scholarly journals Co-localization of Conditional eQTL and GWAS Signatures in Schizophrenia

2017 ◽  
Author(s):  
Amanda Dobbyn ◽  
Laura M. Huckins ◽  
James Boocock ◽  
Laura G. Sloofman ◽  
Benjamin S. Glicksberg ◽  
...  
Keyword(s):  
Gene Expression ◽  
Genome Wide Association Study ◽  
Regulation Of Gene Expression ◽  
Developmental Time ◽  
Tissue Cell ◽  
Genome Wide ◽  
Causal Genes ◽  
Specific Regulation ◽  
Context Specific ◽  
Eqtl Data

ABSTRACTCausal genes and variants within genome-wide association study (GWAS) loci can be identified by integrating GWAS statistics with expression quantitative trait loci (eQTL) and determining which SNPs underlie both GWAS and eQTL signals. Most analyses, however, consider only the marginal eQTL signal, rather than dissecting this signal into multiple independent eQTL for each gene. Here we show that analyzing conditional eQTL signatures, which could be important under specific cellular or temporal contexts, leads to improved fine mapping of GWAS associations. Using genotypes and gene expression levels from post-mortem human brain samples (N=467) reported by the CommonMind Consortium (CMC), we find that conditional eQTL are widespread; 63% of genes with primary eQTL also have conditional eQTL. In addition, genomic features associated with conditional eQTL are consistent with context specific (i.e. tissue, cell type, or developmental time point specific) regulation of gene expression. Integrating the Psychiatric Genomics Consortium schizophrenia (SCZ) GWAS and CMC conditional eQTL data reveals forty loci with strong evidence for co-localization (posterior probability >0.8), including six loci with co-localization of conditional eQTL. Our co-localization analyses support previously reported genes and identify novel genes for schizophrenia risk, and provide specific hypotheses for their functional follow-up.

scholarly journals Genome-wide chromatin binding of transcriptional corepressor Topless-related 1 in Arabidopsis

2020 ◽  
Author(s):  
Thomas Griebel ◽  
Dmitry Lapin ◽  
Barbara Kracher ◽  
Lorenzo Concia ◽  
Moussa Benhamed ◽  
...  
Keyword(s):  
Gene Expression ◽  
Regulation Of Gene Expression ◽  
Plant Responses ◽  
Dna Binding Domains ◽  
Binding Domains ◽  
Genome Wide ◽  
Gene Expression Control ◽  
Specific Regulation ◽  
Transcriptional Corepressors ◽  
And Function

AbstractTimely and specific regulation of gene expression is critical for plant responses to environmental and developmental cues. Transcriptional coregulators have emerged as important factors in gene expression control, although they lack DNA-binding domains and the mechanisms by which they are recruited to and function at the chromatin are poorly understood. Plant Topless-related 1 (TPR1), belonging to a family of transcriptional corepressors found across eukaryotes, contributes to immunity signaling in Arabidopsis thaliana and wild tobacco. We performed chromatin immunoprecipitation and sequencing (ChIP-seq) on an Arabidopsis TPR1-GFP expressing transgenic line to characterize genome-wide TPR1-chromatin associations. The analysis revealed ∼1400 genes bound by TPR1, with the majority of binding sites located at gene upstream regions. Among the TPR1 bound genes, we find not only regulators of immunity but also genes controlling growth and development. To support further analysis of TPR1-chromatin complexes and other transcriptional corepressors in plants, we provide two ways to access the processed ChIP-seq data and enable their broader use by the research community.

scholarly journals Ctcf Haploinsufficiency Mediates Intron Retention in A Tissue-specific Manner

2019 ◽  
Author(s):  
Adel B Alharbi ◽  
Ulf Schmitz ◽  
Amy D Marshall ◽  
Darya Vanichkina ◽  
Rajini Nagarajah ◽  
...  
Keyword(s):  
Gene Expression ◽  
Intron Retention ◽  
Regulation Of Gene Expression ◽  
Splicing Factors ◽  
Tissue Specific ◽  
Genome Wide ◽  
Liver And Kidney ◽  
Specific Regulation ◽  
Dose Dependent

