The GTEx Consortium atlas of genetic regulatory effects across human tissues

2020/09/10 by François Aguet, Shankara Anand, Kristin Ardlie +97 · 6,006 citations
Biochemistry, Genetics and Molecular Biology · #Biology #Computational biology #Gene #Gene expression #Genetic variation #Genetics #Genome #Genomics and Chromatin Dynamics #Human genetic variation #Human genome #RNA #RNA Research and Splicing #RNA modifications and cancer #RNA splicing #Regulation of gene expression

paper · pdf · doi:10.1126/science.aaz1776

published in Science 369(6509), 1318-1330 (American Association for the Advancement of Science)

openalex publication_date 2020/09/10 · openalex created_date 2021/03/15 · openalex updated_date 2026/08/09

Abstract

The Genotype-Tissue Expression (GTEx) project was established to characterize genetic effects on the transcriptome across human tissues and to link these regulatory mechanisms to trait and disease associations. Here, we present analyses of the version 8 data, examining 15,201 RNA-sequencing samples from 49 tissues of 838 postmortem donors. We comprehensively characterize genetic associations for gene expression and splicing in cis and trans, showing that regulatory associations are found for almost all genes, and describe the underlying molecular mechanisms and their contribution to allelic heterogeneity and pleiotropy of complex traits. Leveraging the large diversity of tissues, we provide insights into the tissue specificity of genetic effects and show that cell type composition is a key factor in understanding gene regulatory mechanisms in human tissues.

Citations

• Statistical significance for genomewide studies
• Genetics of rheumatoid arthritis contributes to biology and drug discovery
• The Genotype-Tissue Expression (GTEx) project
• Integrative analysis of 111 reference human epigenomes
• Biological insights from 108 schizophrenia-associated genetic loci
• Integrating common and rare genetic variation in diverse human populations
• Common genetic variants influence human subcortical brain structures
• An integrated encyclopedia of DNA elements in the human genome
• Genetic variants associated with subjective well-being, depressive symptoms, and neuroticism identified through genome-wide analyses
• Genome-wide association analysis of insomnia complaints identifies risk genes and genetic overlap with psychiatric and metabolic traits
• Empirical Bayes Matrix Factorization

