scholarly journals The GTEx Consortium atlas of genetic regulatory effects across human tissues

2019 ◽  
Author(s):  
François Aguet ◽  
Alvaro N Barbeira ◽  
Rodrigo Bonazzola ◽  
Andrew Brown ◽  
Stephane E Castel ◽  
...  
Keyword(s):  
Complex Traits ◽  
Molecular Mechanisms ◽  
Tissue Expression ◽  
Genetic Effects ◽  
Regulatory Mechanisms ◽  
Human Tissues ◽  
Genetic Associations ◽  
Key Factor ◽  
Regulatory Effects ◽  
Almost All

AbstractThe 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 v8 data, based on 17,382 RNA-sequencing samples from 54 tissues of 948 post-mortem donors. We comprehensively characterize genetic associations for gene expression and splicing incisandtrans, 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.

scholarly journals The GTEx Consortium atlas of genetic regulatory effects across human tissues

Science ◽  
2020 ◽  
Vol 369 (6509) ◽  
pp. 1318-1330 ◽  
Author(s):  
Keyword(s):  
Complex Traits ◽  
Molecular Mechanisms ◽  
Tissue Expression ◽  
Genetic Effects ◽  
Regulatory Mechanisms ◽  
Human Tissues ◽  
Genetic Associations ◽  
Key Factor ◽  
Regulatory Effects ◽  
Almost All

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.

scholarly journals A comprehensive catalogue of regulatory variants in the cattle transcriptome

2020 ◽  
Author(s):  
Shuli Liu ◽  
Yahui Gao ◽  
Oriol Canela-Xandri ◽  
Sheng Wang ◽  
Ying Yu ◽  
...  
Keyword(s):  
Gene Expression ◽  
Molecular Mechanisms ◽  
Agronomic Traits ◽  
Economic Value ◽  
Tissue Expression ◽  
Genetic Associations ◽  
Rna Sequences ◽  
Regulatory Variants ◽  
Expression Atlas ◽  
Regulatory Effects

AbstractCharacterization of genetic regulatory variants acting on the transcriptome of livestock is essential for interpreting the molecular mechanisms underlying traits of economic value and for increasing the rate of genetic gain through artificial selection. Here, we build a cattle Genotype-Tissue Expression atlas (cGTEx, http://cgtex.roslin.ed.ac.uk/) for the research community based on 11,642 RNA sequences from publicly available datasets representing over 100 cattle tissues. We describe the landscape of the transcriptome across tissues and report hundreds of thousands of cis- and trans- genetic associations with gene expression and alternative splicing for 24 major tissues. We evaluate the specificity/similarity of these genetic regulatory effects across tissues, and functionally annotate them using a combination of multi-omics data. Finally, we link gene expression in different tissues to 43 economically important traits using a large transcriptome-wide association study (TWAS) to provide novel biological insights into the molecular regulatory mechanisms underpinning agronomic traits in cattle.

scholarly journals The fog of genetics: Known unknowns and unknown unknowns in the genetics of complex traits and diseases

2019 ◽  
Author(s):  
João Pedro de Magalhães ◽  
Jingwei Wang
Keyword(s):  
Genetic Variability ◽  
Genetic Variants ◽  
Genetic Information ◽  
Complex Traits ◽  
Drug Targets ◽  
Molecular Mechanisms ◽  
Genetic Associations ◽  
Missing Heritability ◽  
Genome Space ◽  
Known Unknowns

