Synthesis of 53 tissue and cell line expression QTL datasets reveals master eQTLs
© Zhang et al.; licensee BioMed Central Ltd. 2014
Received: 30 December 2013
Accepted: 18 June 2014
Published: 27 June 2014
Gene expression genetic studies in human tissues and cells identify cis- and trans-acting expression quantitative trait loci (eQTLs). These eQTLs provide insights into regulatory mechanisms underlying disease risk. However, few studies systematically characterized eQTL results across cell and tissues types. We synthesized eQTL results from >50 datasets, including new primary data from human brain, peripheral plaque and kidney samples, in order to discover features of human eQTLs.
We find a substantial number of robust cis-eQTLs and far fewer trans-eQTLs consistent across tissues. Analysis of 45 full human GWAS scans indicates eQTLs are enriched overall, and above nSNPs, among positive statistical signals in genetic mapping studies, and account for a significant fraction of the strongest human trait effects. Expression QTLs are enriched for gene centricity, higher population allele frequencies, in housekeeping genes, and for coincidence with regulatory features, though there is little evidence of 5′ or 3′ positional bias. Several regulatory categories are not enriched including microRNAs and their predicted binding sites and long, intergenic non-coding RNAs. Among the most tissue-ubiquitous cis-eQTLs, there is enrichment for genes involved in xenobiotic metabolism and mitochondrial function, suggesting these eQTLs may have adaptive origins. Several strong eQTLs (CDK5RAP2, NBPFs) coincide with regions of reported human lineage selection. The intersection of new kidney and plaque eQTLs with related GWAS suggest possible gene prioritization. For example, butyrophilins are now linked to arterial pathogenesis via multiple genetic and expression studies. Expression QTL and GWAS results are made available as a community resource through the NHLBI GRASP database [http://apps.nhlbi.nih.gov/grasp/].
Expression QTLs inform the interpretation of human trait variability, and may account for a greater fraction of phenotypic variability than protein-coding variants. The synthesis of available tissue eQTL data highlights many strong cis-eQTLs that may have important biologic roles and could serve as positive controls in future studies. Our results indicate some strong tissue-ubiquitous eQTLs may have adaptive origins in humans. Efforts to expand the genetic, splicing and tissue coverage of known eQTLs will provide further insights into human gene regulation.
Genome-wide genetic analysis of gene expression [1, 2] identifies expression quantitative trait loci (eQTLs) which are mainly regulatory variants associated with cis- expression of nearby genes. Discovery of eQTLs may help elucidate the genetic mechanisms underlying natural variation in gene expression [3, 4]. Identifying these genetic variants may improve our understanding of molecular mechanisms of disease risk, and of potential drug targets. Human cross-tissue allele-specific expression studies indicate a significant fraction of genes are under genetic control by one or more alleles [5–7]. Strong eQTLs are often highly correlated with markers of disease and quantitative traits at loci identified in GWAS [8–13], suggesting that these eQTLs account for a significant fraction of human phenotypic variability. However, to date there are few attempts at characterizing cross-tissue eQTL datasets in a centralized manner.
Thus far, eQTL studies have analyzed gene expression traits measured primarily by DNA microarrays in liver [9, 14–16], multiple blood cell types [17–27], brain regions [24, 28–31], endothelial cells , stomach , skin , and adipose [9, 19]. Expression QTL effects are often partitioned into either cis or trans-acting effects, and few studies have thoroughly characterized trans eQTL associations, in part due to computational burden . Furthermore, approaches to data collection and analysis of cis and trans eQTLs have been relatively non-uniform [34, 35]. Dimas et al. compared eQTLs discovered from 3 blood-related cell types , and found that only ~30% of eQTLs were directly shared across tissues. Later studies undertook multi-tissue comparisons of cis-eQTLs including lymphoblastoid cell lines (LCL) versus skin cells ; LCL, skin, and fat ; liver, omental, and subcutaneous adipose , and re-analysis of the Dimas et al. datasets with new methods . Overall, these later studies found evidence for a high degree of sharing (~50-80%) of cis-eQTLs across tissues, while still indicating a significant minority of cis-eQTLs remain relatively tissue-specific. Prior studies compared at most 4 tissues and generally did not include external validation of signals or studies of trans-eQTLs. Thus, a rigorous comparison, across many tissues and populations with good statistical power remains relatively incomplete.
We sought to collect, standardize, and annotate a variety of eQTL results into a comprehensive central database in order to answer several basic research questions about eQTLs: 1) Are there master/housekeeping cis and trans eQTLs across tissues and what are their biologic functions? 2) What consistent cis and trans-eQTL patterns emerge across datasets including positional genomic location and overlap with regulatory annotations? 3) What genome-wide association (GWAS) variants converge with eQTL peaks? 4) Does integration of disparate eQTL data identify new trans-acting loci?
To address these questions we collected and analyzed available results from 53 eQTL population datasets. These 53 datasets represent analyses from 24 published manuscripts and 13 previously unpublished analyses reflecting >27 cell and tissue types. Most summary-level results are available for download as a subset of the NHLBI Genome-wide Repository of Associations between SNPs and Phenotypes (GRASPdb) .
