Abstract
BackgroundThe vast majority of trait-associated variants identified using genome-wide association studies (GWAS) are noncoding, and therefore assumed to impact gene regulation. However, the majority of trait-associated loci are unexplained by regulatory quantitative trait loci (QTLs).ResultsWe perform a comprehensive characterization of the putative mechanisms by which GWAS loci impact human immune traits. By harmonizing four major immune QTL studies, we identify 26,271 expression QTLs (eQTLs) and 23,121 splicing QTLs (sQTLs) spanning 18 immune cell types. Our colocalization analyses between QTLs and trait-associated loci from 72 GWAS reveals that genetic effects on RNA expression and splicing in immune cells colocalize with 40.4% of GWAS loci for immune-related traits, in many cases increasing the fraction of colocalized loci by two fold compared to previous studies. Notably, we find that the largest contributors of this increase are splicing QTLs, which colocalize on average with 14% of all GWAS loci that do not colocalize with eQTLs. By contrast, we find that cell type-specific eQTLs, and eQTLs with small effect sizes contribute very few new colocalizations. To investigate the 60% of GWAS loci that remain unexplained, we collect H3K27ac CUT&Tag data from rheumatoid arthritis and healthy controls, and find large-scale differences between immune cells from the different disease contexts, including at regions overlapping unexplained GWAS loci.ConclusionAltogether, our work supports RNA splicing as an important mediator of genetic effects on immune traits, and suggests that we must expand our study of regulatory processes in disease contexts to improve functional interpretation of as yet unexplained GWAS loci.
Highlights
The vast majority of trait-associated variants identified using genome-wide association studies (GWAS) are noncoding, and assumed to impact gene regulation
While expression QTLs (eQTLs) overlap with many variants that have been associated with complex traits and diseases [3], several studies that assessed colocalization between GWAS and eQTL variants concluded that only a minority of GWAS loci can be explained by the eQTLs detected in available samples
In addition to differences in gene expression levels, we found that eQTLs that were cell type-specific were located further away from the gene transcription start site in comparison to eQTLs that were shared across immune cell types (Fig. 2e)
Summary
The vast majority of trait-associated variants identified using genome-wide association studies (GWAS) are noncoding, and assumed to impact gene regulation. A paper from the GTEx consortium [15] suggests that ∼20% of GWAS loci show colocalized effect with eQTLs in the tissue most relevant to the trait Another recent study estimated that only an average of 11% of trait narrow-sense heritability could be explained by cis-genetic effects on gene expression levels as measured in GTEx [16]. These observations suggest that very little is known about the genes and mechanisms by which genetic variants impact traits at the vast majority of GWAS loci
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