John P. Ray, Carl G. de Boer, Charles P. Fulco, Caleb A. Lareau, Masahiro Kanai et al.
Genome-wide association studies have associated thousands of genetic variants with complex traits and diseases, but pinpointing the causal variant(s) among those in tight linkage disequilibrium with each associated variant remains a major challenge. Here, we use seven experimental assays to characterize all common variants at the multiple disease-associated TNFAIP3 locus in five disease-relevant immune cell lines, based on a set of features related to regulatory potential. Trait/disease-associated variants are enriched among SNPs prioritized based on either: (1) residing within CRISPRi-sensitive regulatory regions, or (2) localizing in a chromatin accessible region while displaying allele-specific reporter activity. Of the 15 trait/disease-associated haplotypes at TNFAIP3, 9 have at least one variant meeting one or both of these criteria, 5 of which are further supported by genetic fine-mapping. Our work provides a comprehensive strategy to characterize genetic variation at important disease-associated loci, and aids in the effort to identify trait causal genetic variants.
John P. Ray, Carl G. de Boer, Charles P. Fulco, Caleb A. Lareau, Masahiro Kanai, Jacob C. Ulirsch, Ryan Tewhey, Leif S. Ludwig, Steven K. Reilly, Drew T. Bergman, Jesse M. Engreitz, Robbyn Issner, Hilary K. Finucane, Eric S. Lander, Aviv Regev, Nir Hacohen. Prioritizing disease and trait causal variants at the TNFAIP3 locus using functional and genomic features. 2020-03-06. https://doi.org/10.1038/s41467-020-15022-4
Allele-specific 150-bp TNFAIP3-locus oligos were assayed in U937 human immune cells after 100 ng/ml lps for 2 hours using an integrated lentiviral MPRA. 2 biological replicates are represented in the deposited matrix.
Allele-specific 150-bp TNFAIP3-locus oligos were assayed in Jurkat Clone E6-1 human immune cells after 2.5 ug/ml anti-cd3 + 10 ng/ml pma for 1 hour using an integrated lentiviral MPRA. 2 biological replicates are represented in the deposited matrix.
Allele-specific 150-bp TNFAIP3-locus oligos were assayed in GM12878 human immune cells under basal / untreated using an episomal plasmid MPRA. 3 biological replicates are represented in the deposited matrix.
Allele-specific 150-bp TNFAIP3-locus oligos were assayed in Jurkat Clone E6-1 human immune cells after 2.5 ug/ml anti-cd3 + 10 ng/ml pma for 1 hour using an episomal plasmid MPRA. 3 biological replicates are represented in the deposited matrix.
Allele-specific 150-bp TNFAIP3-locus oligos were assayed in GM12878 human immune cells after 2.5 ug/ml anti-igm + 2 ug/ml anti-cd40 for 2 hours using an episomal plasmid MPRA. 3 biological replicates are represented in the deposited matrix.
Allele-specific 150-bp TNFAIP3-locus oligos were assayed in U937 human immune cells under basal / untreated using an integrated lentiviral MPRA. 2 biological replicates are represented in the deposited matrix.
Allele-specific 150-bp TNFAIP3-locus oligos were assayed in BJAB human immune cells under basal / untreated using an integrated lentiviral MPRA. 2 biological replicates are represented in the deposited matrix.
Allele-specific 150-bp TNFAIP3-locus oligos were assayed in Jurkat Clone E6-1 human immune cells under basal / untreated using an episomal plasmid MPRA. 3 biological replicates are represented in the deposited matrix.
Allele-specific 150-bp TNFAIP3-locus oligos were assayed in BJAB human immune cells after 2.5 ug/ml anti-igm + 2 ug/ml anti-cd40 for 2 hours using an integrated lentiviral MPRA. 2 biological replicates are represented in the deposited matrix.
Allele-specific 150-bp TNFAIP3-locus oligos were assayed in Jurkat Clone E6-1 human immune cells under basal / untreated using an integrated lentiviral MPRA. 2 biological replicates are represented in the deposited matrix.
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 15 files (ZIP)description_supplementary_files.pdfGSE136702_20190823_MPRA_tag_count_matrix.txt.gzGSE136702_family.soft.gzGSE136702_MPRA90823_MPRA_probe_SNP_allele_map.txt.gzGSE136702_MPRA_probes_and_barcodeNs_as_in_vector_for_association.fasta.gzGSE136702_probe_barcode_association_3.4E6_2.map.gzGSE136702_ProbeSequences_and_SNP_Genotypes_all.txt.gzpmc_full_text_bioc.jsonreporting_summary.pdfsource_notes.txtsupplementary_data_11_primers.xlsxsupplementary_data_3_collective_variant_function.xlsxsupplementary_data_8_mpra.xlsxsupplementary_data_9_mpra.xlsxsupplementary_information.docx