Polygenic Risk for Alcohol Use Disorder Affects Cellular Responses to Ethanol Exposure in a Human Microglial Cell Model I
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 CLEC7Aexpression, 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. Overall design: Cultures of microglial cells, differentiated from multiple iPSC lines prepared from subjects with AUD and high polygenic risk (HPRS) and unaffected with low polygenic risk (LPRS) were treated with 75 mM ethanol or untreated.  Total cellular RNA was prepared and compared for effects of ethanol treatment or ethanol interaction with AUD-polygenic risk.