Nathan S. Abell, Marianne K. DeGorter, Michael J. Gloudemans, Emily Greenwald, Kevin S. Smith et al.
Associations between genetic variation and traits are often in noncoding regions with strong linkage disequilibrium (LD), where a single causal variant is assumed to underlie the association. We applied a massively parallel reporter assay (MPRA) to functionally evaluate genetic variants in high, local LD for independent cis-expression quantitative trait loci (eQTL). We found that 17.7% of eQTLs exhibit more than one major allelic effect in tight LD. The detected regulatory variants were highly and specifically enriched for activating chromatin structures and allelic transcription factor binding. Integration of MPRA profiles with eQTL/complex trait colocalizations across 114 human traits and diseases identified causal variant sets demonstrating how genetic association signals can manifest through multiple, tightly linked causal variants.
Nathan S. Abell, Marianne K. DeGorter, Michael J. Gloudemans, Emily Greenwald, Kevin S. Smith, Zihuai He, Stephen B. Montgomery. Multiple causal variants underlie genetic associations in humans. 2022-03-17. https://doi.org/10.1126/science.abj5117
A variant-focused library of human genomic fragments centered on selected variants was synthesized as reference/alternate allele pairs with random barcode assignment. Three independent plasmid transfections of GM12878 lymphoblastoid cells were harvested after 24 hours for reporter cDNA and plasmid-DNA barcode sequencing, with expression and allelic effects estimated by negative-binomial DESeq2 contrasts.
Original supplemental and deposited inputs retained for this study. Download files individually or together as a ZIP; nested folders are preserved. Source reuse terms apply, and sequencing reads may be omitted.
Download all 14 files (ZIP)GSE174534_OligoCounts.txt.gzmpra-v2_README.mdmpra-v2_section2-model-inference.ipynbmpraSites-hg38.txtsource_manifest.txtSupplementaryTableS1.txtSupplementaryTableS2.txtSupplementaryTableS3.txtSupplementaryTableS4.txtSupplementaryTableS5.txtSupplementaryTableS6.xlsxSupplementaryTableS7.txtSupplementaryTableS8.txtSupplementaryTableS9.xlsx