NeuralCipher Research overview
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Non-coding variants associated with complex disease can shape gene regulatory networks across multiple genomic loci and cellular contexts. Here, we investigated the functional impact of the Parkinson-disease-associated variant rs11610045 using an isogenic induced pluripotent stem cell model. Using CRISPR-Cas9 editing and reversal, we generated matched clones carrying either the A|A or G|G genotype, enabling controlled comparison of allele-specific effects. We identified widespread genotype-dependent regulation of distal genes, including THBS1 and PDGFB. Affinity purification followed by mass spectrometry revealed differential binding of regulatory proteins to the G|G allele, including the transcription factor TCF7L1. Differentiation into cortical neurons demonstrated context-dependent effects, with 24 genes differentially expressed and PAX5 consistently altered across developmental stages. Together, these findings link a non-coding disease-associated variant to coordinated changes in gene expression and protein binding, support trans-acting mechanisms underlying regulatory variation, and provide a generalizable framework for dissecting disease-associated loci in human cellular models.
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