→ Slides doi:10.7490/f1000research.1112708.1
Noncoding variants play a central role in the genetics of complex traits, but we still lack a full understanding of the molecular pathways through which they act. We quantified the contribution of cis-acting genetic effects at all major stages of gene regulation from chromatin to proteins, in Yoruba lymphoblastoid cell lines (LCLs). We found that most QTLs are associated with transcript expression levels, with consequent effects on ribosome and protein levels. However, eQTLs tend to have significantly reduced effect sizes on protein levels, which suggests that their potential impact on downstream phenotypes is often attenuated or buffered. Additionally, we identified a class of cis QTLs that affect protein abundance with little or no effect on messenger RNA or ribosome levels, which suggests that they may arise from differences in posttranslational regulation. Overall, about ~65% of eQTLs have primary effects on chromatin, whereas the remaining eQTLs are enriched in transcribed regions. Using a novel method, we also detected 2893 splicing QTLs, most of which have little or no effect on gene-level expression. These splicing QTLs are major contributors to complex traits, roughly on a par with variants that affect gene expression levels. Our study provides a comprehensive view of the mechanisms linking genetic variation to variation in human gene regulation.