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Prioritizing disease and trait causal variants at the TNFAIP3 locus using functional and genomic features.

John P RayCarl G de BoerCharles P FulcoCaleb A LareauMasahiro KanaiJacob C UlirschRyan TewheyLeif S LudwigSteven K ReillyDrew T BergmanJesse M EngreitzRobbyn IssnerHilary K FinucaneEric S LanderAviv RegevNir Hacohen
Published in: Nature communications (2020)
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.
Keyphrases
  • genome wide
  • copy number
  • dna methylation
  • transcription factor
  • high resolution
  • dna damage
  • risk assessment
  • oxidative stress
  • mass spectrometry
  • drug induced