Characteristics of 53 gene expression GWAS (eQTL) datasets
Summary of 53 eQTL datasets, their origins and original reported parameters
Tissues (Sample size)
Imputation (SNPs tested)*
Emilsson (23622250) †
DLPFC, VC, CR versus: All samples (n = 742), Alzheimer’s (n = 376), Huntington’s (n = 193)†, Normal (n = 173)
Yes (diff. chr)
PFC_EA + AA + others (n = 269), PFC_AA (n = 147), PFC_EA (n = 112)
PFC (n = 127)
Cortex (n = 364), Cortex:Alzh (n = 176)
Yes (≥1 Mb)
Cortex (n = 193)
Yes (≥1 Mb)
Cortex (n = 93)
Temporal cortex (n = 144), Frontal cortex (n = 143), Cerebellum (n = 143), Pons (n = 142)
Monocytes (n = 1,490)
Yes (≥1 Mb)
Whole peripheral blood (n = 1,469)
Yes (>5 Mb)
Lymphocytes (n = 1,240)
LCL (n ~ 400)
Yes (diff. chr)
LCL (n = 210)
Yes (>1 Mb)
Yes (2.2 million)
CD4 + lymph (n = 200)
Leukocytes (n = 194)
Yes (diff. chr)
Blood (n = 150)
Yes (≥1 Mb)
PaxGene whole blood (n = 110)
Osteoblasts (n = 95)
Yes (diff. chr)
Tcells (n = 85), Fibroblasts (n = 85), LCL (n = 85)
PBMC (n = 80)
Liver (n = 651), Subcutaneous Adipose (n = 701), Omentum (n = 848), Stomach (n = 118)
Yes (>1 Mb)
Liver (n = 427)
Yes (≥1 Mb)
Liver (n = 206), Liver (n = 60)
Liver (n = 149)
Yes (>1 Mb)
Kidney (cortex) (n = 81)
Peripheral artery plaque (n = 202)
Yes (>1 Mb)
Subcutaneous Adipose (n = 150)
Yes (≥1 Mb)
Normal Skin (n = 57), Psoriasis Lesional Skin (n = 53), Psoriasis UninvolvedSkin (n = 53)
Endometrial Tumor (n = 52)
Yes (>5 Mb)
Genotyping and gene expression arrays across the datasets were heterogeneous (Table 1). Genotyping assays included Affymetrix (500 K, 6.0), Illumina (100 K, 300 K, 550 K, 610 Kquad, 650 K) and Perlegen SNP arrays (300 K, 438 K). Only a small proportion of datasets (n = 10, 18.9%) included imputed SNP analysis. Expression assays included custom arrays, Affymetrix (Human ST 1.0 exon, U133 plus A/B/2.0), and Illumina (WG-6 v1, WG-6 v3, HumanRefSeq-8 v2, HT12) arrays, with a mean of 20,246 RNAs interrogated across unique studies. Thus, these analyses primarily reflected mRNA expression of protein-coding genes, with few splice-specific analyses . The datasets utilized different criteria for reporting significant results, including different multiple test correction thresholds and distance thresholds for defining cis-acting eQTLs (range = 100 kb to 5 Mb). As a result of these combined factors, as well as varying statistical power, whether trans analysis was conducted, and the extent of disclosed results, there were a broad range of significant eQTLs defined by the studies (range n = 33–22,473).
Frequency of eGenes and eQTLs across 53 datasets after common annotation
A total of 419,796 eQTLs passed at least nominal statistical correction thresholds in the 53 original sources. These included redundant eQTLs in relatively high linkage disequilibrium (LD) in some datasets. We retained the most significant eQTL for each eGene within each dataset yielding 116,563 “best” eQTLs from the constituent datasets. We mapped all best eQTLs in a common genome build (hg18) and applied a uniform distance threshold (500 kb) across all 53 datasets to define cis and trans-acting variants, finding 106,083 cis-eQTL-eGene associations (91%) and 10,480 trans-eQTL-eGene associations (9%). On average, each eGene is associated with 1.8 eQTLs. For 62,872 unique best eQTLs across datasets, 279 cis eQTLs are found in ≥30% of the datasets (N ≥ 15) (Figure 1B), while only 37 SNPs are trans-associated with eGenes in ≥ 4 datasets (Figure 1C).
