scholarly journals PrediXcan: Trait Mapping Using Human Transcriptome Regulation

2015 ◽  
Author(s):  
Eric R Gamazon ◽  
Heather E Wheeler ◽  
Kaanan Shah ◽  
Sahar V Mozaffari ◽  
Keston Aquino-Michaels ◽  
...  
Keyword(s):  
Gene Expression ◽  
Molecular Mechanisms ◽  
Prediction Models ◽  
Association Studies ◽  
Regulatory Function ◽  
Genetic Profile ◽  
Genome Wide Association Studies ◽  
Reverse Causality ◽  
Reference Transcriptome ◽  
Regulated Gene Expression

Genome-wide association studies (GWAS) have identified thousands of variants robustly associated with complex traits. However, the biological mechanisms underlying these associations are, in general, not well understood. We propose a gene-based association method called PrediXcan that directly tests the molecular mechanisms through which genetic variation affects phenotype. The approach estimates the component of gene expression determined by an individual's genetic profile and correlates the “imputed” gene expression with the phenotype under investigation to identify genes involved in the etiology of the phenotype. The genetically regulated gene expression is estimated using whole-genome tissue-dependent prediction models trained with reference transcriptome datasets. PrediXcan enjoys the benefits of gene- based approaches such as reduced multiple testing burden, more comprehensive annotation of gene function compared to that derived from single variants, and a principled approach to the design of follow-up experiments while also integrating knowledge of regulatory function. Since no actual expression data are used in the analysis of GWAS data - only in silico expression - reverse causality problems are largely avoided. PrediXcan harnesses reference transcriptome data for disease mapping studies. Our results demonstrate that PrediXcan can detect known and novel genes associated with disease traits and provide insights into the mechanism of these associations.

scholarly journals Genomic dissection of 43 serum urate-associated loci provides multiple insights into molecular mechanisms of urate control

2019 ◽  
Author(s):  
James Boocock ◽  
Megan Leask ◽  
Yukinori Okada ◽  
Hirotaka Matsuo ◽  
Yusuke Kawamura ◽  
...  
Keyword(s):  
Gene Expression ◽  
Molecular Mechanisms ◽  
Association Studies ◽  
Organic Anion ◽  
Serum Urate ◽  
Regulatory Function ◽  
Eqtl Analysis ◽  
Genome Wide Association Studies ◽  
Genome Wide ◽  
Causal Genes

AbstractSerum urate is the end-product of purine metabolism. Elevated serum urate is causal of gout and a predictor of renal disease, cardiovascular disease and other metabolic conditions. Genome-wide association studies (GWAS) have reported dozens of loci associated with serum urate control, however there has been little progress in understanding the molecular basis of the associated loci. Here we employed trans-ancestral meta-analysis using data from European and East Asian populations to identify ten new loci for serum urate levels. Genome-wide colocalization with cis-expression quantitative trait loci (eQTL) identified a further five new loci. By cis- and trans-eQTL colocalization analysis we identified 24 and 20 genes respectively where the causal eQTL variant has a high likelihood that it is shared with the serum urate-associated locus. One new locus identified was SLC22A9 that encodes organic anion transporter 7 (OAT7). We demonstrate that OAT7 is a very weak urate-butyrate exchanger. Newly implicated genes identified in the eQTL analysis include those encoding proteins that make up the dystrophin complex, a scaffold for signaling proteins and transporters at the cell membrane; MLXIP that, with the previously identified MLXIPL, is a transcription factor that may regulate serum urate via the pentose-phosphate pathway; and MRPS7 and IDH2 that encode proteins necessary for mitochondrial function. Trans-ancestral functional fine-mapping identified six loci (RREB1, INHBC, HLF, UBE2Q2, SFMBT1, HNF4G) with colocalized eQTL that contained putative causal SNPs (posterior probability of causality > 0.8). This systematic analysis of serum urate GWAS loci has identified candidate causal genes at 19 loci and a network of previously unidentified genes likely involved in control of serum urate levels, further illuminating the molecular mechanisms of urate control.Author SummaryHigh serum urate is a prerequisite for gout and a risk factor for metabolic disease. Previous GWAS have identified numerous loci that are associated with serum urate control, however, only a small handful of these loci have known molecular consequences. The majority of loci are within the non-coding regions of the genome and therefore it is difficult to ascertain how these variants might influence serum urate levels without tangible links to gene expression and / or protein function. We have applied a novel bioinformatic pipeline where we combined population-specific GWAS data with gene expression and genome connectivity information to identify putative causal genes for serum urate associated loci. Overall, we identified 15 novel serum urate loci and show that these loci along with previously identified loci are linked to the expression of 44 genes. We show that some of the variants within these loci have strong predicted regulatory function which can be further tested in functional analyses. This study expands on previous GWAS by identifying further loci implicated in serum urate control and new causal mechanisms supported by gene expression changes.

