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Expression quantitative trait loci

Expression quantitative trait loci (eQTLs) are genomic regions containing genetic variants, such as single nucleotide polymorphisms (SNPs), that are statistically associated with variations in the expression levels of one or more genes, thereby linking DNA sequence differences to molecular phenotypes.^[1] These loci are identified through genome-wide association studies of gene expression data and are classified as cis-eQTLs, which influence nearby genes typically within 1 megabase (Mb), or trans-eQTLs, which affect distant genes on the same or different chromosomes.^[2] By elucidating how genetic variation regulates transcription, eQTLs provide a mechanistic bridge between genotype and observable traits, particularly in complex diseases and polygenic traits.^[3] The foundational eQTL study emerged from genetical genomics in the budding yeast Saccharomyces cerevisiae, where Brem et al. (2002) mapped regulatory loci influencing transcript abundance across a segregant population, revealing both local and distant effects on gene expression. Human eQTL mapping followed in the mid-2000s, initially using microarrays on lymphoblastoid cell lines from the HapMap project, which identified hundreds of cis-eQTLs explaining significant portions of expression variance.^[4] Advances in RNA sequencing and larger cohorts have since expanded these efforts, with projects like the Genotype-Tissue Expression (GTEx) consortium analyzing over 900 donors across 49 tissues to catalog thousands of tissue-specific eQTLs.^[5] eQTL mapping employs statistical association tests, such as linear regression, between genotypes and normalized expression levels, often adjusting for covariates like population structure and batch effects using tools like Matrix eQTL or FastQTL.^[2] Cis-eQTLs are more readily detected due to stronger effect sizes and lower multiple-testing burdens, while trans-eQTLs require larger sample sizes (often thousands) to achieve sufficient power, as demonstrated in the eQTLGen consortium's analysis of blood expression from 31,684 individuals, which uncovered over 14,000 trans loci.^[6] Challenges include accounting for environmental confounders and linkage disequilibrium, but these studies have shown that 20–30% of expression variance is heritable across tissues.^[4] In genomics and disease research, eQTLs integrate with GWAS to prioritize causal variants; for example, SNPs at the SORT1 locus act as liver cis-eQTLs influencing PCSK9 expression and thereby plasma cholesterol levels, explaining myocardial infarction risk.^[1] Similarly, the ORMDL3 cis-eQTL on chromosome 17q21 modulates airway remodeling in childhood asthma.^[7] Recent single-cell eQTL (sc-eQTL) approaches, applied to brain tissues, reveal cell-type-specific regulation, such as microglia-enriched eQTLs for schizophrenia-associated genes, offering finer resolution for heterogeneous tissues.^[8] These insights facilitate functional annotation of non-coding variants and advance precision medicine by predicting expression effects in diverse populations.^[6]

Fundamentals

Definition

Expression quantitative trait loci (eQTLs) are genomic regions where genetic variants, such as single nucleotide polymorphisms (SNPs), contribute to variation in the expression levels of target genes, typically measured as mRNA abundance.^[4] These loci explain a portion of the genetic variance in gene expression phenotypes, serving as a subset of quantitative trait loci (QTLs) that specifically focus on molecular expression traits rather than morphological, physiological, or behavioral phenotypes.^[4] Unlike traditional QTLs, which map genetic influences on observable traits like height or disease severity, eQTLs target the intermediate step of gene regulation.^[9] eQTLs play a crucial role in bridging the gap between genotype and phenotype by quantitatively modulating gene expression, which in turn affects downstream cellular functions, traits, and disease risk.^[9] Genetic variants at eQTLs can alter regulatory elements, such as promoters or enhancers, leading to differences in transcription rates across individuals and populations.^[10] This regulatory mechanism helps elucidate how common genetic variation underlies complex phenotypes, providing insights into the molecular basis of heritability.^[4] A representative example involves a SNP positioned near or within a gene's regulatory region that disrupts or enhances a transcription factor binding site, resulting in variance in the gene's expression levels among individuals carrying different alleles.^[9] eQTLs are broadly classified into cis-acting (local effects on nearby genes) and trans-acting (distant effects on genes across the genome) types.^[4]