Master eQTLs with strong cisgenetic influences across tissues
Most frequently occurring cis -eGenes across all datasets
Best eQTL, [#datasets], fxn*
Most common eQTL, [#datasets], fxn*
rs7143432, , 1.9 kb upstream
rs2274517, , intron
rs2395943, , intron
rs10167387, , intron
rs7606251, , intron
<best eSNP, 
rs335628, , intron
rs441102, , intron
rs4924, , 3′UTR
rs2440468, , intron
rs6512121, , intron
<best eSNP, , intron
rs8180944, , intron
<best eSNP, , intron
rs17553846, , intron
rs11617079, , nSNP
rs3776455, , intron
rs162036, , nSNP
rs1274958, , nSNP
rs12636980, , intron
rs12681998, , intron
rs3780674, , introna
rs10125592, , introna
rs2482911, , intronb
<best eSNP, , intronb
rs11078559, , intron
<best eSNP, , intron
rs10972063, , splice site
rs12119079, , intron
<best eSNP, , intron
rs203462, , nSNPc
rs397969, , 3.5 kb downstreamc
rs4930265, , 3UTRd
rs3750965, , nSNPd
rs11006, , 3UTR
rs4938621, , intron
rs6697508, , intron
<best eSNP, , intron
rs3101493, , 3UTR
<best eSNP, , 3′UTR
rs11065504, , intron
rs3794207, , intron
rs3768324, , intron
rs2649667, , intron
rs324019, , intron
rs841718, , intron
rs1062808, , 3UTR
<best eSNP, , 3′UTR
rs2071002, , nSNP
rs13320, , 3UTRe
<best eSNP, , 3′UTRe
rs2172876, , intronf
rs6965542, , intronf
These genes may represent housekeeping or master cis-eGenes, and could be useful positive controls in future studies. We next extended clustering to 248 high confidence eGenes found in ≥25 of our datasets [Additional file 3] and found eQTLs clustered by tissue type but were also greatly influenced by overlapping study samples. For example there was clustering of eQTLs from different brain anatomical sites derived from the same study samples, whereas an independent brain study which reported fewer eQTLs  was in a distinct cluster from the largest brain eQTL study . Clustering was observed for three eQTL datasets in different blood cells that applied similarly stringent correction thresholds . Pathway and ontology analysis of the 248 clustered cis-eQTLs revealed enrichment of genes involved in antigen processing and presentation and immune function, glutathione S-transferase activity, and mitochondrial function [Additional file 4].
We further characterized putative functional explanations for the 33 most ubiquitous cis-eGenes (Figure 2), for which gene symbols and basic functions are described in [Additional file 5]. All of the eQTL SNPs were common variants (the lowest MAF is 9% in CEU), and their signals were consistently large in effect (Table 2). The most frequent eQTL across datasets was often not the strongest eQTL but was highly correlated with the strongest eQTL, with a few exceptions (NUDT2 pairwise r2 = 0.08, NQO2 r2 = 0.11, MYOM2 r2 = 0.17, GSTM3 r2 = 0.20). These exceptions may reflect coverage differences across studies or allelic heterogeneity of functional variants at some loci. A functional characterization of all SNPs in Table 2 and their perfect proxies (r2 = 1.0 in 1000 Genomes phase I European samples ) indicates ~2/3 of loci had a perfectly correlated nonsynonymous SNP (nSNP), splice site SNP or UTR SNP, although functional interpretation was not always straightforward since there were multiple SNPs with putative function in some cases. We queried the SNPs in Table 2 against ENCODE regulatory features using RegulomeDB . Most of the loci in Table 2 displayed one or more strong eQTL directly overlapping an ENCODE regulatory features (e.g., transcription factor binding site prediction, footprinting motif, chromatin structure features and/or protein binding (ChIP-seq feature)) [Additional file 6], suggesting many of them are likely functional regulatory variants. For example, rs3768324 was the strongest observed eQTL for NDUFS5 in 8 datasets, overlapped abundant regulatory features including ChIP-seq peaks such as POL2, SRF, PAX5 and ELK4, and lay close to the transcription initiation site.
Long-range cis and trans-chromosomal eQTL results
trans -eQTLs (>500 kb) observed in 4 or more datasets
Nearby gene(s) [#datasets], fxn*
NBPF ncRNAs , intron
PPP1R12B, nSNP, splice sitea
ENTPD3, RPL14,3′UTR, intron
other chr + cis
SDHAP3, intron, near TSS
MHC locus d
other chr + cis
MHC locus d
other chr + cis
MHC locus d
rs2395185,rs9268853,rs9268858, +1 other
rs12150547,rs2696425,rs418891, +46 others
rs1864325,rs17762165,rs17688922, +62 others
MAPT,NSF, synonymous, intron
rs199535,rs169201,rs199448, +2 others
rs2532332,rs17659881,rs17660065, +6 others
rs17660595,rs17563986,rs17649553, +53 others
BC033373, ZNF99, ZNF486 + 6 other ZNFs , UTR
PI4KA, CRKL, intron
Our cross-dataset analysis also highlighted some interesting potential new trans signals. Target transcripts and tissue associations are fully described in [Additional file 8]. One set of correlated trans eQTLs on chr19p12 localized near zinc finger (ZNF) gene ZNF429, and was found within a large ZNF cluster including many genes. Notably the correlated eQTLs in this region were specifically associated in trans with the expression of zinc finger genes elsewhere in the genome-wide, including 4p16.3 (ZNF595), 7p11.2 (ZNF479), 7q11.21 (ZNF679), and within 19p12 (ZNF99, ZNF486). However, BLAT analysis  revealed that the chr4 and chr7 transcripts map with 83.5%-85.1% identity to the 19p12 region suggesting that gene homology and probe cross-hybridization could be responsible for the apparent trans associations. A SNP on chromosome 11, rs10902222, demonstrated strong cis associations mainly with PNPLA2 and RPLP2, as well as trans associations with 3 different target regions (LRFN1, HCN2, FAM27B). A BLAT analysis of the SNP and the associated transcripts did not show homology indicating this may represent a new trans-eQTL locus [Additional file 9].