scholarly journals Chronic adolescent exposure to cannabis in mice leads to long-term sex-biased changes in gene expression networks across brain regions

2021 ◽  
Author(s):  
Yanning Zuo ◽  
Attilio Iemolo ◽  
Patricia Montilla-Perez ◽  
Hai-Ri Li ◽  
Xia Yang ◽  
...  
Keyword(s):  
Gene Expression ◽  
Molecular Mechanisms ◽  
Association Studies ◽  
Brain Regions ◽  
Human Cognition ◽  
Genome Wide Association Studies ◽  
Cognitive Behaviors ◽  
Network Analyses ◽  
With Memory ◽  
Adolescent Exposure

Background: The molecular mechanisms underlying the long-lasting behavioral changes associated with adolescent cannabis use are poorly understood. To this end, we performed gene network analyses of multiple brain regions in adult mice exposed during the entire adolescence to Delta-9-tetrahydrocannabinol (THC), the major psychoactive component of cannabis. Methods: Two weeks after the last exposure to THC (10 mg/kg) or vehicle, we measured cognitive behaviors and profiled the transcriptomes of 5 brain regions from 12 female and 12 male mice. We performed differential gene expression analysis and constructed gene coexpression networks (modules) to identify THC-induced transcriptional alterations at the level of individual genes, gene networks, and biological pathways. We integrated the THC-correlated modules with human traits from genome-wide association studies to identify potential regulators of disease-associated networks. Results: THC impaired cognitive behaviors of mice, with memory being more impacted in females than males, which coincided with larger transcriptional changes in the female brain. Modules involved in endocannabinoid signaling and inflammation were correlated with memory deficits in the female dorsal medial striatum and ventral tegmental area, respectively. Converging pathways related to dopamine signaling and addiction were altered in the female amygdala and male nucleus accumbens. Moreover, the connectivity map of THC-correlated modules uncovered intra- and inter-region molecular circuitries influenced by THC. Lastly, modules altered by THC were enriched in genes relevant for human cognition and neuropsychiatric disorders. Conclusions: These findings provide novel insights concerning the genes, pathways and brain regions underlying persistent behavioral deficits induced by adolescent exposure to THC in a sex-specific manner.

scholarly journals A novel quantile regression approach for eQTL discovery

2016 ◽  
Author(s):  
Xiaoyu Song ◽  
Gen Li ◽  
Iuliana Ionita-Laza ◽  
Ying Wei
Keyword(s):  
Gene Expression ◽  
Genetic Variation ◽  
Linear Regression ◽  
Genetic Variants ◽  
Molecular Mechanisms ◽  
Association Studies ◽  
Expression Level ◽  
Special Focus ◽  
Genome Wide Association Studies ◽  
Genome Wide

AbstractOver the past decade, there has been a remarkable improvement in our understanding of the role of genetic variation in complex human diseases, especially via genome-wide association studies. However, the underlying molecular mechanisms are still poorly characterized, impending the development of therapeutic interventions. Identifying genetic variants that influence the expression level of a gene, i.e. expression quantitative trait loci (eQTLs), can help us understand how genetic variants influence traits at the molecular level. While most eQTL studies focus on identifying mean effects on gene expression using linear regression, evidence suggests that genetic variation can impact the entire distribution of the expression level. Indeed, several studies have already investigated higher order associations with a special focus on detecting heteroskedasticity. In this paper, we develop a Quantile Rank-score Based Test (QRBT) to identify eQTLs that are associated with the conditional quantile functions of gene expression. We have applied the proposed QRBT to the Genotype-Tissue Expression project, an international tissue bank for studying the relationship between genetic variation and gene expression in human tissues, and found that the proposed QRBT complements the existing methods, and identifies new eQTLs with heterogeneous effects genome-wideacross different quantile levels. Notably, we show that the eQTLs identified by QRBT but missed by linear regression are more likely to be tissue specific, and also associated with greater enrichment in genome-wide significant SNPs from the GWAS catalog. An R package implementing QRBT is available on our website.

