Common regulatory variation impacts gene expression in a cell type-dependent manner

Abstract

Studies correlating genetic variation to gene expression facilitate the interpretation of common human phenotypes and disease. As functional variants may be operating in a tissue-dependent manner, we performed gene expression profiling and association with genetic variants (single-nucleotide polymorphisms) on three cell types of 75 individuals. We detected cell type-specific genetic effects, with 69 to 80% of regulatory variants operating in a cell type-specific manner, and identified multiple expressive quantitative trait loci (eQTLs) per gene, unique or shared among cell types and positively correlated with the number of transcripts per gene. Cell type-specific eQTLs were found at larger distances from genes and at lower effect size, similar to known enhancers. These data suggest that the complete regulatory variant repertoire can only be uncovered in the context of cell-type specificity.

Fig. 1

Genome-wide map of cis-eQTLs in three cell types; cis-eQTLs at 0.001 permutation threshold are shown as color-coded lines on their corresponding chromosomal location. Internal black lines represent genes with eQTLs in all cell types.

Fig. 2

SNP-probe pair nominal (uncorrected) p-value distributions for the two secondary cell-types conditional on the reference cell type eQTL, significant at 0.001 permutation threshold are shown. The panels on the horizontal axis correspond (from left to right) to (i) the full p-value distribution of the secondary cell type, (ii) the p-value distribution after excluding significant eQTLs at 0.001 permutation threshold in secondary cell type, and (iii) similar to (ii) at 0.01 permutation threshold.

Fig. 3

Localization of cis-eQTLs A) Distance to transcription start site (TSS) of all independent cis-eQTLs in each cell type (0.001 permutation threshold). A) shared in all three cell types (0.001 permutation threshold). C) cell type-specific cis-eQTLs (0.001 permutation threshold).

Fig. 4

Fine-scale overlap of regulatory signals in three cell types A) Cell type-shared and cell type-specific independent cis-eQTLs (regulatory intervals) for all genes with a significant association at the 0.001 permutation threshold. B) genes significant in at least two cell types C) genes significant in all three cell types.