We additionally searched for distant eQTLs in 1 or more dataset with P < 5E-8 that overlapped long range regulatory interaction sites via ENCODE chromosome conformation capture carbon copy (5C) data . Two SNPs had evidence for long-range interactions and eQTL association at this stringent threshold. Both SNPs were associated with expression in subcutaneous adipose (rs932562, P < 2.9E-22 for WFDC2 (10.2 Mb away) ; rs1045001, P < 1.9E-8 for RHBDL1 (0.62 Mb away) ) [Additional file 10]. However, the 5C interactions for both SNPs were more localized (up to 150 kb and 450 kb, respectively) than the eQTL associations (10.2 Mb and 6.6 Mb away) [Additional file 10]. Both variants also exhibit more localized, strong cis associations in other tissue datasets. This suggests medium-range regulatory effects of these variants, possibly corresponding to features identified by 5C, may in turn further influence longer range gene regulation megabases away.
Significance of eQTLs relative to distance from eGenes
A minority of SNPs > 500 kb away from their associated eGenes were highly significant (0.5%, P < 1 × 10-50, 13.4% with P < 5e-8) (Figure 4A). Nonetheless, there were 7,075 significant eQTLs that are >500 kb distant from their associated eGene. The relative proportions of SNPs mapping within genes they are associated with, cis (1 bp-500 kb), trans (same chromosome >500 kb) and trans (different chromosome) is shown in Figure 3. Comparison across major tissue groups indicated an enrichment of trans (different chromosome) results in brain eQTLs relative to other tissue types (e.g., P < 0.002 relative to blood eQTLs).
Enrichment of eQTLs within regulatory, selection and chromosomal features
eQTLs compared to human genome regulatory features.
Genome regulatory track
Nucleotides per track
Patrocles (miRNA database)
ENCODE 5C interactions †
IHS sites (Z-score > 3)
F ST sites (Z-score > 3)
PolymiRTS predicted miRNA binding sites
Housekeeping genes are more often eQTLs
Expression QTL concordance with GWAS peak signals
Expression QTLs from the current study were compared against the NHGRI GWAS catalog. Since many eQTL studies did not conduct imputation we also assessed the overlap with LD perfect proxies for the GWAS catalog SNPs (r2 = 1) . Among 8,845 unique GWAS SNPs, 926 were directly found among 62,872 unique best eQTLs (~10.5% overlap) [Additional file 13]. For these 926 common SNPs, there was significant positive correlation in strength of signal (assessed by P-values) between reported eQTL and trait GWAS associations (Spearman’s P = 2.75 × 10-26, [Additional file 14]. When LD partners (r2 = 1) are incorporated ~22% of GWAS catalog signals corresponded to a best eQTL association in our database. The NHGRI catalog was limited to selected top results, thus we further compared both eQTL and nSNP distributions within the test distributions of 45 full GWA trait scans for a variety of human disease, dichotomous and quantitative traits. For most GWA scans (n = 38/45) we found significant enrichment of eQTL SNPs among significant GWA results across the full test statistic distributions [Additional file 15]. Non-synonymous SNPs showed less enrichment (n = 13) and were significantly depleted in some scans (n = 2). This pattern persisted at the significant tail of the distribution (limiting to GWAS P < 1E-2) where 25 of 45 GWA were enriched for eQTL SNPs whereas only 3 GWA showed enrichment for nSNPs and 11 indicated depletion of nSNPs among significant results.
Novel plaque and kidney eQTLs linked to GWAS results
To our knowledge, the plaque and kidney eQTLs in this study are the first reports for these tissues. We queried eQTLs from these tissues against non-anthropomorphic GWAS results in the GRASP database. Results are reported for kidney in [Additional file 16] and peripheral artery plaque in [Additional file 17]. Serum creatinine and creatinine estimated glomerular filtration rate are associated with rs835223 , which is also associated with DAB2 expression levels in kidney here (P < 1.4E-5). Antibodies in systemic lupus erythematosus (SLE) accumulate in tissues including the glomeruli of kidney. SNP rs7808907 is associated with IRF5 expression levels in kidney (P < 3.9E-13) and was previously associated anti-double stranded DNA autoantibody status in SLE .
SNP rs2133189 was previously linked to coronary artery disease (CAD) susceptibility  and is strongly linked here to peripheral artery plaque expression levels of AIDA (P < 2.1E-20). Other peripheral plaque eQTLs for SNPs previously linked to CAD or myocardial infarction include BTN3A1 (rs6929846 eQTL P < 2.8E-07, myocardial infarction P < 3.5E-24 ), ZNF344 (rs4803750 eQTL P < 3.8E-05, atherogenic dyslipidemia P < 1.3E-33 ), NBEAL1 (rs6725887 eQTL P < 2.7E-06, CAD P < 1.1E-09 ), ENST00000318084 (rs10764881 eQTL P < 2.7E-05, CAD P < 1.4E-09 ).
