TY - JOUR
T1 - Polygenic risk for alcohol use disorder affects cellular responses to ethanol exposure in a human microglial cell model
AU - Li, Xindi
AU - Liu, Jiayi
AU - Boreland, Andrew J.
AU - Kapadia, Sneha
AU - Zhang, Siwei
AU - Stillitano, Alessandro C.
AU - Abbo, Yara
AU - Clark, Lorraine
AU - Lai, Dongbing
AU - Liu, Yunlong
AU - Barr, Peter B.
AU - Meyers, Jacquelyn L.
AU - Kamarajan, Chella
AU - Kuang, Weipeng
AU - Agrawal, Arpana
AU - Slesinger, Paul A.
AU - Dick, Danielle
AU - Salvatore, Jessica
AU - Tischfield, Jay
AU - Duan, Jubao
AU - Edenberg, Howard J.
AU - Kreimer, Anat
AU - Hart, Ronald P.
AU - Pang, Zhiping P.
N1 - Publisher Copyright:
© 2024 The Authors, some rights reserved.
PY - 2024/11/8
Y1 - 2024/11/8
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/85209165300
U2 - 10.1126/sciadv.ado5820
DO - 10.1126/sciadv.ado5820
M3 - Article
C2 - 39514655
AN - SCOPUS:85209165300
SN - 2375-2548
VL - 10
JO - Science Advances
JF - Science Advances
IS - 45
M1 - eado5820
ER -