Historical Development

The concept of expression quantitative trait loci (eQTLs) originated in early genetic studies of model organisms, with the first genome-wide identification occurring in 2002 through an analysis of gene expression variation in a cross between laboratory and wild strains of the yeast Saccharomyces cerevisiae. This pioneering work by Brem et al. utilized microarray technology to link single nucleotide polymorphisms (SNPs) to transcript levels across thousands of genes, revealing hotspots of regulatory variation and establishing eQTL mapping as a method to dissect the genetic basis of expression traits. Subsequent yeast studies expanded on this foundation, confirming the prevalence of both local (cis) and distant (trans) regulatory effects in simple eukaryotes. The transition to mammalian models began in the early 2000s, leveraging microarray data from mouse crosses to map eQTLs in tissues like liver and brain. A seminal 2003 study by Schadt et al. integrated expression profiles from 111 F2 intercross mice derived from C57BL/6J and DBA/2J strains with genotype data, identifying thousands of eQTLs and demonstrating their potential to infer causal relationships between gene expression and complex phenotypes such as obesity. These efforts highlighted tissue-specific regulatory variation and paved the way for human applications, where initial eQTL mapping relied on lymphoblastoid cell lines from population cohorts. Key advancements in human eQTL research emerged in 2007 with two influential publications in Nature Genetics. Stranger et al. analyzed expression data from 210 individuals of diverse ancestries, identifying over 1,300 cis-eQTLs and showing that common genetic variants explain a substantial portion of expression variability. Concurrently, Dixon et al. performed a genome-wide association study on global gene expression in 400 children, uncovering 3,000 eQTLs and linking them to disease-relevant pathways like asthma susceptibility. These studies were enabled by the International HapMap Project, which provided dense SNP genotype data from diverse populations to power association analyses in cell lines. The subsequent 1000 Genomes Project further enriched eQTL discovery by cataloging rare variants and haplotypes across global populations, facilitating finer-resolution mapping in later cohorts.^[11] The 2010s marked a shift toward large-scale, multi-tissue consortia, exemplified by the Genotype-Tissue Expression (GTEx) project launched by the NIH in 2010.^[12] GTEx's pilot phase in 2015 analyzed RNA from 44 tissues across 175 postmortem donors, mapping over 25 million eQTLs and revealing widespread tissue specificity in regulatory effects. Subsequent phases of GTEx, including version 8 released in 2017, expanded to 49 tissues from 948 donors, cataloging millions more tissue-specific eQTLs and enabling deeper insights into regulatory variation.^[5] This resource has since driven systems-level insights into how genetic variation influences expression across human physiology.

Classification

Cis-eQTLs

Cis-eQTLs, or cis-acting expression quantitative trait loci, are genetic variants that influence the expression levels of nearby genes, typically defined as those located within 1 megabase (Mb) of the gene's transcription start site.^[13] These variants are often found in regulatory regions such as promoters, enhancers, or introns, where they can directly modulate local gene regulation.^[13] In contrast to trans-eQTLs, which operate at greater genomic distances and generally exhibit smaller effect sizes, cis-eQTLs tend to produce more potent and detectable regulatory effects due to their proximity.^[13] The primary mechanisms by which cis-eQTLs affect gene expression involve alterations to local cis-regulatory elements. For instance, a variant may disrupt or create binding sites for transcription factors, thereby changing the recruitment of these proteins to DNA and influencing transcriptional initiation.^[14] Similarly, cis-eQTLs can modify chromatin accessibility, such as by affecting histone modifications or nucleosome positioning, which in turn impacts the openness of DNA regions for transcription machinery.^[15] These direct, local interactions make cis-eQTLs key players in fine-tuning gene expression in a tissue-specific manner. Cis-eQTLs are more prevalent and easier to detect than their trans counterparts, with large-scale studies identifying thousands of such loci per tissue across diverse human samples.^[13] They frequently colocalize with disease-associated variants from genome-wide association studies (GWAS), suggesting that many complex trait signals operate through cis-regulatory changes in gene expression.^[16] This overlap highlights the implications of cis-eQTLs in disease etiology, as they provide mechanistic insights into how non-coding variants contribute to phenotypic variation. A well-known example of a cis-eQTL is the single nucleotide polymorphism (SNP) rs4988235 upstream of the lactase gene (LCT), which regulates lactase persistence in adults. This variant, located approximately 14 kilobases upstream in an enhancer element, increases LCT expression in individuals carrying the persistence-associated allele, enabling continued lactose digestion beyond infancy. This adaptation exemplifies how cis-eQTLs can drive evolutionary traits by altering local regulatory control.^[17]^[18]