In this study, we systematically characterized and annotated eQTL results from 53 genome-wide gene expression GWAS datasets. Overall 19,038 genes had at least one eQTL significantly associated with their expression. Even if a substantial proportion of these represent false discoveries, a large proportion of human genes seem to have common genetic influences on their expression level, consistent with prior surveys using sensitive allelic specific expression methods [6, 59]. Given that few studies have explicitly assessed genome-wide genetic effects on splicing and alternate isoforms in human tissues there likely remain many additional genetic effects on expression to be discovered. Regional cis-eQTLs predominate genome-wide over trans-eQTLs, though limitations in statistical and computational power have hampered trans-eQTL discovery and validation.
We identified many cis and several trans-eQTLs that have evidence for consistent association across more than one study or tissue. These human master cis- and trans-eQTLs may serve as potential positive controls in future studies and may reveal important aspects of regulatory interactions and human biology and evolution. Furthermore, future researchers searching for and claiming tissue-specific eQTLs could screen their results against the results we collated and deposited in the GRASP database to ensure there is no prior evidence in other tissues. The strong effects and common allele frequencies of these variants may also make them useful in sample forensics in expression-based research .
Ubiquitous cis-eQTLs were enriched for housekeeping genes consistent with a prior study  and for several biological categories including antigen presentation, mitochondrial function and S-glutathione transferase activity. We speculate these strong cis-eQTLs of common allele frequency could represent beneficial alleles arisen in human evolution that may enhance immune function, mitochondrial function and xenobiotic metabolism. Glutathione S-transferases are responsible for detoxification of many compounds and five such transcripts were found among strong cis-eQTLs (1p13.3: GSTM1, GSTM3, GSTM4, 22q11.23: GSTT1, 10q25.1: GSTO2). GSTM1 and GSTT1 have previously been reported to be subject to copy number variation influencing gene expression [62, 63]. Results integrated across studies here reveal other members of the glutathione are subject to strong genetic regulation. Mitochondrial-associated transcripts were significantly enriched making up 12.1% of the cis-eGenes present in ≥25 datasets. These include genes that encode mitochondrial proteins involved in the electron transport chain and ATP synthesis (NDUFS5, COX7A2L, ATP5S), membrane functions (AKAP10, FECH, SURF1, TIMM10), transport (SLC25A16), and mitochondrial protein synthesis (MRPL19, MRPL21, MRPL43). While overall eQTL results were not enriched for overlap with selection features as defined by integrated haplotype scores or fixation index (FST), several of the master eQTL regions correspond with regions identified as containing human lineage-specific events . These include CDK5RAP2 which appears to be under positive selection and may be involved in increased human brain size [65, 66], and the SRGAP2 and NBPF gene cluster on chromosome 1 which demonstrates human lineage copy number increases and is suspected to play a role in increased neuronal branching in development [67–69].
We examined positional effects of eQTLs with respect to associated transcripts, regulatory features and across chromosomes. The strongest eQTLs cluster around their associated gene transcript regions, a pattern that appears universal across tissues and datasets, and is consistent with prior reports considering smaller numbers of tissues (e.g., ). A variety of regulatory features overlap eQTLs more than expected by chance, as others have also reported [70, 71]. This is partially expected given gene co-centricity of these features and eQTLs. Features that lacked significant enrichment among eQTLs included microRNA coding regions and targets, human enhancer regions and non-coding RNAs. Thus, these features may account for a smaller proportion of functional genetic regulation of gene expression. This may be a property of more distant location from coding genes (i.e., enhancers, non-coding RNAs) but could also suggest less tolerance of functional variation in these features. Analysis across chromosomes reveals that chromosomes 21 and 22, in particular, display higher rates of cis-eQTLs after adjusting for a number of factors including gene number, coding length and number of variants. Notably, chromosomes 21 and 22 have been subject to major shifts in primate and human evolution .
Unlike the abundant cis-eQTLs, there appear to be few trans-eQTL hotspots across the genome. Many studies have chosen not to calculate long range cis- or trans-eQTL effects. Furthermore, given the large multiple testing burden discriminating true positives from false positives is challenging, particularly with limited statistical power, and if replication is not attempted. Homologous transcript mapping and cross-hybridization artifacts may also confound trans-eQTL discovery in some cases. Nonetheless, a few trans-acting regions have emerged with consistent evidence across a number of studies, including the HLA region (6p21.32), ARHGEF3 (3p14.3), the MAPT region (17q21.31), HBG (11p15.4), SUOX-IKZF4-RPS26 (12q13.2), and now RPLP2-PNPLA2 (11p15.5). Most of these regions have been implicated by human disease GWAS. Combining data across studies and tissues may help resolve mechanisms, key targets, and the extent of targeted expression networks. For example, our study suggests that RPS26-associated variants may be the key trans regulators at 12q13.2. Data from subcutaneous adipose included in the current study suggest rs4731702 near KLF14 (7q32.3) is associated in trans with SLC7A10 expression, which supports SLC7A10 as an important trans adipose target associated with metabolic traits as previously suggested . Greater sample sizes may be needed to find and validate more trans-eQTLs, or the application of other approaches such as analysis of co-expressed modules , multi-species studies or addition of functional screens.
