A vast resource of allelic expression data spanning human tissues

Abstract

Allele expression (AE) analysis robustly measures cis-regulatory effects. Here, we present and demonstrate the utility of a vast AE resource generated from the GTEx v8 release, containing 15,253 samples spanning 54 human tissues for a total of 431 million measurements of AE at the SNP level and 153 million measurements at the haplotype level. In addition, we develop an extension of our tool phASER that allows effect sizes of cis-regulatory variants to be estimated using haplotype-level AE data. This AE resource is the largest to date, and we are able to make haplotype-level data publicly available. We anticipate that the availability of this resource will enable future studies of regulatory variation across human tissues.

Keywords: ASE; Allelic expression; Functional genomics; GTEx; Genomics; Regulatory variation; eQTL.

Fig. 1

Capturing cis-regulatory effects with phased allelic expression data. a The presence of a heterozygous cis-regulatory variant or eQTL produces an expression-level imbalance between the two haplotypes, which can be detected using allelic expression analysis. b RNA-seq reads overlapping heterozygous SNPs in expressed regions of the gene can be used to quantify the expression of alleles relative to one another. These SNPs can be phased with each other and their counts aggregated to produce haplotype-level expression estimates, or haplotypic counts. The effects of regulatory variants can be captured by phasing them with haplotypic counts. c Spearman correlation across the 49 GTEx v8 tissues where eQTLs were called between eQTL effect size (allelic fold change, aFC) and effect size measured using AE data from the single SNP with the highest coverage (SNP AE) or haplotype-level AE generated with phASER (phASER). Results are shown with and without allelic mapping bias correction from WASP. In each tissue, only a single top significant (FDR < 5%) eQTL per gene was analyzed. p values were calculated using a Wilcoxon paired signed rank test. For boxplots, bottom whisker: Q1 − 1.5*interquartile range (IQR), top whisker: Q3 + 1.5*IQR, box: IQR, and center: median

Fig. 2

The GTEx v8 haplotype-level allelic expression resource. a Number of genes per tissue with haplotype-level AE data (AE genes) in at least 1 individual versus the median number of samples with data per gene. b Percentage of AE genes with significant allelic imbalance (binomial test, gene-level FDR < 5%) in at least n samples per gene using all samples (blue) or excluding samples heterozygous for any top (FDR < 5%) or independent GTEx eQTL (permutation p < 1e−4) (red). Faded points are values for individual tissues, and solid points are the median across tissues. Proportions above data points indicate the reduction in percentage of AE genes with imbalance after removing eQTL heterozygotes. A full summary of these statistics across tissues and sample thresholds is available in Additional file 3: Table S2. c The effect of the number of heterozygous variants in or proximal to gene promoters (< 10 kb upstream of TSS) on allelic imbalance stratified by minor allele frequency. Plotted values are effect estimates and 95% confidence intervals (see the “Promoter variant effect modeling” section in the “Methods” section)