Polygenic Risk for Alcohol Use Disorder Affects Cellular Responses to Ethanol Exposure in a Human Microglial Cell Model

Overview

Journal Sci Adv

Specialties Biology
Science

Date 2024 Nov 8

PMID 39514655

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

Affiliations

Soon will be listed here.

Abstract

Polygenic risk scores (PRSs) assess genetic susceptibility to alcohol use disorder (AUD), yet their molecular implications remain underexplored. Neuroimmune interactions, particularly in microglia, are recognized as notable contributors to AUD pathophysiology. We investigated the interplay between AUD PRS and ethanol in human microglia derived from iPSCs from individuals with AUD high-PRS (diagnosed with AUD) or low-PRS (unaffected). Ethanol exposure induced elevated CD68 expression and morphological changes in microglia, with differential responses between high-PRS and low-PRS microglial cells. Transcriptomic analysis revealed expression differences in MHCII complex and phagocytosis-related genes following ethanol exposure; high-PRS microglial cells displayed enhanced phagocytosis and increased expression, unlike low-PRS microglial cells. Synapse numbers in cocultures of induced neurons with microglia after alcohol exposure were lower in high-RPS cocultures, 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.

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