcohol use disorder has a strong genetic component, but we know little about how genetic risk actually translates to cellular and molecular changes in the brain,” said study author Zhiping Pang, the Henry Rutgers Professor of NeuroMetabolism and director of the Center for NeuroMetabolism at Rutgers University. “Microglia, as the brain’s immune cells, are increasingly recognized as central players in how the brain responds to alcohol and other insults. We were interested in whether polygenic risk for alcohol use disorder might shape microglial responses to alcohol exposure and influence neuroimmune function in a human cellular context.”
Pang and his colleagues used induced pluripotent stem cells (cells reprogrammed from adult blood samples) to generate microglia from people with high or low genetic risk for alcohol use disorder. These cells were then exposed to ethanol in a controlled lab environment, allowing the team to examine how genetic predispositions shape microglial responses to alcohol. The participants were drawn from the Collaborative Study on the Genetics of Alcoholism, a long-running project that links genetic data with clinical diagnoses of alcohol use disorder.
The study focused on 18 participants: eight with alcohol use disorder and polygenic risk scores in the top 75th percentile, and ten controls with low risk scores and no history of the disorder. From each participant, the researchers created stem cell lines that were then developed into microglial cells. These cells were confirmed to be functionally similar to adult human microglia, based on both their appearance and gene expression patterns.
Once developed, the microglia were exposed to ethanol for seven days at concentrations mimicking heavy drinking. The team monitored how the cells changed at both a molecular and functional level, comparing those derived from high-risk versus low-risk individuals.
The first major difference emerged in the baseline state of the microglia: even before alcohol exposure, high-risk cells showed elevated expression of genes involved in cell division and reduced expression of genes related to immune signaling and antigen presentation. This suggests that the genetic risk for alcohol use disorder may influence microglial development and function from the outset.
After alcohol exposure, microglia from high-risk individuals exhibited more pronounced changes. Both high- and low-risk cells showed activation, but high-risk cells shifted more dramatically from a branched, resting state to a rounded, activated shape—indicative of heightened immune reactivity. These cells also displayed stronger gene expression changes, particularly in pathways related to immune responses and phagocytosis—the process by which microglia engulf and break down cellular debris, pathogens, or even synapses.
One gene, CLEC7A, stood out. It was significantly upregulated in high-risk microglia following ethanol exposure. This gene encodes a receptor involved in recognizing foreign particles and initiating phagocytosis. Follow-up experiments confirmed that CLEC7A protein levels also rose, and phagocytic activity increased substantially in high-risk cells—both when using artificial particles and synaptic material from neurons.
“What stood out was the distinct difference in microglial behavior between individuals with high and low genetic risk for alcohol use disorder,” Pang told PsyPost. “The enhanced phagocytic activity and elevated CLEC7A expression in high-PRS microglia after ethanol exposure suggest that these cells are biologically primed to respond differently to alcohol, which we did not fully anticipate.”
This finding led researchers to test how microglia might influence neurons in the context of alcohol exposure. They created co-cultures combining neurons and microglia and observed the effects of alcohol. In the absence of microglia, neurons exposed to alcohol showed increased synaptic activity. This effect persisted when low-risk microglia were added. But when neurons were co-cultured with high-risk microglia, alcohol no longer enhanced synaptic connections—suggesting that these immune cells were pruning or removing synapses in response to ethanol.
These results highlight a potential mechanism through which genetic predisposition could heighten vulnerability to alcohol use disorder. If microglia in genetically susceptible individuals are more prone to immune activation and synapse pruning, alcohol might accelerate the loss of healthy brain connectivity, potentially reinforcing problematic behaviors and impairing cognitive function.
“Genetic risk for alcohol use disorder doesn’t just influence behavior—it may also alter how the brain’s immune cells respond to alcohol,” Pang explained. “People with a higher genetic risk for alcohol use disorder may have brain immune cells (called microglia) that react more strongly to alcohol. This heightened response could lead to unnecessary trimming of brain connections over time, which may change how the brain functions and, ultimately, how a person behaves, such as increasing their risk of heavy drinking.”
As with all research, the study has limitations. The microglia were studied in a two-dimensional culture system, which does not fully replicate the complexity of the human brain. Although the cells were derived from real people, they were reprogrammed and studied in an artificial environment that may not perfectly capture long-term effects of alcohol use.
Additionally, the researchers focused on a short window of alcohol exposure—just seven days—rather than chronic exposure over months or years. It’s also unclear how past drinking behavior might have influenced the stem cells used, given that some were taken from individuals already diagnosed with alcohol use disorder.
Despite the limitations, the study provides a valuable model for understanding how genetic risk translates into functional changes in the brain’s immune system. By using human-derived microglia and polygenic risk scores, the researchers were able to link inherited risk directly to cellular behavior. Their findings suggest that treatments for alcohol use disorder might one day be tailored to an individual’s genetic profile—especially if interventions can target overactive microglial responses.
“Our next steps include integrating human neurons and microglia in more advanced 3D culture systems, i.e. brain organoids, to better understand how these immune changes affect synaptic connectivity,” Pang said. “We also aim to explore therapeutic interventions that could mitigate the harmful effects of alcohol in genetically vulnerable individuals.”
“This work highlights the importance of studying human-specific biology in psychiatric disorders. By combining genetic risk scores with human cellular models, we can start to unravel how inherited risk influences brain cell function—and ultimately behavior—in a way that animal models may not fully capture.”
The study, “Polygenic risk for alcohol use disorder affects cellular responses to ethanol exposure in a human microglial cell model,” was authored by Xindi Li, Jiayi Liu, Andrew J. Boreland, Sneha Kapadia, Siwei Zhang, Alessandro C. Stillitano, Yara Abbo, Lorraine Clark, Dongbing Lai, Yunlong Liu, Peter B. Barr, Jacquelyn L. Meyers, Chella Kamarajan, Weipeng Kuang, Arpana Agrawal, Paul A. Slesinger, Danielle Dick, Jessica Salvatore, Jay Tischfield, Jubao Duan, Howard J. Edenberg, Anat Kreimer, Ronald P. Hart, and Zhiping P. Pang.
