Assessing the ability of various genomic features to prioritize causal non-coding variants associated with diseases and traits [CRISPR guide-seq]

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. 2-4 replicates per experiment. CRISPRa targeted each of 2501 variants with an average of 5 guides per variant and CRISPRi targeted open chromatin of U937, Jurkat, and BJAB cell lines with an average of 30 guides per element. CRISPRa had 770 nontargeting guides CRIPSRi had 6282 nontargeting guides, both of which served as negative controls for each respective experiment. TNFAIP3 expression was measured using RNA Prime-flow with probes targeted to the TNFAIP3 transcript