AbstractAssociating genetic variants with phenotypes is not only important to understand the underlying biology but also to identify potential drug targets for treating diseases. It is widely accepted that for most complex traits many associations remain to be discovered, the so-called “missing heritability.” Yet missing heritability can be estimated, it is a known unknown, and we argue is only a fraction of the unknowns in genetics. The majority of possible genetic variants in the genome space are either too rare to be detected or even entirely absent from populations, and therefore do not contribute to estimates of phenotypic or genetic variability. We call these unknown unknowns in genetics the “fog of genetics.” Using data from the 1000 Genomes Project we then show that larger genes with greater genetic diversity are more likely to be associated with human traits, demonstrating that genetic associations are biased towards particular types of genes and that the genetic information we are lacking about traits and diseases is potentially immense. Our results and model have multiple implications for how genetic variability is perceived to influence complex traits, provide insights on molecular mechanisms of disease and for drug discovery efforts based on genetic information.

scholarly journals Unfulfilled Inflammatory Resolution: A Key Factor in the Pathogenesis of Psoriasis

2020 ◽  
Author(s):  
Zohreh Jadali
Keyword(s):  
Inflammatory Response ◽  
Chronic Inflammation ◽  
Molecular Mechanisms ◽  
Inflammatory Responses ◽  
Inflammatory Diseases ◽  
Relevant Literature ◽  
Regulatory Mechanisms ◽  
Immune Mediated ◽  
Key Factor ◽  
Inflammation Resolution

Recent literature has highlighted the importance of chronic inflammation in psoriasis pathogenesis. Non-resolving inflammation can trigger progressive tissue damage and inflammatory mediator release which in turn perpetuate the inflammatory cycle. Under normal conditions, inflammatory responses are tightly controlled through several mechanisms that restore normal tissue function and structure. Defects in regulatory mechanisms of the inflammatory response can result in persistent unresolved inflammation and further increases of inflammation. Therefore, this review focuses on defects in regulatory mechanisms of inflammatory responses that lead to uncontrolled chronic inflammation in psoriasis. Databases such as Pubmed Embase, ISI, and Iranian databases including Iranmedex, and SID were researched to identify relevant literature. The results of this review indicate that dysregulation of the inflammatory response may be a likely cause of various immune-mediated inflammatory disorders such as psoriasis. Based on current findings, advances in understanding the cellular and molecular mechanisms involved in inflammation resolution are not only improving our knowledge of the pathogenesis of chronic inflammatory diseases but also supporting the development of new therapeutic strategies.

scholarly journals Rare variants regulate expression of nearby individual genes in multiple tissues

PLoS Genetics ◽  
2021 ◽  
Vol 17 (6) ◽  
pp. e1009596
Author(s):  
Jiajin Li ◽  
Nahyun Kong ◽  
Buhm Han ◽  
Jae Hoon Sul
Keyword(s):  
Gene Expression ◽  
Complex Traits ◽  
Statistical Power ◽  
Rare Variants ◽  
Small Sample Size ◽  
Tissue Expression ◽  
Small Sample ◽  
Ratio Test ◽  
Common Variants ◽  
Regulatory Effects

The rapid decrease in sequencing cost has enabled genetic studies to discover rare variants associated with complex diseases and traits. Once this association is identified, the next step is to understand the genetic mechanism of rare variants on how the variants influence diseases. Similar to the hypothesis of common variants, rare variants may affect diseases by regulating gene expression, and recently, several studies have identified the effects of rare variants on gene expression using heritability and expression outlier analyses. However, identifying individual genes whose expression is regulated by rare variants has been challenging due to the relatively small sample size of expression quantitative trait loci studies and statistical approaches not optimized to detect the effects of rare variants. In this study, we analyze whole-genome sequencing and RNA-seq data of 681 European individuals collected for the Genotype-Tissue Expression (GTEx) project (v8) to identify individual genes in 49 human tissues whose expression is regulated by rare variants. To improve statistical power, we develop an approach based on a likelihood ratio test that combines effects of multiple rare variants in a nonlinear manner and has higher power than previous approaches. Using GTEx data, we identify many genes regulated by rare variants, and some of them are only regulated by rare variants and not by common variants. We also find that genes regulated by rare variants are enriched for expression outliers and disease-causing genes. These results suggest the regulatory effects of rare variants, which would be important in interpreting associations of rare variants with complex traits.