AbstractCTCF is a master regulator of gene transcription and chromatin organization with occupancy at thousands of DNA target sites. CTCF is essential for embryonic development and somatic cell viability and has been characterized as a haploinsufficient tumor suppressor. Increasing evidence demonstrates CTCF as a key player in several alternative splicing (AS) regulatory mechanisms, including transcription elongation, regulation of splicing factors, and epigenetic regulation. However, the genome-wide impact of Ctcf dosage on AS has not been investigated. We examined the effect of Ctcf haploinsufficiency on gene expression and AS in multiple tissues from Ctcf hemizygous (Ctcf+/-) mice. Distinct tissue-specific differences in gene expression and AS were observed in Ctcf+/- mice compared to wildtype mice. We observed a surprisingly large number of increased intron retention (IR) events in Ctcf+/- liver and kidney, specifically in genes associated with cytoskeletal organization, splicing and metabolism. This study provides further evidence for Ctcf dose-dependent and tissue-specific regulation of gene expression and AS. Our data provide a strong foundation for elucidating the mechanistic role of CTCF in AS regulation and its biological consequences.

scholarly journals Epigenetic Element-Based Transcriptome-Wide Association Study Identifies Novel Genes for Bipolar Disorder

2021 ◽  
Author(s):  
Shi Yao ◽  
Hao Wu ◽  
Tong-Tong Liu ◽  
Jia-Hao Wang ◽  
Jing-Miao Ding ◽  
...  
Keyword(s):  
Gene Expression ◽  
Bipolar Disorder ◽  
Association Study ◽  
Candidate Genes ◽  
Genome Wide Association Study ◽  
Disease Risk ◽  
Association Studies ◽  
Cerebellar Hemisphere ◽  
Genome Wide ◽  
Causal Genes

Abstract Since the bipolar disorder (BD) signals identified by genome-wide association study (GWAS) often reside in the non-coding regions, understanding the biological relevance of these genetic loci has proven to be complicated. Transcriptome-wide association studies (TWAS) providing a powerful approach to identify novel disease risk genes and uncover possible causal genes at loci identified previously by GWAS. However, these methods did not consider the importance of epigenetic regulation in gene expression. Here, we developed a novel epigenetic element-based transcriptome-wide association study (ETWAS) that tested the effects of genetic variants on gene expression levels with the epigenetic features as prior and further mediated the association between predicted expression and BD. We conducted an ETWAS consisting of 20 352 cases and 31 358 controls and identified 44 transcriptome-wide significant hits. We found 14 conditionally independent genes, and 10 genes that did not previously implicate with BD were regarded as novel candidate genes, such as ASB16 in the cerebellar hemisphere (P = 9.29 × 10–8). We demonstrated that several genome-wide significant signals from the BD GWAS driven by genetically regulated expression, and NEK4 explained 90.1% of the GWAS signal. Additionally, ETWAS identified genes could explain heritability beyond that explained by GWAS-associated SNPs (P = 5.60 × 10–66). By querying the SNPs in the final models of identified genes in phenome databases, we identified several phenotypes previously associated with BD, such as schizophrenia and depression. In conclusion, ETWAS is a powerful method, and we identified several novel candidate genes associated with BD.

scholarly journals Epigenetic Element-Based Transcriptome-Wide Association Study Identifies Novel Genes for Bipolar Disorder

2020 ◽  
Author(s):  
Shi Yao ◽  
Jing-Miao Ding ◽  
Hao Wu ◽  
Ruo-Han Hao ◽  
Yu Rong ◽  
...  
Keyword(s):  
Gene Expression ◽  
Bipolar Disorder ◽  
Association Study ◽  
Candidate Genes ◽  
Genome Wide Association Study ◽  
Disease Risk ◽  
Association Studies ◽  
Cerebellar Hemisphere ◽  
Genome Wide ◽  
Causal Genes

