How non-coding genetic variants linked to Alzheimer’s affect TSPAN14, studied using combined genomics and single-cell gene silencing

A total of 93 candidate causal variants and 94 effector genes have been identified for 35 Alzheimer disease loci.

• Ten brain-relevant genomics datasets were integrated to fine-map Alzheimer disease variants and identify effector genes.
• A single-cell CRISPRi Perturb-seq screen was performed targeting 74 candidate regulatory regions in human microglial cells.
• The screen validated 21 variant-gene pairs associated with Alzheimer disease.
• An intronic region at the TSPAN14 locus was identified as a microglial-specific enhancer activated by the Alzheimer disease-risk haplotype.
• Deletion of this enhancer region reduced TSPAN14 expression, disrupted cell-adhesion pathways, and lowered secretion of pro-inflammatory cytokines IL-6 and IL-8.

Simplified