Abstract
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.
Highlights
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
At least 49 Genome-wide association studies (GWAS) have identified genome-wide significant SNPs in the TNFAIP3 locus that together are associated with 16 human diseases and phenotypes, including lupus (SLE), rheumatoid arthritis (RA), psoriasis, inflammatory skin disorder (ISD), celiac disease, inflammatory bowel disease (IBD), and multiple sclerosis (MS)
Rather than focusing only on disease-associated SNPs, we systematically examined all common SNPs (MAF > 0.01) in the ~300 kb topologically associating domain (TAD) containing TNFAIP3, and 150 kb on either side of the TAD because it is known that regulatory regions can affect the expression of genes outside of TADs28 (Fig. 1b, top; Supplementary Fig. 1)
Summary
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. Genome-wide association studies (GWAS) have revealed >100,000 associations of genetic variants with human traits and diseases (e.g. autoimmune disease), but it remains a challenge to pinpoint the causal variant(s) that account for the association by altering disease risk and determine their functions[1,2,3,4] This is because they are often in tight linkage disequilibrium (LD) with non-causal variants and, in the vast majority of cases, lie in non-coding regions, where it is more challenging to predict the impact and relevant context of variants. Various assays have been proposed for identifying potentially causal variants, based on the variant’s relation to or impact on different molecular features in a relevant cell type These assays can be categorized into four classes, depending on (i) whether they involve observations of natural systems or engineered experimental perturbations and (ii) whether they pertain to a region or an individual variant. Examples include using ATAC-seq, DNase-I-seq, and H3K27ac ChIP-seq[1,4,9,10], as well as testing whether the variant lies in spatial proximity to a target gene, based on topological assays such as 4C or HiC11,12
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