AbstractSince the bipolar disorder (BD) signals identified by genome-wide association study (GWAS) often reside in the non-coding regions, understanding the biological relevance of these genetic loci has proven to be complicated. Transcriptome-wide association studies (TWAS) providing a powerful approach to identify novel disease risk genes and uncover possible causal genes at loci identified previously by GWAS. However, these methods did not consider the importance of epigenetic regulation in gene expression. Here, we developed a novel epigenetic element-based transcriptome-wide association study (ETWAS) that tests the effects of genetic variants on gene expression levels with the epigenetic features as prior and further mediates the association between predicted expression and BD. We conducted an ETWAS consisting of 20,352 cases and 31,358 controls and identified 44 transcriptome-wide significant hits. We found 14 conditionally independent genes, and 11 did not previously implicate with BD, which is regarded as novel candidate genes, such as ASB16 in the cerebellar hemisphere (P = 9.29×10−8). We demonstrated that several genome-wide significant signals from the BD GWAS driven by genetically regulated expression, and conditioning of NEK4 explaining 90.1% of the GWAS signal. Additionally, ETWAS identified genes could explain heritability beyond that explained by GWAS-associated SNPs (P = 0.019). By querying the SNPs in the final model of identified genes in phenome databases, we identified several phenotypes previously associated with BD, such as schizophrenia and depression. In conclusion, ETWAS is a powerful method, and we identified several novel candidate genes associated with BD.

scholarly journals Identification of unique venous thromboembolism-susceptibility variants in African-Americans

2017 ◽  
Vol 117 (04) ◽  
pp. 758-768 ◽  
Author(s):  
Sebastian Armasu ◽  
Bryan McCauley ◽  
Iftikhar Kullo ◽  
Hugues Sicotte ◽  
Jyotishman Pathak ◽  
...  
Keyword(s):  
Gene Expression ◽  
Venous Thromboembolism ◽  
African Americans ◽  
Differential Expression ◽  
White Women ◽  
Genome Wide Association Study ◽  
Expression Data ◽  
Significant Differential Expression ◽  
Genome Wide ◽  
A Genome

SummaryTo identify novel single nucleotide polymorphisms (SNPs) associated with venous thromboembolism (VTE) in African-Americans (AAs), we performed a genome-wide association study (GWAS) of VTE in AAs using the Electronic Medical Records and Genomics (eMERGE) Network, comprised of seven sites each with DNA biobanks (total ~39,200 unique DNA samples) with genome-wide SNP data (imputed to 1000 Genomes Project cosmopolitan reference panel) and linked to electronic health records (EHRs). Using a validated EHR-driven phenotype extraction algorithm, we identified VTE cases and controls and tested for an association between each SNP and VTE using unconditional logistic regression, adjusted for age, sex, stroke, site-platform combination and sickle cell risk genotype. Among 393 AA VTE cases and 4,941 AA controls, three intragenic SNPs reached genome-wide significance: LEMD3 rs138916004 (OR=3.2; p=1.3E-08), LY86 rs3804476 (OR=1.8; p=2E-08) and LOC100130298 rs142143628 (OR=4.5; p=4.4E-08); all three SNPs validated using internal cross-validation, parametric bootstrap and meta-analysis methods. LEMD3 rs138916004 and LOC100130298 rs142143628 are only present in Africans (1000G data). LEMD3 showed a significant differential expression in both NCBI Gene Expression Omnibus (GEO) and the Mayo Clinic gene expression data, LOC100130298 showed a significant differential expression only in the GEO expression data, and LY86 showed a significant differential expression only in the Mayo expression data. LEMD3 encodes for an antagonist of TGF-β-induced cell proliferation arrest. LY86 encodes for MD-1 which down-regulates the pro-inflammatory response to lipopolysaccharide; LY86 variation was previously associated with VTE in white women; LOC100130298 is a non-coding RNA gene with unknown regulatory activity in gene expression and epigenetics.Supplementary Material to this article is available online at www.thrombosis-online.com.

