Alzheimer's disease risk allele of <i>PICALM</i> causes detrimental lipid droplets in microglia.

ABSTRACT: Despite genome-wide association studies of late-onset Alzheimer's disease (LOAD) having identified many genetic risk loci^1-6, the underlying disease mechanisms remain largely unknown. Determining causal disease variants and their LOAD-relevant cellular phenotypes has been a challenge. Leveraging our approach for identifying functional GWAS risk variants showing allele-specific open chromatin (ASoC)⁷, we systematically identified putative causal LOAD risk variants in human induced pluripotent stem cells (iPSC)-derived neurons, astrocytes, and microglia (MG) and linked PICALM risk allele to a previously unappreciated MG-specific role of PICALM in lipid droplet (LD) accumulation. ASoC mapping uncovered functional risk variants for 26 LOAD risk loci, mostly

SUBMITTER: Kozlova A 

PROVIDER: S-EPMC11142308 | biostudies-literature | 2024 May

REPOSITORIES: biostudies-literature