Identification of alcohol use disorder-associated and ethanol-responsive proteins and candidate biomarkers using human cortical organoids
Year: 2026
Type: preprint
Abstract: Genome-wide association studies of alcohol use disorder (AUD) have identified >100 loci, yet the functional impact and the downstream molecular mechanisms are not well understood. As functional effectors of genes, proteins provide direct insight into disease mechanisms. However, most proteomic alterations in postmortem human brains of AUD likely reflect a combination of inherited susceptibility (AUD-associated), the consequences of alcohol exposure (ethanol-responsive), other environmental and lifestyle factors, as well as sample preparation. Here, we profiled the proteome of human microglia-containing cortical organoids derived from human induced pluripotent stem cells from individuals with AUD (n=11) and without (n=5), paired with or without intermittent ethanol exposure. To maximize statistical power, donors were selected based on high or low genetic liability for AUD as measured by polygenic scores. Among 8,952 proteins that passed quality control, 1,038 were AUD-associated and 718 were ethanol-responsive. AUD-associated proteins were enriched for neuronal signaling, immune, mitochondrial, and extracellular matrix pathways, whereas ethanol-responsive proteins were enriched for RNA processing, ribosome biogenesis, protein translation, vesicle trafficking, and membrane transport pathways. Twenty ethanol-responsive proteins were replicated in a postmortem human prefrontal cortex proteomic dataset. Using UK Biobank plasma proteomics data, we identified 26 candidate AUD-associated biomarkers and 9 candidate ethanol-responsive biomarkers. We also found that major proteomic variation was significantly correlated with AUD polygenic scores. Together, these findings reveal distinct proteomic signatures of inherited susceptibility to AUD and ethanol exposure, providing new insights into mechanisms underlying AUD and identifying candidate circulating biomarkers for further investigation.
Language: English
Subfield: Pathology and Forensic Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: green
Funders: Children's Hospital of Philadelphia, University of Pennsylvania, State University of New York, Washington University in St. Louis, University of Connecticut, SUNY Downstate Medical Center, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, National Institute on Alcohol Abuse and Alcoholism, National Institute of Neurological Disorders and Stroke
Awards: Training in Translating Neuroscience to Therapies, Translational genetic analysis in human and mouse GWAS to identify the genomic architecture of alcohol sensitivity and tolerance, Cellular and genomic mechanisms of the impact of ethanol on human neural model, Collaborative Study on the Genetics of Alcoholism (COGA).
OpenAlex ID: W7214577883