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Polygenic risk for alcohol use disorder affects cellular responses to ethanol exposure in a human microglial cell model

Year: 2024
Type: article
Abstract: Polygenic risk scores (PRS) assess genetic susceptibility to Alcohol Use Disorder (AUD), yet their molecular implications remain underexplored. Neuroimmune interactions, particularly in microglia, are recognized as significant contributors to AUD pathophysiology. We investigated the interplay between AUD PRS and ethanol in human microglia derived from iPSCs from individuals with high- or low-PRS (HPRS or LPRS) of AUD. Ethanol exposure induced elevated CD68 expression and morphological changes in microglia, with differential responses between HPRS and LPRS microglial cells. Transcriptomic analysis revealed expression differences in MHCII complex and phagocytosis-related genes following ethanol exposure; HPRS microglial cells displayed enhanced phagocytosis and increased CLEC7A expression, unlike LPRS microglial cells. Synapse numbers in co-cultures of induced neurons with microglia after alcohol exposure were lower in HRPS co-cultures, suggesting possible excess synapse pruning. This study provides insights into the intricate relationship between AUD PRS, ethanol, and microglial function, potentially influencing neuronal functions in developing AUD.
DOI: 10.1126/sciadv.ado5820
Authors: 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, Zhiping P. Pang
Institutions: Rutgers, The State University of New Jersey, Endeavor Health, University of Chicago, Indiana University School of Medicine, SUNY Downstate Health Sciences University, Icahn School of Medicine at Mount Sinai
Language: English
Subfield: Neurology
Open Access status: gold
Estimated APC paid: $4,500
Funders: Robert Wood Johnson Foundation, University of Pennsylvania, State University of New York, Washington University in St. Louis, University of Connecticut, National Institutes of Health, 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 on Aging, National Institute of Mental Health, National Institute of General Medical Sciences, National Center for Advancing Translational Sciences
Awards: G105681295, G1083756078, G1202258440, G2009883761, G2988041300, G3485904311, G3667159241, Rutgers University Biotechnology Training Program, Cellular and genomic mechanisms of the impact of ethanol on human neural model
OpenAlex ID: W4404166215
FWCI: 2.539
Cites: 105
Cited by: 19
Related to: 10