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FUNCTIONAL EVALUATION OF GENETIC VARIANTS RELATED TO POLYGENIC RISK FOR ALZHEIMER’S DISEASE USING A MASSIVELY PARALLEL REPORTER ASSAY
Danna Perlaza Menesesand 16 co-authors
Sant Pau Memory Unit, IR SANT PAU, Hospital de la Santa Creu i Sant Pau
FENS Forum 2026 (2026)
Barcelona, Spain
Board PS05-09AM-120
Presentation
Date TBA
Board: PS05-09AM-120
Event Information
Poster Board
PS05-09AM-120
Poster
View posterAbstract
Synapse degeneration is a primary neuropathological feature associated with cognitive decline in Alzheimer’s disease (AD). We previously described a synapse-specific Polygenic Risk Score (PRS) with 72% diagnostic accuracy in an AD cohort. The aim of this study was to determine whether variants within linkage disequilibrium (LD) blocks represented by the PRS have regulatory activity in vitro.
An oligonucleotide library comprising 137 putative regulatory variants, each represented by five barcodes per allele, was cloned into the pMPRA1 vector. Plasmids were transfected into HEK293 cells (n=5), followed by DNA and RNA extraction and Illumina MiSeq sequencing. Using the mpra R package, tag counts were normalized to 10 million reads, and paired RNA/DNA log ratios were calculated per barcode. Differential allelic activity was tested using weighted linear models (mpralm), with multiple testing correction via the Benjamini–Hochberg method.
Approximately 15 million DNA and RNA reads were obtained across five independent experiments. Thirty-five of the 137 SNPs showed significant differential regulatory activity between alleles (adjusted p < 0.05). Three of the SNPs that showed regulatory activity were included in the PRS (BIN1: rs17014923 and rs35114168; DLG2: rs286043); the remaining 32 were captured on LD blocks within the synaptic PRS.
All LD blocks captured by the synaptic PRS harbor variants with regulatory activity in vitro, supporting a mechanism where altered expression of these specific loci could lead to a modified cumulative risk for AD. Further investigation of these regulatory effects at synapses could guide future therapeutic strategies for AD.
An oligonucleotide library comprising 137 putative regulatory variants, each represented by five barcodes per allele, was cloned into the pMPRA1 vector. Plasmids were transfected into HEK293 cells (n=5), followed by DNA and RNA extraction and Illumina MiSeq sequencing. Using the mpra R package, tag counts were normalized to 10 million reads, and paired RNA/DNA log ratios were calculated per barcode. Differential allelic activity was tested using weighted linear models (mpralm), with multiple testing correction via the Benjamini–Hochberg method.
Approximately 15 million DNA and RNA reads were obtained across five independent experiments. Thirty-five of the 137 SNPs showed significant differential regulatory activity between alleles (adjusted p < 0.05). Three of the SNPs that showed regulatory activity were included in the PRS (BIN1: rs17014923 and rs35114168; DLG2: rs286043); the remaining 32 were captured on LD blocks within the synaptic PRS.
All LD blocks captured by the synaptic PRS harbor variants with regulatory activity in vitro, supporting a mechanism where altered expression of these specific loci could lead to a modified cumulative risk for AD. Further investigation of these regulatory effects at synapses could guide future therapeutic strategies for AD.
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