Polygenic risk for alcohol use disorder affects cellular responses to ethanol exposure in a human microglial cell model
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 <i>CLEC7A</i> 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.
Authors
- Jessica E. Salvatore (ORCID: https://orcid.org/0000-0001-5504-5087)
- Peter B. Barr (ORCID: https://orcid.org/0000-0001-9321-657X)
- Zhiping P. Pang (ORCID: https://orcid.org/0000-0002-6183-1233)
- Sneha Kapadia
- Arpana Agrawal (ORCID: https://orcid.org/0000-0002-0313-793X)
- Weipeng Kuang (ORCID: https://orcid.org/0009-0008-2622-2556)
- Jubao Duan (ORCID: https://orcid.org/0000-0002-7215-3220)
- Danielle M. Dick (ORCID: https://orcid.org/0000-0002-1636-893X)
- Jay A. Tischfield (ORCID: https://orcid.org/0000-0003-3217-8287)
- Jacquelyn L. Meyers (ORCID: https://orcid.org/0000-0003-3863-8555)
- Lorraine N. Clark (ORCID: https://orcid.org/0000-0001-5899-4616)
- Howard J. Edenberg (ORCID: https://orcid.org/0000-0003-0344-9690)
- Andrew J. Boreland (ORCID: https://orcid.org/0000-0002-1786-3473)
- Ronald P. Hart (ORCID: https://orcid.org/0000-0003-4836-8712)
- Dongbing Lai (ORCID: https://orcid.org/0000-0001-7803-580X)
- Anat Kreimer (ORCID: https://orcid.org/0000-0002-3066-5498)
- Chella Kamarajan
- Paul A. Slesinger
- Alessandro C. Stillitano (ORCID: https://orcid.org/0000-0003-3072-3667)
- Yara Abbo (ORCID: https://orcid.org/0000-0003-3581-7582)
- Yunlong Liu (ORCID: https://orcid.org/0000-0002-2699-626X)
- Jiayi Liu (ORCID: https://orcid.org/0000-0001-6432-0124)
- Siwei Zhang (ORCID: https://orcid.org/0000-0002-1646-063X)
- Xindi Li (ORCID: https://orcid.org/0009-0002-9027-6993)
Institutions
- Rutgers, The State University of New Jersey (US)
- NorthShore University HealthSystem (US)
- SUNY Downstate Health Sciences University (US)
- Washington University in St. Louis (US)
- Johnson University (US)
- University of Chicago (US)
- Indiana University School of Medicine
- Saint Louis University (US)
- Indiana University – Purdue University Indianapolis (US)
- Icahn School of Medicine at Mount Sinai (US)
Publication Details
- Journal
- Science Advances
- Published
- 2024-11-08
- DOI
- https://doi.org/10.1126/sciadv.ado5820
- Citations
- 13
- Primary Topic
- Neuroinflammation and Neurodegeneration Mechanisms
- Type
- article
- Field-Weighted Citation Impact
- 3.22
Funders
- Robert Wood Johnson Foundation
- 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