QTLbase: an integrative resource for quantitative trait loci across multiple human molecular phenotypes

Abstract

Recent advances in genome sequencing and functional genomic profiling have promoted many large-scale quantitative trait locus (QTL) studies, which connect genotypes with tissue/cell type-specific cellular functions from transcriptional to post-translational level. However, no comprehensive resource can perform QTL lookup across multiple molecular phenotypes and investigate the potential cascade effect of functional variants. We developed a versatile resource, named QTLbase, for interpreting the possible molecular functions of genetic variants, as well as their tissue/cell-type specificity. Overall, QTLbase has five key functions: (i) curating and compiling genome-wide QTL summary statistics for 13 human molecular traits from 233 independent studies; (ii) mapping QTL-relevant tissue/cell types to 78 unified terms according to a standard anatomogram; (iii) normalizing variant and trait information uniformly, yielding >170 million significant QTLs; (iv) providing a rich web client that enables phenome- and tissue-wise visualization; and (v) integrating the most comprehensive genomic features and functional predictions to annotate the potential QTL mechanisms. QTLbase provides a one-stop shop for QTL retrieval and comparison across multiple tissues and multiple layers of molecular complexity, and will greatly help researchers interrogate the biological mechanism of causal variants and guide the direction of functional validation. QTLbase is freely available at http://mulinlab.org/qtlbase.

Figure 1.

The data structure and general function of QTLbase.

Figure 2.

QTLbase variant-level query results. (A) Major result panels show matched QTL types, basic QTL statistics, and a heat map plot of associated QTLs across traits and tissues for the queried variant. (B) Trait-wise plot of associated QTLs in specific tissue/cell type for queried variant. (C) Tissue-wise plot of associated QTLs on specific trait for queried variant. (D) Summary statistics table of associated QTLs. (E) Floating panel for functional annotations.

Figure 3.

QTLbase trait-level query results. (A) Heat map plot of associated QTLs across variants and tissues. (B) Variant-wise plot of associated QTLs in specific tissue for a queried trait.

Figure 4.

Supporting evidence from QTLbase for the regulatory mechanism of rs12041331. rs12041331 is supported by three independent eQTL studies [Bonder et al. (55), Zhernakova et al. (54) and Urmo Võsa et al. (56)] in blood and is associated with PEAR1 gene expression. rs12041331 is also a hQTL linked to a nearby enhancer marker H3K4me1 in naïve CD4+ T cells [Lu Chen et al. (30)] and has been reported as a mQTL affecting a CpG site (cg20948486) in the PEAR1 promoter (highlighted with a blue box) in CD16+ neutrophils [Lu Chen et al. (30)]. H3K27ac, H3K4me1 and H3K4me3 histone modification ChIP-seq profiles, CTCF ChIP-seq profile and DHS clusters for HUVECs and K562 cells are shown (data from ENCODE).