Nana Matoba, Jessica C McAfee, Oleh Krupa, Jess Bell, Brandon D Le et al.
Genetic association studies have identified hundreds of largely non-coding loci associated with inter-individual differences in the structure of the human cortex, though the specific genetic variants that impact regulatory activity are unknown. We implemented a Massively Parallel Reporter Assay (MPRA) to measure the regulatory activity of 9,092 cortical structure associated DNA variants in human neural progenitor cells during Wnt stimulation and at baseline. We identified 918 variants with regulatory potential from 150 cortical structure associated loci (76% of loci studied), of which >50% showed allelic effects. Wnt stimulation modified regulatory activity at a subset of loci that functioned as condition-dependent enhancers. Regulatory activity in MPRA was largely induced by Alu elements that were hypothesized to contribute to cortical expansion. The regionally specific impact of genetic variants that disrupt motifs is likely mediated through the levels of transcription factor expression during development, further clarifying the molecular mechanisms altering cortical structure.
Nana Matoba, Jessica C McAfee, Oleh Krupa, Jess Bell, Brandon D Le, Jordan M Valone, Gregory E Crawford, Hyejung Won, Jason L Stein. Massively parallel assessment of gene regulatory activity at human cortical structure associated variants. 2025-02-13. https://doi.org/10.1101/2025.02.08.635393
Both alleles of 9,052 cortical-structure-associated variants from 198 ENIGMA GWAS loci were tested as 150-bp episomal reporter elements in primary human neural progenitor cells under baseline vehicle treatment. The table combines allele-level regulatory activity, vehicle allelic effects, and the published stimulation-versus-vehicle comparisons where available.
This table contains the paper's separately reported caQTL subset: both alleles of 502 chromatin-accessibility-associated SNPs in 150-bp sequences from primary human neural progenitor chromatin-accessible peaks. The publication reports this caQTL analysis without a vehicle-versus-CHIR condition label, so it is represented as its own analytical experiment and should not be interpreted as a CHIR-specific result.
Both alleles of 9,052 cortical-structure-associated variants from 198 ENIGMA GWAS loci were tested as 150-bp episomal reporter elements in primary human neural progenitor cells after Wnt pathway stimulation. The table combines allele-level regulatory activity, CHIR-condition allelic effects, and the published stimulation-versus-vehicle comparisons where available.
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