Trans-eQTLs

Trans-eQTLs are genetic variants that influence gene expression at distant genomic locations, defined as more than 1 megabase (Mb) away from the target gene or on different chromosomes.^[19] Unlike cis-eQTLs, which act locally, trans-eQTLs typically exert their effects through indirect mechanisms involving diffusible factors such as transcription factors or signaling pathways.^[1] These variants often regulate master regulators that, in turn, control networks of downstream genes, leading to coordinated changes in expression across multiple loci.^[20] Trans-eQTLs generally exhibit lower effect sizes and are fewer in number compared to cis-eQTLs, with large-scale studies identifying hundreds of high-confidence trans-eQTLs affecting thousands of transcripts in specific cell types.^[19] Their indirect nature means regulation occurs via intermediaries, such as transcription factors like IKZF1 or NFKBIA, which propagate effects through pathways including NF-κB signaling.^[20] Detecting trans-eQTLs presents significant challenges due to higher noise levels from multiple potential regulatory intermediaries and the risk of false positives from mapping errors or multiple testing.^[20] These factors contribute to modest statistical power in standard analyses, often requiring advanced multivariate methods to distinguish true signals.^[19] Trans-eQTL target genes show enrichment in immune-related processes, particularly in the HLA region and interferon response pathways, reflecting their role in systemic regulation.^[20] For instance, in lymphoblastoid cell lines, the trans-eQTL rs6899963 influences the expression of multiple cytokine-related genes, demonstrating coordinated immune modulation from a single locus.^[19]

Identification Methods

Data Requirements

Expression quantitative trait loci (eQTL) studies require paired genotype and gene expression data from the same individuals to identify genetic variants associated with variation in gene expression levels. Genotype data typically derive from high-density single nucleotide polymorphism (SNP) arrays or whole-genome sequencing (WGS), providing comprehensive coverage of common and rare variants across the genome. For instance, the GTEx project utilized WGS from over 800 donors with median coverage of approximately 30x, focusing on variants with minor allele frequency (MAF) ≥1% to ensure sufficient statistical power for detection. Similarly, imputation using reference panels like the 1000 Genomes Project or TOPMed enhances variant density, allowing inclusion of up to millions of SNPs while maintaining linkage disequilibrium information.^[21]^[2] Gene expression data are obtained through RNA sequencing (RNA-seq) or, in earlier studies, microarray platforms, measured in relevant tissues or cell types to capture context-specific regulatory effects. RNA-seq is preferred for its ability to quantify transcript abundance across the transcriptome with high dynamic range, as exemplified by GTEx's use of Illumina TruSeq kits generating ~80 million paired-end reads per sample aligned to the human reference genome (GRCh38). Crucially, expression profiles must be matched to genotypes from the same samples to enable cis- and trans-association testing, with post-mortem or biopsy tissues often used in human studies to reflect physiological conditions. Microarrays, such as the Affymetrix Human Gene 1.0 ST array, remain viable for legacy datasets but offer lower resolution for alternative isoforms and low-abundance transcripts.^[21]^[2] Sample size is a critical determinant of eQTL discovery power, with minimum requirements scaling by effect type and tissue. For cis-eQTLs, which localize nearby genetic variants, hundreds of samples per tissue suffice to detect moderate-effect loci, as demonstrated by GTEx analyses requiring at least 70 samples per tissue across 49 sites to achieve robust significance. Trans-eQTLs, involving distal or cross-chromosomal effects with smaller effect sizes, demand larger cohorts—often thousands of individuals—to overcome multiple-testing burdens and noise, with meta-analyses across studies recommended for enhanced resolution. These thresholds ensure sufficient heritability capture, as smaller cohorts risk missing low-frequency or tissue-specific signals.^[21]^[2] Preprocessing is essential to mitigate technical artifacts and biological confounders before eQTL mapping. Quality control (QC) for genotypes involves filtering low-call-rate variants (e.g., <95%), Hardy-Weinberg deviations, and relatedness checks using tools like PLINK, followed by imputation with methods such as Michigan Impute2 or Minimac4. Expression data undergo alignment (e.g., STAR for RNA-seq), quantification (e.g., RSEM), and filtering of low-expressed genes (<1 count per million in >50% samples), with normalization via trimmed mean of M-values (TMM) or quantile methods to stabilize variance across samples. Batch effects from sequencing runs or protocols are addressed through probabilistic estimation of expression residuals (PEER) factors, scaled by sample size (e.g., 15 factors for <150 samples, up to 60 for larger sets), while covariates like age, sex, and principal components (PCs) from genotyping are included to adjust for population structure and demographics. These steps ensure data integrity for subsequent statistical association testing.^[21]^[2]