Prior studies suggested enrichment of eQTLs among some full GWAS scans and among topmost significant results. Here we examined a greater number of tissue eQTLs and GWAS results. Among 45 full human GWAS scans of disease and non-disease traits, we observe a consistent pattern whereby there is enrichment of eQTLs above and beyond nonsynonymous SNPs, and across the significant tail of the statistical distributions. This suggests that eQTLs contribute to the multi-genic nature of many complex human traits and may account for a greater proportion of variance than protein-coding variation . In an analysis focused on strongest GWAS results from the NHGRI catalog we observe significant correlation between the strength of signal for GWAS and expression traits. Concordant strongest GWAS and eQTL SNPs establish a conservative floor indicating ~10% of GWAS phenotype signals are likely directly attributable to genetic regulation of expression. The true proportion of functional regulatory variants is likely much higher given functional alleles in LD, and incomplete coverage in the available eQTL results for variants and human populations, alternative splicing, non-coding RNAs, and tissue-specific expression. Overall these results imply that eQTLs will remain a critical component in interpreting genetic associations and prioritizing replication candidates for a variety of traits.
The addition of new tissue eQTLs may continue to suggest new mechanisms or reinforce prior hypotheses for functional variants. Here we report the first human kidney and plaque eQTLs. Kidney eQTLs corresponded with several prior kidney-related GWAS findings. Several findings of peripheral plaque eQTLs were for variants previously associated in GWAS of coronary artery disease or myocardial infarction. Notably, a prior study reported rs6929846 to be associated with myocardial infarction in a Japanese GWAS sample and replicated the finding in a subsequent Japanese sample . Yamada et al. also provided evidence for rs6929846 transcriptional effects on BTN2A1 expression, and immunohistological positivity for BTN2A1 in human myocardial infarction lesions, and coronary endothelium, arterioles and capillaries . Our study links the same SNP to expression levels of nearby BTN3A1 in peripheral artery plaque (P < 2.8E-7). This locus contains 6 butyrophilin genes and 1 butyrophilin pseudogene. The combination of these results suggests butyrophilin genes may play roles in coronary artery disease pathogenesis, possibly through roles in antigen presentation and T cell stimulation .
Beyond limitations in the analysis of trans-eQTLs this study has several significant limitations. The full gene expression-SNP datasets are generally unavailable, so the current catalog is limited by significant results available from individual studies, and probe annotations are often missing limiting precise localization and assessment of potential probe artifacts. The specific studies are biased mainly toward more readily available tissues, including blood, B-lymphoblastoid cell lines and brain autopsy tissues. Studies were further biased by their non-uniform transcript and genetic content and statistical power. Overall these limitations suggest the current database would most likely be prone to false negatives, thus lack of association at a specific locus cannot be viewed as definitive.
The decrease in the cost of genome-wide genotyping, sequencing and expression profiling means that larger sample sizes are increasingly feasible for eQTL studies. Applying RNA sequencing to eQTL studies may increase discoveries particularly with regard to genetically regulated alternative splicing [3, 4]. While still in early stages, the study of additional RNA types such as long non-coding RNAs  and micro RNAs and their targets [77, 78] and corresponding tissue-specific QTLs is leading to new insights. Deeper profiling of eQTLs via dense imputation with a modern 1000 Genomes based genetic map should increase eQTLs and improve fine mapping as recently demonstrated . Profiling a greater proportion of human tissues as undertaken by the GTex project should further aid in defining tissue-specific eQTLs . These are important goals since eQTLs seem to account for a significant proportion of human phenotypic and disease variability. Many areas require further study at the population level including detailed probing of extensive tissue and cell types, and ascertainment of QTLs related to splicing [4, 24], RNA decay mechanisms , non-coding RNA [76, 82], and epigenetic mechanisms such as methylation [28, 83–85]. A deeper understanding of RNA-driven QTLs, whether cis or trans, tissue-specific or ubiquitous, coding or non-coding, splicing-, decay- or epigenetic-related may be critical to the interpretation of human phenotypic variability, in order to further disease risk prediction, understand causal mechanisms, and enable targeted therapies.
Expression QTLs inform the interpretation of human trait variability, and may account for a greater fraction of phenotypic variability than protein-coding variants. Our analysis of >50 eQTL datasets, in a more extensive set of tissues than previously characterized, highlights the gene centricity of eQTLs and their overlap with regulatory features, as well as their strong enrichment in significant GWAS results for a wide variety of traits. Novel trans-eQTLs are suggested by our study but overall their identification remains challenging. Using new eQTL data from kidney and peripheral plaque we note intersections with GWAS for renal and arterial disease associations which may suggest causal genes or functional mechanisms. This large-scale synthesis of available tissue eQTL data identifies many strong and relatively ubiquitous cis-eQTLs that could serve as positive controls in future studies. Our results also suggest some of these common and strong tissue-ubiquitous eQTLs may have adaptive origins in humans. Efforts to expand the genetic, splicing and tissue coverage of known eQTLs will provide further insights into human gene regulation.
