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Genome-wide discovery of lupus genetic risk variant allelic regulatory activity

By Xiaoming Lu, Xiaoting Chen, Carmy Forney, Omer Donmez, Daniel Miller, Sreeja Parameswaran, Ted Hong, Yongbo Huang, Mario Pujato, Tareian Cazares, Emily R. Miraldi, John P Ray, Carl G. de Boer, John B. Harley, Matthew T Weirauch, Leah C. Kottyan

Posted 20 Jan 2020
bioRxiv DOI: 10.1101/2020.01.20.906701

Genome-wide association studies of Systemic Lupus Erythematosus (SLE) nominate 3,073 genetic variants at 91 risk loci. To systematically screen these variants for allelic transcriptional enhancer activity, we constructed a massively parallel reporter assay (MPRA) library comprising 12,396 DNA oligonucleotides containing the genomic context around every allele of each SLE variant. Transfection into EBV-infected B cells revealed 482 variants with enhancer activity, with 51 variants showing genotype-dependent (allelic) enhancer activity at 27 risk loci. In-depth analysis of allelic transcription factor (TF) binding at and around these 51 variants identified one class of TFs whose DNA-binding motif tends to be directly altered by the risk variant and a second, larger class of TFs that also bind allelically but do not have their motifs directly altered by the variant. Collectively, our approach provides a blueprint for the discovery of allelic gene regulation at risk loci for any disease and offers insight into the transcriptional regulatory mechanisms underlying SLE.

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