Global discovery of lupus genetic risk variant allelic enhancer activity

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. Boer, John B. Harley, Matthew T. Weirauch () and Leah C. Kottyan ()
Additional contact information
Xiaoming Lu: Center for Autoimmune Genomics and Etiology, Cincinnati Children’s Hospital Medical Center
Xiaoting Chen: Center for Autoimmune Genomics and Etiology, Cincinnati Children’s Hospital Medical Center
Carmy Forney: Center for Autoimmune Genomics and Etiology, Cincinnati Children’s Hospital Medical Center
Omer Donmez: Center for Autoimmune Genomics and Etiology, Cincinnati Children’s Hospital Medical Center
Daniel Miller: Center for Autoimmune Genomics and Etiology, Cincinnati Children’s Hospital Medical Center
Sreeja Parameswaran: Center for Autoimmune Genomics and Etiology, Cincinnati Children’s Hospital Medical Center
Ted Hong: Center for Autoimmune Genomics and Etiology, Cincinnati Children’s Hospital Medical Center
Yongbo Huang: Center for Autoimmune Genomics and Etiology, Cincinnati Children’s Hospital Medical Center
Mario Pujato: Cincinnati Children’s Hospital Medical Center
Tareian Cazares: Cincinnati Children’s Hospital Medical Center
Emily R. Miraldi: Cincinnati Children’s Hospital Medical Center
John P. Ray: Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard University
Carl G. Boer: Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard University
John B. Harley: Center for Autoimmune Genomics and Etiology, Cincinnati Children’s Hospital Medical Center
Matthew T. Weirauch: Center for Autoimmune Genomics and Etiology, Cincinnati Children’s Hospital Medical Center
Leah C. Kottyan: Center for Autoimmune Genomics and Etiology, Cincinnati Children’s Hospital Medical Center

Nature Communications, 2021, vol. 12, issue 1, 1-13

Abstract: Abstract Genome-wide association studies of Systemic Lupus Erythematosus (SLE) nominate 3073 genetic variants at 91 risk loci. To systematically screen these variants for allelic transcriptional enhancer activity, we construct 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 the Epstein-Barr virus-transformed B cell line GM12878 reveals 482 variants with enhancer activity, with 51 variants showing genotype-dependent (allelic) enhancer activity at 27 risk loci. Comparison of MPRA results in GM12878 and Jurkat T cell lines highlights shared and unique allelic transcriptional regulatory mechanisms at SLE risk loci. In-depth analysis of allelic transcription factor (TF) binding at and around allelic variants identifies one class of TFs whose DNA-binding motif tends to be directly altered by the risk variant and a second class of TFs that bind allelically without direct alteration of their motif 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.

Date: 2021
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DOI: 10.1038/s41467-021-21854-5

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