Statistical Analysis

The primary statistical approach for identifying expression quantitative trait loci (eQTLs) involves association testing between genetic variants, typically single nucleotide polymorphisms (SNPs), and gene expression levels. This is commonly performed using linear regression models under an additive genetic model, where the normalized gene expression level Y for a given gene is modeled as a function of the genotype dosage G (coded as 0, 1, or 2 for the number of minor alleles):

Y = \beta_0 + \beta_1 G + \epsilon,

with \beta_0 as the intercept, \beta_1 as the effect size of the SNP on expression, and \epsilon as the error term assumed to follow a normal distribution.^[22] This model tests the null hypothesis that \beta_1 = 0, yielding a p-value for the association, and is applied to each SNP-gene pair within a defined genomic window (e.g., ±1 Mb for cis-eQTLs).^[23] Given the large number of tests conducted in genome-wide eQTL studies—often millions of SNP-gene pairs—multiple testing correction is essential to control the false discovery rate (FDR) or family-wise error rate. Common methods include the Bonferroni correction, which divides the desired significance level (e.g., 0.05) by the number of tests, or FDR procedures such as the Benjamini-Hochberg method, targeting an FDR threshold like 5%.^[24] For stringent genome-wide significance, a p-value threshold of 5 × 10^{-8} is sometimes adopted, analogous to GWAS standards, though eQTL analyses more frequently use permutation-based empirical FDR to account for the correlation structure in expression data.^[25] To refine eQTL mappings and distinguish independent signals from those in linkage disequilibrium, conditional analysis is employed. This involves iteratively including the top-associated SNP as a covariate in subsequent regression models to identify secondary signals, enabling fine-mapping of causal variants within a locus.^[26] Additionally, colocalization methods, such as COLOC or eCAVIAR, integrate eQTL data with GWAS summary statistics to assess whether the same genetic variant underlies both expression and trait associations, providing evidence for shared causal mechanisms.^[27]^[28] Efficient software tools facilitate these analyses on large datasets. Matrix eQTL implements linear regression via optimized matrix operations, enabling rapid computation for thousands of genes and millions of SNPs.^[22] FastQTL extends this with adaptive permutation procedures for accurate multiple testing correction, supporting both linear models and more complex covariates while achieving substantial speed gains over traditional methods.^[25]

Applications and Resources

In Biomedical Research

Expression quantitative trait loci (eQTLs) play a pivotal role in biomedical research by linking non-coding genetic variants identified in genome-wide association studies (GWAS) to their functional consequences on gene expression, thereby prioritizing candidate causal variants and target genes. Colocalization analyses, such as those employing the eCAVIAR method, assess whether GWAS signals overlap with eQTL effects, indicating shared causal variants. For instance, in type 2 diabetes-related traits like fasting glucose and proinsulin levels, colocalization has identified pancreatic islet-specific eQTLs for genes such as ADCY5 and MADD, highlighting how non-coding variants disrupt regulatory mechanisms in relevant tissues.^[29] Similarly, in schizophrenia, eQTL colocalization with brain tissue data has enriched GWAS loci, revealing target genes like those involved in synaptic function and implicating non-neural tissues in disease etiology. Tissue-specific eQTLs provide disease-specific insights, particularly for neurological disorders where brain cell-type resolution is crucial. Studies mapping cis-eQTLs across eight human brain cell types, including neurons, astrocytes, and microglia, have identified over 6,000 eGenes, with 43% exhibiting cell-type specificity and strongest effects in microglia. These eQTLs colocalize with GWAS signals for disorders such as schizophrenia, bipolar disorder, and Alzheimer's disease, uncovering novel risk genes like SLC39A13 in excitatory neurons and GRID2 in microglia, which inform cell-specific pathogenic mechanisms. In immune diseases, a 2012 study found that trans-eQTLs—acting distally across the genome—demonstrate heightened relevance, as SNPs associated with autoimmune or hematological traits are twice as likely to drive trans-eQTL effects compared to other traits. Examples include the SLE risk variant rs4917014, which modulates C1QB and interferon response genes via IKZF1, and type 1 diabetes loci like rs3184504 influencing interferon-γ pathways.^[30] Integrating eQTLs with epigenomic data enhances functional annotation and causal variant identification by incorporating regulatory context, such as chromatin accessibility. The eQTeL Bayesian framework couples genetic variants with epigenetic features like DNase I hypersensitivity sites from ENCODE and Roadmap Epigenomics to pinpoint causal SNPs affecting expression. Applied to heart tissue, this approach detected thousands of regulatory variants overlapping transcription factor motifs, prioritizing those with high posterior probabilities for traits like cardiac function. GTEx-derived eQTLs illustrate broad applicability in complex traits, where regulatory effects explain a median of 19.5% (interquartile range 11.9–29.0%) of disease heritability across 21 conditions, including schizophrenia and type 2 diabetes, by annotating GWAS loci with tissue-matched expression data. This partitioning underscores eQTLs' role in bridging genetic associations to molecular mechanisms, guiding precision medicine efforts.

