Global discovery of lupus genetic risk variant allelic enhancer activity

• Published in: Nature communications Vol. 12; no. 1; pp. 1611 - 13
• Main Authors: Lu, Xiaoming, Chen, Xiaoting, Forney, Carmy, Donmez, Omer, Miller, Daniel, Parameswaran, Sreeja, Hong, Ted, Huang, Yongbo, Pujato, Mario, Cazares, Tareian, Miraldi, Emily R., Ray, John P., de Boer, Carl G., Harley, John B., Weirauch, Matthew T., Kottyan, Leah C.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 12.03.2021; Nature Publishing Group; Nature Portfolio
• Subjects: 38/15; 38/22; 38/23; 38/88; 38/90; 38/91; 49/109; 49/47; 631/208/191; 631/208/200; 692/699/1670/1613; Alleles; Autoimmune diseases; B-Lymphocytes; Binding; Biotechnology; Cell Line; Cell lines; Chromatin; Chronic conditions; Deoxyribonucleic acid; DNA; Epstein-Barr virus; Gene Expression Regulation; Gene regulation; Genetic diversity; Genetic Predisposition to Disease - genetics; Genetic variance; Genome-wide association studies; Genome-Wide Association Study; Genomes; Genotype; Genotypes; Herpesvirus 4, Human; Humanities and Social Sciences; Humans; Loci; Lupus; Lupus Erythematosus, Systemic - genetics; Lymphocytes; Lymphocytes T; multidisciplinary; Oligonucleotides; Quantitative Trait Loci; Regulatory mechanisms (biology); Risk analysis; Science; Science (multidisciplinary); Synaptogyrins - genetics; Systemic lupus erythematosus; T-Lymphocytes; Transcription factors; Transfection
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-021-21854-5

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. Thousands of genetic variants have been associated with lupus, but causal variants and mechanisms are unknown. Here, the authors combine a massively parallel reporter assay with genome-wide ChIP experiments to identify risk variants with allelic enhancer activity mediated through transcription factor binding.