(W1184) NEUROGENOMICS STUDY OF STEM CELL-DERIVED NEURAL MODELS IDENTIFIES FUNCTIONAL RISK VARIANTS FOR BRAIN DISORDERS AND IMPLICATES MICROGLIA-SPECIFIC ROLE OF PICALM IN ALZHEIMER'S DISEASE

Abstract: Despite genome-wide association studies (GWAS) 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 and linked PICALM risk allele to a previously unrecognized microglia-specific role of PICALM in lipid droplet (LD) accumulation. ASoC mapping uncovered functional risk variants for 26 LOAD risk loci, mostly specific to microglia. At the microglia-specific PICALM locus, the LOAD risk allele of rs10792832 reduced transcription factor (PU.1) binding and PICALM expression, impairing the uptake of amyloid beta (Aβ) and myelin debris. Interestingly, microglia carrying the PICALM risk allele showed transcriptional enrichment of pathways for cholesterol synthesis and LD formation. Genetic and pharmacological perturbations of microglia further established a causal link between reduced PICALM expression, LD accumulation, and phagocytosis deficits. Our work elucidates the selective LOAD vulnerability in microglia for the PICALM locus through detrimental LD accumulation, providing a neurobiological basis that can be exploited for developing novel clinical interventions.

Funding Source: R01AG063175 (J.D. and G.T.), R01AG081374 (J.D.), RF1AG079141 (G.T.). R01 AG073260 (H.J.B.), and U01 AG072439 (H.J.B.). A.S. is supported by a BrightFocus fellowship. R01MH116281 and R01MH106575 (to J.D.).

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