scholarly journals The Transcription Factor MAFF Regulates an Atherosclerosis Relevant Network Connecting Inflammation and Cholesterol Metabolism

Circulation ◽  
2021 ◽  
Author(s):  
Moritz von Scheidt ◽  
Yuqi Zhao ◽  
Thomas Q. de Aguiar Vallim ◽  
Nam Che ◽  
Michael Wierer ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Molecular Mechanisms ◽  
Prediction Models ◽  
Cholesterol Metabolism ◽  
Association Studies ◽  
Experimental Studies ◽  
Genome Wide Association Studies ◽  
Inflammatory Conditions

Background: Coronary artery disease (CAD) is a multifactorial condition with both genetic and exogenous causes. The contribution of tissue specific functional networks to the development of atherosclerosis remains largely unclear. The aim of this study was to identify and characterise central regulators and networks leading to atherosclerosis. Methods: Based on several hundred genes known to affect atherosclerosis risk in mouse (as demonstrated in knock-out models) and human (as shown by genome-wide association studies (GWAS)) liver gene regulatory networks were modeled. The hierarchical order and regulatory directions of genes within the network were based on Bayesian prediction models as well as experimental studies including chromatin immunoprecipitation DNA-Sequencing (ChIP-Seq), ChIP mass spectrometry (ChIP-MS), overexpression, siRNA knockdown in mouse and human liver cells, and knockout mouse experiments. Bioinformatics and correlation analyses were used to clarify associations between central genes and CAD phenotypes in both human and mouse. Results: The transcription factor MAFF interacted as a key driver of a liver network with three human genes at CAD GWAS loci and eleven atherosclerotic murine genes. Most importantly, expression levels of the low-density lipoprotein receptor ( LDLR ) gene correlated with MAFF in 600 CAD patients undergoing bypass surgery (STARNET) and a hybrid mouse diversity panel involving 105 different inbred mouse strains. Molecular mechanisms of MAFF were tested under non-inflammatory conditions showing a positive correlation between MAFF and LDLR in vitro and in vivo . Interestingly, after LPS stimulation (inflammatory conditions) an inverse correlation between MAFF and LDLR in vitro and in vivo was observed. ChIP-MS revealed that the human CAD GWAS candidate BACH1 assists MAFF in the presence of LPS stimulation with respective heterodimers binding at the MAF recognition element (MARE) of the LDLR promoter to transcriptionally downregulate LDLR expression. Conclusions: The transcription factor MAFF was identified as a novel central regulator of an atherosclerosis/CAD relevant liver network. MAFF triggered context specific expression of LDLR and other genes known to affect CAD risk. Our results suggest that MAFF is a missing link between inflammation, lipid and lipoprotein metabolism and a possible treatment target.

scholarly journals The Colon Transcriptome Explorer (CoTrEx) 2.0: a Reference Web-Based Resource for Exploring Population-Based Normal Colon Gene Expression

2021 ◽  
Author(s):  
Virginia Díez-Obrero ◽  
Ferran Moratalla-Navarro ◽  
Christopher Dampier ◽  
Matthew Devall ◽  
Robert Carreras-Torres ◽  
...  
Keyword(s):  
Gene Expression ◽  
Prediction Models ◽  
Expression Profiles ◽  
Association Studies ◽  
Genome Wide Association Studies ◽  
Normal Colon ◽  
Colon Tissue ◽  
Web Based ◽  
Normal Colon Tissue ◽  
High Interest

Gene expression data is key for the functional annotation of single nucleotide polymorphisms (SNPs) identified in genome-wide association studies (GWAS). Expression and splicing quantitative trait loci (e/sQTLs) in normal colon tissue, such as those from the University of Barcelona and University of Virginia RNA sequencing project (BarcUVa-Seq) and the Genotype-Tissue Expression project (GTEx), are required to gain biological insight of colon-related diseases risk loci. Moreover, transcriptome-wide association studies (TWAS) rely on reference gene expression imputation panels in the tissue of interest to nominate susceptibility genes. Also, it is of high interest to study the relationships between genes in a network framework. For facilitating these analyses, we have updated and expanded the scope of the Colon Transcriptome Explorer (CoTrEx) to the version 2.0. This web-based resource provides exhaustive visualization and analysis of transcriptome-wide gene expression profiles of normal colon tissue from BarcUVa-Seq and GTEx. In addition to the integration of new datasets, CoTrEx 2.0 provides additional e/sQTLs sets, as well as gene expression prediction models and regulatory and co-expression networks. It is freely available at https://barcuvaseq.org/cotrex/. Overall, it is of high interest for researchers aiming to investigate the genetic susceptibility to colon-related complex traits and diseases.

