Abstract
BackgroundPrevious expression quantitative trait loci (eQTL) studies have identified thousands of genetic variants to be associated with gene expression at the mRNA level in the human liver. However, protein expression often correlates poorly with mRNA levels. Thus, protein quantitative trait loci (pQTL) study is required to identify genetic variants that regulate protein expression in human livers.ResultsWe conducted a genome-wide pQTL study in 287 normal human liver samples and identified 900 local pQTL variants and 4026 distant pQTL variants. We further discovered 53 genome hotspots of pQTL variants. Transcriptional region mapping analysis showed that 1133 pQTL variants are in transcriptional regulatory regions. Genomic region enrichment analysis of the identified pQTL variants revealed 804 potential regulatory interactions among 595 predicted regulators (e.g., non-coding RNAs) and 394 proteins. Moreover, pQTL variants and trait-variant integration analysis implied several novel mechanisms underlying the relationships between protein expression and liver diseases, such as alcohol dependence. Notably, over 2000 of the identified pQTL variants have not been reported in previous eQTL studies, suggesting extensive involvement of genetic polymorphisms in post-transcriptional regulation of protein expression in human livers.ConclusionsWe have partially established protein expression regulation networks in human livers and generated a wealth of pQTL data that could serve as a valuable resource for the scientific community.
Highlights
High-throughput sequencing technologies enabled the analysis of genome-wide expression quantitative trait loci to study the transcriptional and posttranscriptional regulatory mechanisms involved in the regulation of mRNA expression [1]
Absolute quantification and subcellular location of hepatic proteins A total of 1508 proteins were absolutely quantified in 287 human liver S9 fractions (HLS9) samples using the data-independent acquisition (DIA)-total protein approach (TPA) proteomic method (Additional file 1: Fig. S1 and Additional file 2: Data file S1)
The number of proteins quantified in the present study is much less than the number of mRNAexpressing genes in human livers as documented in GTEx (1508 vs 26,560) [10], which is likely due to that many transcripts are not translated into proteins, and the concentrations of many proteins are below the limit of detection of our proteomics assay
Summary
High-throughput sequencing technologies enabled the analysis of genome-wide expression quantitative trait loci (eQTL) to study the transcriptional and posttranscriptional regulatory mechanisms involved in the regulation of mRNA expression [1]. We recently developed a label-free APQ method named DIA-TPA that uses MS2 intensity signals from DIA data and an improved total protein approach (TPA); this method enabled high-throughput global absolute protein quantification and was successfully used to absolutely quantify human liver proteomes [17]. Previous expression quantitative trait loci (eQTL) studies have identified thousands of genetic variants to be associated with gene expression at the mRNA level in the human liver. Protein quantitative trait loci (pQTL) study is required to identify genetic variants that regulate protein expression in human livers
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