Cited by

• Mapping trans -eQTLs at single-cell resolution using Latent Interaction Variational Inference
• PCSK9 and Breast Cancer Survival: A Mendelian Randomization Study
• Imputed transcriptional patterns in ancient genomes reveal molecular targets of selection
• Genetic subtyping of obesity reveals biological insights into the uncoupling of adiposity from its cardiometabolic comorbidities
• Multipopulation GWAS for venous thromboembolism identifies novel loci followed by experimental validation in zebrafish
• Trans-ancestry genome-wide study of depression identifies 697 associations implicating cell types and pharmacotherapies
• Genomic landscape underlying pituitary epigenome divergence between stickleback ecotypes
• Genome-wide association studies of infant and toddler temperament in European and multi-ancestry populations
• Escape from X inactivation drives sex differences in gene expression
• Multi-region m6A epitranscriptome profiling of the human brain reveals spatial and temporal variation and enrichment of disease-associated loci
• Extensive co-regulation of neighboring genes complicates the use of eQTLs in target gene prioritization
• A reconstruction of the mammalian secretory pathway identifies mechanisms regulating antibody production
• Genome-wide association meta-analysis of age at onset of walking in over 70,000 infants of European ancestry
• Evolutionary History and Functional Divergence of Hydroxycarboxylic Acid Receptors in Primates
• Long-term isolation and archaic introgression shape functional genetic variation in Near Oceania
• Uncovering the shared genetic components of thyroid disorders and reproductive health
• Transcriptome-wide association studies implicate RCC1 and PHACTR4 in prostate cancer survival
• Effective gene expression prediction from sequence by integrating long-range interactions
• Genetically Regulated Gene Expression in the Brain Associated With Chronic Pain: Relationships With Clinical Traits and Potential for Drug Repurposing
• A Joint Promoterome-Proteome Atlas Highlights the Molecular Diversity of Human Skeletal Muscles
• Large-scale genome-wide analyses with proteomics integration reveal novel loci and biological insights into frailty
• AlphaGenome: advancing regulatory variant effect prediction with a unified DNA sequence model
• A transcriptome-based human universal senescence index (hUSI) robustly predicts cellular senescence under various conditions
• Polygenic overlap between subjective well-being and psychiatric disorders and cross-ancestry validation
• Pan-transcriptome reveals a large accessory genome contribution to gene expression variation in yeast
• Digital phenotyping from wearables using AI characterizes psychiatric disorders and identifies genetic associations
• Using drift coefficients as a basis for inferring times, effective population sizes, and genetic adaptations
• The cell-type–specific genetic architecture of chronic pain in brain and dorsal root ganglia
• Mendelian randomisation with proxy exposures: challenges and opportunities
• Paired DNA and RNA sequencing uncovers common and rare variation regulating human retinal gene expression
• A comparison of deep multiomics profiles across ethnicity, geography, and age
• CCC-GPU: a graphics processing unit (GPU)-accelerated nonlinear correlation coefficient for large-scale transcriptomic analyses
• Reduced circulating levels of CXCL14 are associated with cardiovascular damage in people living with HIV
• Multi-ancestry genome-wide meta-analysis of 56,241 individuals identifies known and novel cross-population and ancestry-specific associations as novel risk loci for Alzheimer’s disease
• Hacia el aprendizaje experiencial
• Multiomics Research: Principles and Challenges in Integrated Analysis
• Genetic regulation of gene expression across multiple tissues in chickens
• A genetically informed brain atlas for enhancing brain imaging genomics
• Multi-omics approaches for understanding gene-environment interactions in noncommunicable diseases: techniques, translation, and equity issues
• Actively Protective Combinatorial Analysis: a Scalable Novel Method for Detecting Variants that Contribute to Reduced Disease Prevalence in High-Risk Individuals
• Bayesian estimation of gene constraint from an evolutionary model with gene features
• Mendelian randomization with proxy exposures: challenges and opportunities
• Incorporating LLM Embeddings for Variation Across the Human Genome
• Effects of introgressed Neanderthal alleles on present-day brain morphology
• Opportunities for RNA sequencing in physiology: from big data to understanding homeostasis and heterogeneity
• The DNA virome varies with human genes and environments
• Cellular Aging Signatures in the Plasma Proteome Record Human Health and Disease
• Establishing the relationship between brain cellular senescence and brain structure
• Massively parallel analysis of genotype-dependent enhancer activity among atopic dermatitis genetic risk variants
• Diverse Patterns of Allele-Specific Expression in Healthy Human Tissues
• Urobiota analysis and genome-wide association study in pediatric recurrent urinary tract infections and vesicoureteral reflux
• Genotype‐by‐sex interaction analyses for alcohol use disorder across biobanks
• Mechanistic insights into sex differences in atrial electrophysiology and arrhythmia vulnerability through sex‐specific computational models
• Measurement characteristics and genome-wide correlates of lifetime brain atrophy estimated from a single MRI
• Impact of polymorphisms on gene expression and splicing in response to exercise and diet-induced weight loss in human skeletal muscle tissues
• Allele Specific Expression Quality Control Fills Critical Gap in Transcriptome Assisted Rare Variant Interpretation
• m6A deficiency induces dopaminergic neurodegeneration and progressive parkinsonism through a pathogenic loop with mitochondria
• Integrative genomics sheds light on the immunogenetics of tuberculosis in cattle
• Asian diversity in human immune cells
• Kidney multiome-based genetic scorecard reveals convergent coding and regulatory variants
• Characterization of DNA methylation clock algorithms applied to diverse tissue types
• Genetic pathways regulating the longitudinal acquisition of cocaine self-administration in a panel of inbred and recombinant inbred mice
• Colocalization of eQTLs With Type 2 Diabetes and Glycemic Traits Using Whole-Genome Sequences in Diverse Populations From the NHLBI Trans-Omics in Precision Medicine (TOPMed) Program