Approvals for published eQTL studies are described in their original publications. New eQTL samples (kidney, peripheral artery plaque) described in conjunction with this study were collected with written informed consent and under institutional approvals. For the kidney eQTL study ethical approval for the study was obtained from the Stanford University Institutional Review Board (IRB protocol 3941). That study was conducted according to the principles expressed in the Declaration of Helsinki. Multi-institutional approvals for the collection of peripheral artery plaque tissue were previously described .
Selection and collection of eQTL datasets
Many eQTL studies have been published in human and non-human species across a broad range of tissue and cell types. Early eQTL studies focused on the heritability and genetic basis of gene expression including several studies on lymphoblastoid cell lines used in the HapMap project. Several studies evaluated genetic variants related to drug response in cell lines. We focused our studies primarily on minimally altered human cells and tissues. Only one of the largest analyses of HapMap LCL samples was included here , and drug response, methylation, miRNA and non-human eQTL studies were excluded. Several published eQTL studies were not included since authors disclosed few results. Included studies, their citations and parameters are described in Table 1 and [Additional file 1]. The predominant tissue datasets are brain (n = 24 studies) and blood (n = 14), with other tissues including liver, adipose depots, kidney, skin, stomach and peripheral artery plaque. Previously unpublished data on kidney and peripheral artery plaque eQTLs are described in [Additional file 18]. Some previously published results were more extensively shared for the current analysis including liver, adipose and stomach , and lymphocytes .
Unifying eQTL and eGene annotations into a cross-dataset database
The workflow of the complete analysis is delineated in [Additional file 19]. We define genes whose expression levels are significantly associated with SNPs as eGenes. The term does not explicitly imply a specific transcript isoform since this information is often indeterminable with available data, but is likely to reflect expression variation in dominant gene isoforms. We refer to SNPs associated significantly in combination with an eGene as eQTLs (expression QTL SNPs). After we removed duplicate entries in some datasets, we used custom programs to map remaining identifiers either directly to unique NCBI Entrez Gene IDs, or via alias identifiers for heterogeneous gene names, in order to create a harmonized eGene dataset for further analysis. Only the strongest eQTL was kept for each eGene in each study in most subsequent analyses. Unified genomic locations (see Method below) for each eGene and eQTL in hg18/b36 reference were used to recalculate eQTL-eGene distances and direction (5′/- or 3′/+), and this dataset was used for subsequent analysis.
Filtering of low quality SNPs and unification of SNP genomic coordinates
Studies either reported no SNP coordinates, or reported them in hg18 or hg19 frameworks. We mapped all of the SNP rsIDs reported in 53 datasets to dbSNP130 and used dbSNP reference genome mappings to obtain uniform genomic position for SNPs in hg18/Build 36.3. We removed SNPs which mapped to >1 location, or to the pseudo-autosomal region. For SNPs not initially mapped by this approach we checked for alias SNP identifiers to link to dbSNP130, and used the alias IDs when available to complete mapping. In this manner the majority of eQTLs were mapped to a single genomic position with high confidence.
Genomic locations for each gene boundary were retrieved from NCBI RefSeq 56 (GRCh36.3 assembly) using hg18/b36 reference. If multiple transcripts/isoforms are transcribed from the same genomic locus/gene region the maximal union of boundaries was used. Data were retrieved using the biomaRt package , available through the Bioconductor repository . eQTLs ≤ 500 kb from associated eGenes were defined as cis. Those eQTLs > 500 kb were defined as trans, and further segmented into those being trans on the same or different chromosomes.
Summary of eGenes and eQTLs mapped to different categories
In total 419,796 eQTLs were reported from the 53 eQTL datasets. Among them, 359,268 eQTLs and their associated eGenes were mapped to RefSeq gene symbols or gene aliases, indicating both eQTL and eGene genomic positions in the RefSeq database. We selected the strongest eQTL per eGene per unique dataset yielding 116,563 best eQTLs (106,083 cis and 10,480 trans with the 500 kb threshold). Among these, there were 62,872 unique SNP identifiers that were the best eQTL in 1 or more dataset, for a total of 19,038 mapped eGenes.
Unsupervised hierarchical clustering
Unsupervised hierarchical clustering was used to assess patterns of regulatory variants across different tissues and cell types. Initially a 19,038 × 53 data matrix was constructed. Given the sparse nature of the matrix (most eGenes are unique to 1 study), we generated clusters based on eGenes present in higher proportions of studies (n = 15-53). The heatmap function in R 2.11 was used to do clustering with the Disfun parameter set to binary.