scholarly journals Autosomal sex-biased genetic regulation of the stress response

2020 ◽  
Author(s):  
Sarah R. Moore ◽  
Thorhildur Halldorsdottir ◽  
Jade Martins ◽  
Susanne Lucae ◽  
Bertram Müller-Myhsok ◽  
...  
Keyword(s):  
Gene Expression ◽  
Sex Differences ◽  
Psychiatric Disorders ◽  
Association Studies ◽  
Genetic Regulation ◽  
Transcriptional Response ◽  
Genetic Profile ◽  
Genome Wide Association Studies ◽  
Stress Hormone ◽  
Males And Females

ABSTRACTSubstantial sex differences have been reported in the physiological response to stress at multiple levels, including the release of the stress hormone, cortisol. How these differences relate to differential risks for stress-related psychiatric disorders is still poorly understood. We have previously identified genomic variants in males regulating the initial transcriptional response to cortisol via glucocorticoid receptor (GR) activation, and these variants are associated with risk for major depressive disorder (MDD) and other psychiatric disorders. Here, we extend these investigations to a sample of males and females in order to examine sex-biased genetic regulation of the transcriptional response to the stress hormone.Gene expression levels in peripheral blood were obtained before and after GR-stimulation with the selective GR agonist dexamethasone to identify differential expression following GR-activation (GR-DE) in 93 women and 196 men. We first explored sex differences in the transcriptional GR-response followed by the identification of sex-biased expression quantitative trait loci (eQTLs) by associating gene expression and genotype data stratified by sex.While GR-response transcripts mostly overlapped between males and females, GR-response eQTLs showed strong sex-bias. A total of 804 significant GR-response cis-eQTL bins were found in the joint sample, 648 in females only, and 705 in males only. However, only 46 sex-biased GR-eQTL transcripts (etranscripts) overlapped between the sexes. The sets of associated sex-biased GR eQTL SNPs (eSNPs) were located in different functional genomic elements. Male and female sex-biased etranscripts were enriched within postmortem brain transcriptional profiles associated with MDD specifically in males and females in the cingulate cortex but not other brain regions. Female-biased GR-eSNPs were enriched among SNPs linked to MDD in genome wide association studies (GWAS). Finally, transcriptional sensitive genetic profile scores indexing sex-biased larger transcriptional changes to GR-stimulation were predictive of depression status and depressive symptoms in a sex-concordant manner in a child and adolescent cohort (n = 584).Taken together, while the GR-DE effects were similar between females and males, the genetic moderation of these effects was highly sex-biased and associated with depression-related molecular profiles and symptoms in a similarly sex-biased manner. These results suggest potential of GR-response eQTLs as sex-biased biomarkers of risk for stress-related psychiatric disorders.

scholarly journals TCF19 Impacts a Network of Inflammatory and DNA Damage Response Genes in the Pancreatic β-Cell

Metabolites ◽  
2021 ◽  
Vol 11 (8) ◽  
pp. 513
Author(s):  
Grace H. Yang ◽  
Danielle A. Fontaine ◽  
Sukanya Lodh ◽  
Joseph T. Blumer ◽  
Avtar Roopra ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Damage ◽  
Dna Damage Response ◽  
Association Studies ◽  
Cell Cycle Gene ◽  
Genome Wide Association Studies ◽  
Β Cell ◽  
Nucleotide Incorporation ◽  
Damage Response ◽  
The Impact

Transcription factor 19 (TCF19) is a gene associated with type 1 diabetes (T1DM) and type 2 diabetes (T2DM) in genome-wide association studies. Prior studies have demonstrated that Tcf19 knockdown impairs β-cell proliferation and increases apoptosis. However, little is known about its role in diabetes pathogenesis or the effects of TCF19 gain-of-function. The aim of this study was to examine the impact of TCF19 overexpression in INS-1 β-cells and human islets on proliferation and gene expression. With TCF19 overexpression, there was an increase in nucleotide incorporation without any change in cell cycle gene expression, alluding to an alternate process of nucleotide incorporation. Analysis of RNA-seq of TCF19 overexpressing cells revealed increased expression of several DNA damage response (DDR) genes, as well as a tightly linked set of genes involved in viral responses, immune system processes, and inflammation. This connectivity between DNA damage and inflammatory gene expression has not been well studied in the β-cell and suggests a novel role for TCF19 in regulating these pathways. Future studies determining how TCF19 may modulate these pathways can provide potential targets for improving β-cell survival.

