GSE136702
Assessing the ability of various genomic features to prioritize causal non-coding variants associated with diseases and traits [MPRA]
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 used seven experimental assays to characterize all common variants at the multiple disease-associated TNFAIP3 locus in three disease-relevant immune cell types, based on a set of features related to regulatory potential. Trait/disease-associated variants were 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 had at least one variant meeting one or both of these criteria, with 3 of these haplotypes having a single prioritized variant. 5 of the 9 prioritized variants were further supported by genetic fine-mapping in our and other studies. Our work provides evidence for the efficacy and limitations of strategies for prioritizing disease- and trait-associated genetic variants.  Overall design: Massively parallel reporter assays to study variant effects on reporter expression, 2-3 replicates, 3 cell types, 4 cell lines, lentiviral and transfection