Comparison of eQTLs to NHGRI GWAS catalog
The NHGRI GWAS catalog (March-22-2013) was downloaded . Expression SNPs strongly associated with the gene expression traits were cross-referenced with SNPs in the GWAS catalog. Two sets of eQTLs were compared (160,580 unique eQTLs and 62,872 unique best eQTLs) against two sets of SNPs derived from the GWAS catalog (8,845 unique SNPs and 40,573 unique SNPs plus those in tight LD (r^2 = 1 in CEU based on SNAP  queries)) yielding four pair-wise comparisons.
Enrichment of eQTLs over protein-coding SNPs in full GWA trait scans
Full GWA trait scan statistics (n = 45 scans) were identified as part of the NHLBI GRASP database  and downloaded. Genomic lambda values were calculated relative to the null expectation for the full GWA distributions . Likewise, lambda values were calculated within each GWAS for expression SNPs from the current study (n = 62,872 best eSNPs) and nSNPs (based on dbSNP annotation, n = 100,601). Further lambda values were calculated restricted to those GWAS results with P < 1E-2. The ratios for enrichment were determined by comparing lambda values of eQTLs versus non-eQTLs, and nSNPs versus non-nSNPs. Komologorov-Smirnoff tests were applied to test differences in the distributions under each criterion. Individual lead cis-eQTLs and trans-eQTLs were directly assessed for presence in the GRASP database containing results from among 1,390 GWAS studies.
Comparison to human genome and regulatory features
We compared only the 62,872 unique best eQTLs to regulatory tracks. To take into account the different size of features (base pairs) reported by different tracks, for each regulatory track, the probability of any random base overlapping each track was calculated as the number of unique bases in each track divided by the total bases in the genome (3,080,436,451). Based on this probability, the expected number of overlaps between 62,872 single base position eQTLs and each track was computed. Binominal tests indicated whether observed overlaps were greater than expected by chance.
Regulatory tracks (B36 coordinates) were downloaded from the UCSC Genome Browser  or other sites. The 22 regulatory features include ENCODE histone modification sites, transcription factor and CTCF insulator sites in lymphoblastoid cell lines, ORegAnno (Open Regulatory Annotation) , predicted TFBS (UCSC conserved transcriptional factor binding sites), Vista Enhancers , human selection sites as determined by FST and IHS (integrated haplotype scores), human microRNAs (miRbase13), TargetScan (predicted miRNA targets) , Patrocles (experimentally supported miRNA sites) , PolymiRTS (predicted SNP-miRNA binding sites) , UCSC functional RNAs (e.g., tRNA), UCSC CpG islands, long intergenic non-coding RNAs , and long-range 5C experiments in targeted ENCODE regions . Specific top cis- and trans-eQTL SNPs were queried against ENCODE data using RegulomeDB .
The unique best cis-eQTLs were analyzed for differential representation by chromosomes. The total number of cis-eQTLs for each chromosome was divided by 4 distinct features to produce 4 rankings for enrichment: 1) total chromosome length (GRCh37.p11), 2) number of CCDS genes (release 11), 3) length of HuRef RNAs, and 4) number of HuRef variants. The chromosome rankings by the 4 metrics were averaged to produce an overall rank for over-representation of cis-eQTLs.
Housekeeping gene analysis
Housekeeping transcripts were defined based on previous analysis of 18 human tissues . Within our dataset 2,207 eGenes were designated as housekeeping genes and 16,831 as non-housekeeping genes. Frequencies of each eGene across dataset were calculated for housekeeping and non-housekeeping genes and compared by Student’s t-test.
Availability of supporting data
The primary data for some of the eQTL studies is available in public repositories as described in the original reports. The summary level eQTL results data sets supporting the results of this article are largely available in the full download of the NHLBI Genome-wide Repository of Associations between SNPs and Phenotypes (GRASPdb) [Build 1.0, http://apps.nhlbi.nih.gov/grasp/] .
XZ and ADJ were supported by NIH Intramural Funds. The authors acknowledge Heather E. Wheeler for contribution to the kidney eQTL data. The kidney eQTL work was supported by the Glenn Center for Aging. The Genotype-Tissue Expression (GTEx) Project was supported by the Common Fund of the Office of the Director of the National Institutes of Health (commonfund.nih.gov/GTEx). The GTEx datasets used for the analyses described in this manuscript were obtained from: GTEx Portal on 08/06/2013. Additional funds were provided by the NCI, NHGRI, NHLBI, NIDA, NIMH, and NINDS. Donors were enrolled at Biospecimen Source Sites funded by NCI\SAIC-Frederick, Inc. (SAIC-F) subcontracts to the National Disease Research Interchange (10XS170), Roswell Park Cancer Institute (10XS171), and Science Care, Inc. (X10S172). The Laboratory, Data Analysis, and Coordinating Center (LDACC) was funded through a contract (HHSN268201000029C) to the The Broad Institute, Inc. Biorepository operations were funded through an SAIC-F subcontract to Van Andel Institute (10ST1035). Additional data repository and project management were provided by SAIC-F (HHSN261200800001E). The Brain Bank was supported by a supplement to University of Miami grant DA006227. Statistical Methods development grants were made to the University of Geneva (MH090941), the University of Chicago (MH090951 & MH090937), the University of North Carolina - Chapel Hill (MH090936) and to Harvard University (MH090948).
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