Public Databases

Several public databases serve as key repositories for expression quantitative trait loci (eQTL) data, enabling researchers to access, query, and integrate genetic associations with gene expression across tissues and populations. These resources provide summary statistics, visualization tools, and cross-referencing capabilities to facilitate meta-analyses and downstream applications in genomics.^[31] The GTEx Portal is a central resource for human tissue-specific eQTLs, derived from RNA sequencing and genotyping data collected from 946 postmortem donors across 54 tissues and cell types. Launched in 2015 as part of the NIH Common Fund's Genotype-Tissue Expression project, it offers open-access datasets including cis- and trans-eQTL summary statistics, gene expression profiles, and interactive tools for querying associations between variants and gene expression levels. The portal's latest major release (V10, 2024) encompasses 19,788 samples, supporting analyses of tissue-shared and tissue-specific regulatory effects.^[32]^[31] eQTLGen provides a large-scale meta-analysis of blood-based eQTLs from 31,684 individuals of primarily European ancestry across 37 cohorts, focusing on cis- and trans-effects to identify thousands of genetic loci influencing gene expression. Established by the eQTLGen Consortium, this resource delivers summary statistics for over 16,000 genes, enabling polygenic score construction and prioritization of trait-associated variants. It supports download of pre-computed associations and serves as a benchmark for blood-derived eQTL studies.^[33]^[34] Other notable resources include FUMA, a web-based platform for functional mapping and annotation of genetic associations that integrates eQTL data with positional mapping, chromatin interactions, and pathway analyses to prioritize candidate genes from genome-wide association studies (GWAS). FUMA facilitates interactive visualization of eQTL overlaps and gene sets, aiding interpretation of regulatory mechanisms.^[35] QTLbase2 offers an integrative catalog of QTL summary statistics across multiple human molecular phenotypes, including eQTLs from over 95 tissue and cell types, compiled from over 370 studies (as of 2022); it enables cross-phenotype comparisons and variant-level queries for multi-omics research. For cross-omics integration, resources like QTLbase2 provide summary statistics that link eQTLs with other QTL types, supporting meta-eQTL analyses and colocalization with GWAS catalogs to infer causal variants.^[36]^[37] The eQTL Catalogue is an open database of uniformly processed human gene expression and splicing QTLs from multiple studies, including bulk and single-cell RNA-seq datasets across various tissues. As of release 7 (June 2024), it incorporates data from over 20 studies, enabling cross-study comparisons and colocalization analyses.^[38]