scholarly journals Multi-tissue polygenic models for transcriptome-wide association studies

2017 ◽  
Author(s):  
Yongjin Park ◽  
Abhishek Sarkar ◽  
Kunal Bhutani ◽  
Manolis Kellis
Keyword(s):  
Gene Expression ◽  
Predictive Models ◽  
Quantitative Trait ◽  
Tissue Specificity ◽  
Association Studies ◽  
Cell Types ◽  
Tissue Expression ◽  
Multivariate Model ◽  
Human Tissues ◽  
Regulatory Effects

I.ABSTRACTTranscriptome-wide association studies (TWAS) have proven to be a powerful tool to identify genes associated with human diseases by aggregating cis-regulatory effects on gene expression. However, TWAS relies on building predictive models of gene expression, which are sensitive to the sample size and tissue on which they are trained. The Gene Tissue Expression Project has produced reference transcriptomes across 53 human tissues and cell types; however, the data is highly sparse, making it difficult to build polygenic models in relevant tissues for TWAS. Here, we propose fQTL, a multi-tissue, multivariate model for mapping expression quantitative trait loci and predicting gene expression. Our model decomposes eQTL effects into SNP-specific and tissue-specific components, pooling information across relevant tissues to effectively boost sample sizes. In simulation, we demonstrate that our multi-tissue approach outperforms single-tissue approaches in identifying causal eQTLs and tissues of action. Using our method, we fit polygenic models for 13,461 genes, characterized the tissue-specificity of the learned cis-eQTLs, and performed TWAS for Alzheimer’s disease and schizophrenia, identifying 107 and 382 associated genes, respectively.

scholarly journals Genetic regulation of DNA methylation across tissues reveals thousands of molecular links to complex traits

2021 ◽  
Author(s):  
Meritxell Oliva ◽  
Kathryn Demanelis ◽  
Farzana Jasmine ◽  
Yihao Lu ◽  
Habibul Hahsan ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Complex Traits ◽  
Tissue Specificity ◽  
Genetic Regulation ◽  
Tissue Expression ◽  
Regulatory Mechanisms ◽  
Rna Seq ◽  
Functional Elements ◽  
Phenotype Data ◽  
Molecular Regulatory Mechanisms

Abstract Epigenetic modifications of chromosomes, including DNA methylation (DNAm), play a fundamental role in gene regulation in humans. We generated DNAm data for 987 samples from the Genotype-Tissue Expression (GTEx) project, representing 9 tissue types and 424 subjects. We integrated GTEx RNA-seq data to examine methylome-transcriptome associations, their tissue specificity, and their overlap with regulatory regions. We mapped DNAm quantitative trait loci in cis (mQTLs), contrasted mQTLs with expression QTLs (eQTLs) with respect to functional elements, and assessed their relative contributions to complex traits. We identified thousands of mQTL links to traits in locations lacking a relevant eQTL. By integrating genetic, diverse -omics and phenotype data, we contribute to the understanding of molecular regulatory mechanisms in human tissues and their association with complex traits.

scholarly journals Cell type–specific genetic regulation of gene expression across human tissues

Science ◽  
2020 ◽  
Vol 369 (6509) ◽  
pp. eaaz8528 ◽  
Author(s):  
Sarah Kim-Hellmuth ◽  
François Aguet ◽  
Meritxell Oliva ◽  
Manuel Muñoz-Aguirre ◽  
Silva Kasela ◽  
...  
Keyword(s):  
Complex Traits ◽  
Functional Characterization ◽  
Genetic Regulation ◽  
Regulation Of Gene Expression ◽  
Human Tissues ◽  
Genetic Associations ◽  
Cell Type ◽  
Wide Range ◽  
Type Interaction ◽  
Bulk Tissue