scholarly journals Molecular Mechanisms of ZC3H12C/Reg-3 Biological Activity and Its Involvement in Psoriasis Pathology

2021 ◽  
Vol 22 (14) ◽  
pp. 7311
Author(s):  
Mateusz Wawro ◽  
Jakub Kochan ◽  
Weronika Sowinska ◽  
Aleksandra Solecka ◽  
Karolina Wawro ◽  
...  
Keyword(s):  
Family Member ◽  
Cellular Localization ◽  
Molecular Mechanisms ◽  
Inflammatory Diseases ◽  
Association Studies ◽  
Psoriasis Patient ◽  
Genome Wide Association Studies ◽  
Mrna Levels ◽  
Transcript Levels

The members of the ZC3H12/MCPIP/Regnase family of RNases have emerged as important regulators of inflammation. In contrast to Regnase-1, -2 and -4, a thorough characterization of Regnase-3 (Reg-3) has not yet been explored. Here we demonstrate that Reg-3 differs from other family members in terms of NYN/PIN domain features, cellular localization pattern and substrate specificity. Together with Reg-1, the most comprehensively characterized family member, Reg-3 shared IL-6, IER-3 and Reg-1 mRNAs, but not IL-1β mRNA, as substrates. In addition, Reg-3 was found to be the only family member which regulates transcript levels of TNF, a cytokine implicated in chronic inflammatory diseases including psoriasis. Previous meta-analysis of genome-wide association studies revealed Reg-3 to be among new psoriasis susceptibility loci. Here we demonstrate that Reg-3 transcript levels are increased in psoriasis patient skin tissue and in an experimental model of psoriasis, supporting the immunomodulatory role of Reg-3 in psoriasis, possibly through degradation of mRNA for TNF and other factors such as Reg-1. On the other hand, Reg-1 was found to destabilize Reg-3 transcripts, suggesting reciprocal regulation between Reg-3 and Reg-1 in the skin. We found that either Reg-1 or Reg-3 were expressed in human keratinocytes in vitro. However, in contrast to robustly upregulated Reg-1 mRNA levels, Reg-3 expression was not affected in the epidermis of psoriasis patients. Taken together, these data suggest that epidermal levels of Reg-3 are negatively regulated by Reg-1 in psoriasis, and that Reg-1 and Reg-3 are both involved in psoriasis pathophysiology through controlling, at least in part different transcripts.

scholarly journals Polygenic Risk Score of Longevity Predicts Longer Survival Across an Age Continuum

2020 ◽  
Author(s):  
Niccolo’ Tesi ◽  
Sven J van der Lee ◽  
Marc Hulsman ◽  
Iris E Jansen ◽  
Najada Stringa ◽  
...  
Keyword(s):  
Older Adults ◽  
Cellular Response ◽  
Molecular Mechanisms ◽  
Association Studies ◽  
Risk Scores ◽  
Human Longevity ◽  
Polygenic Risk Score ◽  
Genome Wide Association Studies ◽  
Polygenic Risk ◽  
Age Related

Abstract Studying the genome of centenarians may give insights into the molecular mechanisms underlying extreme human longevity and the escape of age-related diseases. Here, we set out to construct polygenic risk scores (PRSs) for longevity and to investigate the functions of longevity-associated variants. Using a cohort of centenarians with maintained cognitive health (N = 343), a population-matched cohort of older adults from 5 cohorts (N = 2905), and summary statistics data from genome-wide association studies on parental longevity, we constructed a PRS including 330 variants that significantly discriminated between centenarians and older adults. This PRS was also associated with longer survival in an independent sample of younger individuals (p = .02), leading up to a 4-year difference in survival based on common genetic factors only. We show that this PRS was, in part, able to compensate for the deleterious effect of the APOE-ε4 allele. Using an integrative framework, we annotated the 330 variants included in this PRS by the genes they associate with. We find that they are enriched with genes associated with cellular differentiation, developmental processes, and cellular response to stress. Together, our results indicate that an extended human life span is, in part, the result of a constellation of variants each exerting small advantageous effects on aging-related biological mechanisms that maintain overall health and decrease the risk of age-related diseases.

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