Challenges and Advances

Current Limitations

Despite significant advances, eQTL research faces persistent power limitations, particularly in detecting rare variants and weak trans-eQTL effects, which often require sample sizes exceeding thousands to achieve adequate statistical power.^[39] Small sample sizes in many studies increase the risk of false negatives, exacerbated by stringent multiple-testing corrections that further reduce detection sensitivity.^[40] For instance, the GTEx consortium's 838 postmortem donors have not yet saturated eQTL discovery, underscoring the need for even larger cohorts to uncover subtle regulatory effects.^[39] Single-cell eQTL analyses compound these issues due to data sparsity and noise, demanding substantially larger datasets for reliable identification.^[41] Tissue and context specificity pose another major challenge, as bulk tissue eQTL mapping aggregates signals across heterogeneous cell types, obscuring cell-type-specific regulatory effects.^[42] Environmental factors and disease states can modulate eQTL strengths, introducing confounders that vary by context and reduce reproducibility across studies.^[40] For example, eQTL effects in blood may not generalize to other tissues like the synovium, necessitating tissue-specific datasets that are currently limited in availability and scale.^[40] Interpretation of eQTLs remains challenging, with difficulties in distinguishing causal variants from those in linkage disequilibrium, especially in regions of complex polygenic regulation.^[42] Polygenic effects and epistatic interactions further complicate prioritization, as correlated variants often confound causal inference without advanced fine-mapping.^[41] Integrating eQTL data with other omics layers, such as epigenomics, is hindered by incomplete tools for multi-omics reconciliation, limiting mechanistic insights.^[41] Population biases severely limit eQTL generalizability, with over 80-95% of samples in major resources like GTEx and eQTLGen derived from European ancestries, underrepresenting global diversity.^[43] This skew leads to allele frequency differences that reduce cross-ancestry portability of eQTL predictions, with up to 17% of European-common variants showing poor transferability to African ancestries due to rarity and altered linkage disequilibrium.^[44] Admixture and unadjusted population structure can confound associations, inflating type I errors or missing ancestry-specific effects in diverse cohorts.^[45]

Emerging Techniques

Recent advancements in expression quantitative trait loci (eQTL) studies have shifted toward single-cell resolution to dissect cell-type-specific genetic regulation, overcoming the averaging effects of bulk tissue analyses. Single-cell eQTL mapping (sc-eQTL) leverages single-cell RNA sequencing (scRNA-seq) to identify genetic variants influencing gene expression in individual cells, revealing nuanced regulatory mechanisms in heterogeneous populations like immune cells. For instance, a large-scale study of 1.27 million peripheral blood mononuclear cells from 982 donors mapped 26,597 cis-eQTLs and 990 trans-eQTLs across 14 immune cell types, including naïve and memory B cells, CD4+ and CD8+ T cells, demonstrating that over 90% of sc-eQTLs are cell-type-specific.^[46] This approach has linked 305 autoimmune disease loci to specific immune cell expressions, such as 57 multiple sclerosis risk variants via EAF2 in B cells, enhancing causal inference for immune-related disorders.^[46] Further, sc-eQTL analyses in monocytes and T cells from healthy donors have identified response eQTLs under immune stimulation, with variants like SLFN5-rs11080327 modulating expression in T lymphocytes (p < 5e-6), applicable to COVID-19 severity.^[47] In cancer immunotherapy contexts, sc-eQTL mapping in circulating immune cells from non-small cell lung cancer patients detected 9,147 eQTL pairs, including 245 treatment-specific ones in monocytes and CD8+ T cells, enriching immune response pathways.^[48] Multi-omics integration has emerged as a powerful strategy to strengthen causal inferences in eQTL studies by combining expression data with epigenomic (e.g., ATAC-seq) and proteomic profiles. Methods like Multi-INTACT integrate eQTLs with proteomics and metabolomics to infer causal genes, identifying 52% to 109% more metabolite-linked causal genes than expression- or protein-alone analyses, illuminating pathways in complex traits.^[49] For example, colocalization of monocyte eQTLs with ATAC-seq chromatin accessibility and transcription factor binding has prioritized variants like ADCY3 for obesity (posterior probability PP4 = 0.825) and CD55 for immune regulation.^[47] Similarly, integrating brain eQTLs with proteomics in Alzheimer's disease studies has pinpointed cell-type-specific causal genes, such as those in microglia, by linking genetic signals across layers for enhanced disease mechanism resolution. In protein quantitative trait loci (pQTL) contexts, eQTL-pQTL overlap has validated 18 causal proteins in multiple sclerosis plasma and brain, supporting drug target prioritization.^[50] Machine learning, particularly deep learning, has revolutionized eQTL effect prediction by modeling complex regulatory networks from genomic sequences. The Enformer architecture, a transformer-based deep learning model, predicts gene expression from 200 kb DNA sequences with long-range interactions, achieving Pearson correlations of 0.85 for CAGE data—surpassing prior models by 4% and aiding eQTL fine-mapping with improved sum of log odds (SLDP) Z-scores from 6.3 to 6.9 across 648 datasets.^[51] This enables prioritization of noncoding variants, closing one-third of the gap to experimental accuracy in enhancer and promoter effects. More recently, PromoterAI, fine-tuned on rare promoter variants and multi-omics features like histone modifications, predicts expression-altering mutations correlating with eQTLs and protein abundance, enriching Mendelian disease diagnostics by 6% in patient cohorts.^[52] These models dissect regulatory syntax in networks, forecasting variant impacts on traits like type 2 diabetes via islet cell predictions.^[53] Longitudinal and dynamic eQTL analyses using time-series data are advancing insights into temporal regulation during development and disease progression. In psoriatic skin, immunosuppression revealed 953 eGenes with 98 dynamic eQTLs modulated by inflammation (FDR < 0.05), such as magnified IL37 effects (beta = -0.79), colocalizing with psoriasis risk loci and enriching NRF2 pathways.^[54] The trajectory-inference-based dynamic single-cell Mendelian randomization (ti-scMR) integrates scRNA-seq timelines with genetics to identify causal genes, uncovering 35 in B cell differentiation (e.g., humoral response pathways) and 6 in multiple sclerosis oligodendrocytes (e.g., ATP8A2). Post-2023 extensions to nascent RNA have distinguished early versus late eQTL mechanisms in brain and kidney, highlighting developmental shifts. These approaches capture condition-dependent effects, informing disease trajectories beyond static bulk eQTLs.