The Genotype-Tissue Expression (GTEx) project has identified expression and splicing quantitative trait loci in cis (QTLs) for the majority of genes across a wide range of human tissues. However, the functional characterization of these QTLs has been limited by the heterogeneous cellular composition of GTEx tissue samples. We mapped interactions between computational estimates of cell type abundance and genotype to identify cell type–interaction QTLs for seven cell types and show that cell type–interaction expression QTLs (eQTLs) provide finer resolution to tissue specificity than bulk tissue cis-eQTLs. Analyses of genetic associations with 87 complex traits show a contribution from cell type–interaction QTLs and enables the discovery of hundreds of previously unidentified colocalized loci that are masked in bulk tissue.

scholarly journals Distant regulatory effects of genetic variation in multiple human tissues

2016 ◽  
Author(s):  
Brian Jo ◽  
Yuan He ◽  
Benjamin J. Strober ◽  
Princy Parsana ◽  
François Aguet ◽  
...  
Keyword(s):  
Genetic Variation ◽  
Complex Traits ◽  
Disease Risk ◽  
Tissue Expression ◽  
Human Tissues ◽  
Sequencing Data ◽  
Cellular Mechanisms ◽  
Regulation Of Expression ◽  
Tissue Specific ◽  
Project Data

AbstractUnderstanding the genetics of gene regulation provides information on the cellular mechanisms through which genetic variation influences complex traits. Expression quantitative trait loci, or eQTLs, are enriched for polymorphisms that have been found to be associated with disease risk. While most analyses of human data has focused on regulation of expression by nearby variants (cis-eQTLs), distal or trans-eQTLs may have broader effects on the transcriptome and important phenotypic consequences, necessitating a comprehensive study of the effects of genetic variants on distal gene transcription levels. In this work, we identify trans-eQTLs in the Genotype Tissue Expression (GTEx) project data1, consisting of 449 individuals with RNA-sequencing data across 44 tissue types. We find 81 genes with a trans-eQTL in at least one tissue, and we demonstrate that trans-eQTLs are more likely than cis-eQTLs to have effects specific to a single tissue. We evaluate the genomic and functional properties of trans-eQTL variants, identifying strong enrichment in enhancer elements and Piwi-interacting RNA clusters. Finally, we describe three tissue-specific regulatory loci underlying relevant disease associations: 9q22 in thyroid that has a role in thyroid cancer, 5q31 in skeletal muscle, and a previously reported master regulator near KLF14 in adipose. These analyses provide a comprehensive characterization of trans-eQTLs across human tissues, which contribute to an improved understanding of the tissue-specific cellular mechanisms of regulatory genetic variation.

scholarly journals Genetic effects on gene expression across human tissues

Nature ◽  
2017 ◽  
Vol 550 (7675) ◽  
pp. 204-213 ◽  
Author(s):  
Keyword(s):  
Gene Expression ◽  
Genetic Basis ◽  
Tissue Expression ◽  
Genetic Effects ◽  
Human Tissues ◽  
Cellular Mechanisms ◽  
Genetic Traits ◽  
Expression Levels ◽  
Gene Expression Levels

Abstract Characterization of the molecular function of the human genome and its variation across individuals is essential for identifying the cellular mechanisms that underlie human genetic traits and diseases. The Genotype-Tissue Expression (GTEx) project aims to characterize variation in gene expression levels across individuals and diverse tissues of the human body, many of which are not easily accessible. Here we describe genetic effects on gene expression levels across 44 human tissues. We find that local genetic variation affects gene expression levels for the majority of genes, and we further identify inter-chromosomal genetic effects for 93 genes and 112 loci. On the basis of the identified genetic effects, we characterize patterns of tissue specificity, compare local and distal effects, and evaluate the functional properties of the genetic effects. We also demonstrate that multi-tissue, multi-individual data can be used to identify genes and pathways affected by human disease-associated variation, enabling a mechanistic interpretation of gene regulation and the genetic basis of disease.

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