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

Area of Science:

• Genetics
• Genomics
• Immunology

Background:

• Genome-wide association studies (GWAS) identify thousands of genetic variants linked to complex traits and diseases.
• Distinguishing causal variants from linked variants in linkage disequilibrium remains a significant hurdle in genetic research.

Purpose of the Study:

• To develop and apply a comprehensive strategy for characterizing genetic variants at disease-associated loci.
• To identify causal variants within the TNFAIP3 locus using experimental assays and regulatory potential features.

Main Methods:

• Utilized seven experimental assays to assess common variants at the TNFAIP3 locus in five immune cell lines.
• Prioritized single nucleotide polymorphisms (SNPs) based on CRISPRi-sensitivity, chromatin accessibility, and allele-specific reporter activity.
• Integrated genetic fine-mapping data for further validation.

Main Results:

• Trait/disease-associated variants were enriched in regulatory regions identified by CRISPRi sensitivity or chromatin accessibility with allele-specific activity.
• Nine out of 15 trait/disease-associated haplotypes at TNFAIP3 contained variants meeting these prioritization criteria.
• Five of these haplotypes were further supported by genetic fine-mapping analyses.

Conclusions:

• The study presents a robust strategy for characterizing genetic variation at complex disease-associated loci.
• This approach aids in the identification of trait-causal genetic variants, particularly at the TNFAIP3 locus.
• The findings contribute to a deeper understanding of the genetic architecture underlying immune-related diseases.