Biological Sciences Division
Published November 8, 2024 | Version v1
Journal article Open

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

Creators

  • 1. Rutgers University
  • 2. University of Chicago
  • 3. Indiana University
  • 4. SUNY Downstate Health Sciences University
  • 5. Washington University in St. Louis
  • 6. Icahn School of Medicine at Mount Sinai

Description

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 CLEC7A 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.

Notes

Due to the large number of authors, only the first 20 and the University of Chicago authors are included on the above author list. Please download the article for the complete list of authors.

Data availability

RNA-seq data are available on the Gene Expression Omnibus (GEO): GSE255988 for microglial cell mRNA sequencing and GSE271585 for iPSC mRNA sequencing. The source code for data processing and analysis for this study has been deposited on Zenodo (https://zenodo.org/doi/10.5281/zenodo.12773329). All data needed to evaluate the conclusions in the paper are present in the paper and/or the Supplementary Materials.

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Additional details

Identifiers

DOI
10.1126/sciadv.ado5820
Other
oai:uchicago.tind.io:13952

Funding

National Institute on Alcohol Abuse and Alcoholism
R01AA023797
National Institutes of Health
U10AA008401
National Institute of General Medical Sciences
T32GM008339
National Center for Advancing Translational Sciences
TL1TR003019

UChicago Information

Division(s)
Biological Sciences Division
Department(s)
Psychiatry and Behavioral Neuroscience