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Aug 27, 2025 · Small sample sizes and the need for stringent multiple-testing corrections remain significant barriers in eQTL studies. These challenges can ...
[38]
eQTL analysis: A bridge from genome to mechanism - ScienceDirect
Sep 17, 2025 · Expression quantitative trait locus (eQTL) refers to a genetic variation associated with the expression of specific genes.
[39]
Leveraging cell-type specificity and similarity improves single-cell eQTL fine-mapping
**Summary of Challenges in Current eQTL Analysis from https://www.biorxiv.org/content/10.1101/2025.03.05.641709v1.full-text:**
[40]
Equitable machine learning counteracts ancestral bias in precision ...
Mar 10, 2025 · Individuals with European ancestry are dramatically over-represented in omics databases (Supplemental Figure 1B).
[41]
https://www.sciencedirect.com/science/article/pii/S2352304225003393
[42]
Impact of admixture and ancestry on eQTL analysis and GWAS ...
Sep 11, 2020 · We provide a local ancestry map for admixed individuals in the GTEx v8 release and describe the impact of ancestry and admixture on gene expression, eQTLs, and ...
[43]
Single-cell eQTL mapping identifies cell type–specific genetic ...
Apr 8, 2022 · These studies examined both proximal (cis) and distal (trans) genetic variants affecting gene expression in 14 different immune cell types.Single-Cell Eqtl Mapping... · Single-Cell Eqtl Analysis... · Single-Cell Eqtls Replicate...<|separator|>
[44]
Unveiling genetic signatures of immune response in immune-related ...
Aug 4, 2025 · We map genetic effects on gene expression (expression quantitative trait locus, eQTL) using single-cell transcriptomes of 152 samples from 38 ...
[45]
Single‐cell‐eQTL mapping in circulating immune cells reveals ...
Jun 14, 2025 · To investigate how germline variants shape immune gene regulation during ICI treatment, we performed single‐cell‐eQTL (sc‐eQTL) analysis and ...
[46]
Integrative analysis of the genome, transcriptome, and proteome identifies causal mechanisms of complex traits
**Summary of Multi-INTACT Method and Key Findings:**
[47]
Multiomics integration prioritizes potential drug targets for multiple ...
We prioritized 18 potential drug targets in plasma and brain, elucidating the underlying pathology and providing evidence for potential drug discovery and ...Missing: ATAC- | Show results with:ATAC-
[48]
Effective gene expression prediction from sequence by integrating ...
Oct 4, 2021 · We report substantially improved gene expression prediction accuracy from DNA sequences through the use of a deep learning architecture, called Enformer.
[49]
Predicting expression-altering promoter mutations with deep learning
May 29, 2025 · Deep-learning models trained on large-scale functional genomics datasets have the potential to learn the regulatory syntax underlying ...
[50]
Deep learning models predict regulatory variants in pancreatic islets ...
Jan 27, 2020 · We demonstrate that CNN-based analyses can refine association signals at T2D-associated loci and provide experimental validation for one such signal.
[51]
Immunosuppression causes dynamic changes in expression QTLs ...
Oct 7, 2023 · We report 953 expression quantitative trait loci (eQTLs). Of those, 116 eQTLs have effect sizes that were modulated by local skin inflammation (eQTL ...Missing: series | Show results with:series