• Knowledge preservation in the era of big science and AI: strategies for sustainable scientific research
• 6PPD-quinone exposure and Alzheimer’s disease: insights from integrative network pharmacology, transcriptomics, machine learning, and molecular docking
• BTS: a scalable Bayesian Tissue Score for prioritizing GWAS variants and their functional contexts across >1,000s of omics datasets
• New insights into the genetic etiology of Alzheimer’s disease and related dementias
• Learning Explainable Imaging-Genetics Associations Related to a Neurological Disorder
• Genome-wide association studies
• The emerging roles of long non-coding RNAs in the nervous system
• WILDS: A Benchmark of in-the-Wild Distribution Shifts
• Towards Agents That Know When They Don't Know: Uncertainty as a Control Signal for Structured Reasoning
• Comprehensively stratifying MCIs into distinct risk subtypes based on brain imaging genetics fusion learning
• Systematic evaluation of the impact of promoter proximal short tandem repeats on expression
• Phylogenetic Relatedness Does not Predict Patterns of Parallel Transcriptome Adaptation in Drosophila
• Dissecting the IL‐6 pathway in cardiometabolic disease: A Mendelian randomization study on both IL6 and IL6R
• Identification and Reproducibility of Novel Combinatorial Genetic Risk Factors for Endometriosis across UK and US Patient Cohorts
• Plasma proteomic associations with genetics and health in the UK Biobank
• Integrating polygenic signals and single-cell multiomics identifies cell-type-specific regulomes critical for immune- and aging-related diseases
• Beyond Single Variants: A Pathway-Based Approach to Explore the Genetic Basis of Memory
• Multi-group Gaussian Processes
• Enigma: An Efficient Model for Deciphering Regulatory Genomics
• Systematic analysis of nonsense variants uncovers peptide release rate as a novel modifier of nonsense-mediated mRNA decay
• Genome-Wide Association Study of Hypoglycemia in Adults With Diabetes in the Million Veteran Program
• Ultra-fast genetic colocalisation across millions of traits
• Generative modeling for RNA splicing prediction and design
• A Genomic Language Model for Zero-Shot Prediction of Promoter Variant Effects
• The splice of life: an isoform-centric view of disease, technology, and therapeutics
• Single-cell multiomics of neuron activation reveals context-specific genetics of brain disorders
• Comparative transcriptomics analysis of histone deacetylases, transcription factors, and ion channel genes in human iPSC-cardiomyocytes vs. the adult human heart
• Domain-specific mechanisms of YAP1 variants in ocular coloboma revealed by in-vitro and organoid studies
• Genetic subtraction reveals divergent pathways and targets in anxiety-related and anxiety-independent TMD
• Advancing regulatory variant effect prediction with AlphaGenome
• Genome-wide association study of long COVID
• Systematic differences in discovery of genetic effects on gene expression and complex traits
• Oncogenic roles of young human de novo genes and their potential as neoantigens in cancer immunotherapy
• Eigenvector-based sparse canonical correlation analysis: Fast computation for estimation of multiple canonical vectors
• Multi-tissue expression and splicing data prioritise anatomical subsite- and sex-specific colorectal cancer susceptibility genes
• Adiponectin and gastric fundus: A potential target for gut–brain axis dysfunctions
• Variant Set Distillation
• Cell2Sentence: Teaching Large Language Models the Language of Biology
• RCSB Protein Data Bank (RCSB.org): delivery of experimentally-determined PDB structures alongside one million computed structure models of proteins from artificial intelligence/machine learning
• Sources of gene expression variation in a globally diverse human cohort
• Single-cell chromatin state analysis with Signac
• Genetic and functional analysis of unproductive splicing using LeafCutter2
• An alternative framework for transcriptome-wide association studies to detect and decipher gene-trait associations
• Epigenome‐Wide Association Study of Asthma Exacerbations in Europeans
• Bridging the splicing gap in human genetics with long-read RNA sequencing: finding the protein isoform drivers of disease
• Brain expression quantitative trait locus and network analyses reveal downstream effects and putative drivers for brain-related diseases
• Enhancing the Accuracy of Network Medicine Through Understanding the Impact of Sample Size in Gene Co-expression Networks
• Training-Free Out-of-Distribution Detection for Pathology Whole-Slide Images
• Global impact of unproductive splicing on human gene expression
• Genome-wide association analysis provides insights into the molecular etiology of dilated cardiomyopathy
• eQTL Catalogue 2023: New datasets, X chromosome QTLs, and improved detection and visualisation of transcript-level QTLs
• Exaggerated false positives by popular differential expression methods when analyzing human population samples
• Genetic Analysis of Lung Cancer and the Germline Impact on Somatic Mutation Burden
• The genetic basis for DNA methylation variation across tissues and development
• Expanding scope of genetic studies in the era of biobanks
• The UCSC Genome Browser database: 2021 update
• DeepBD: A Grounded Agentic Workflow for Variant Prioritization and Diagnosis of Genetic Birth Defects
• Flimma: a federated and privacy-preserving tool for differential gene expression analysis
• GeneZip: Region-Aware Compression for Long Context DNA Modeling
• Meta-analysis of genome-wide associations and polygenic risk prediction for atrial fibrillation in more than 180,000 cases
• OmicsLM: A Multimodal Large Language Model for Multi-Sample Omics Reasoning
• Genetic analysis of the human microglial transcriptome across brain regions, aging and disease pathologies
• Trans-ethnic GWAS meta-analysis of idiopathic spermatogenic failure highlights the immune-mediated nature of Sertoli cell-only syndrome
• Disruption of the cerebrospinal fluid–plasma protein balance in cognitive impairment and aging

Related

• The Genotype-Tissue Expression (GTEx) project
• Sources of gene expression variation in a globally diverse human cohort
• Diverse Patterns of Allele-Specific Expression in Healthy Human Tissues
• An Empirical Bayes Regression for Multi-tissue eQTL Data Analysis
• Prediction of causal genes at GWAS loci with pleiotropic gene regulatory effects using sets of correlated instrumental variables