scholarly journals Exploiting the GTEx resources to decipher the mechanisms at GWAS loci

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Alvaro N. Barbeira ◽  
◽  
Rodrigo Bonazzola ◽  
Eric R. Gamazon ◽  
Yanyu Liang ◽  
...  
Keyword(s):  
Complex Traits ◽  
Target Genes ◽  
Genome Wide Association Study ◽  
Data Driven ◽  
Functional Interpretation ◽  
Transcriptome Regulation ◽  
Genome Wide ◽  
Causal Genes ◽  
Dose Dependent ◽  
Single Approach

AbstractThe resources generated by the GTEx consortium offer unprecedented opportunities to advance our understanding of the biology of human diseases. Here, we present an in-depth examination of the phenotypic consequences of transcriptome regulation and a blueprint for the functional interpretation of genome-wide association study-discovered loci. Across a broad set of complex traits and diseases, we demonstrate widespread dose-dependent effects of RNA expression and splicing. We develop a data-driven framework to benchmark methods that prioritize causal genes and find no single approach outperforms the combination of multiple approaches. Using colocalization and association approaches that take into account the observed allelic heterogeneity of gene expression, we propose potential target genes for 47% (2519 out of 5385) of the GWAS loci examined.

scholarly journals A loop-counting method for covariate-corrected low-rank biclustering of gene-expression and genome-wide association study data

2018 ◽  
Vol 14 (5) ◽  
pp. e1006105 ◽  
Author(s):  
Aaditya V. Rangan ◽  
Caroline C. McGrouther ◽  
John Kelsoe ◽  
Nicholas Schork ◽  
Eli Stahl ◽  
...  
Keyword(s):  
Gene Expression ◽  
Association Study ◽  
Genome Wide Association Study ◽  
Study Data ◽  
Genome Wide Association ◽  
Low Rank ◽  
Counting Method ◽  
Genome Wide

scholarly journals Genome-wide H3K9 Acetylation Level Increases with Age-Dependent Senescence of Flag Leaf in Rice (Oryza sativa)

2021 ◽  
Author(s):  
Yu Zhang ◽  
Yanyun Li ◽  
Yuanyuan Zhang ◽  
Zeyu Zhang ◽  
Deyu Zhang ◽  
...  
Keyword(s):  
Gene Expression ◽  
Oryza Sativa ◽  
Leaf Senescence ◽  
Epigenetic Modification ◽  
Flag Leaf ◽  
Regulation Of Gene Expression ◽  
Leaf Aging ◽  
Genome Wide ◽  
Age Dependent ◽  
H3k9 Acetylation

Flag leaf senescence is an important biological process that drives the remobilization of nutrients to the growing organs of rice. Leaf senescence is controlled by genetic information via gene expression and epigenetic modification, but the precise mechanism is as of yet unclear. Here, we analyzed genome-wide acetylated lysine residue 9 of histone H3 (H3K9ac) enrichment by chromatin immunoprecipitation-sequencing (ChIP-seq) and examined its association with transcriptomes by RNA-seq during flag leaf aging in rice (Oryza sativa). We found that genome-wide H3K9 acetylation levels increased with age-dependent senescence in rice flag leaf, and there was a positive correlation between the density and breadth of H3K9ac and gene expression and transcript elongation. A set of 1,249 up-regulated, differentially expressed genes (DEGs) and 996 down-regulated DEGs showing a strong relationship between temporal changes in gene expression and gain/loss of H3K9ac was observed during rice flag leaf aging. We produced a landscape of H3K9 acetylation- modified gene expression targets that includes known senescence-associated genes, metabolism-related genes, as well as miRNA biosynthesis- related genes. Our findings reveal a complex regulatory network of metabolism- and senescence-related pathways mediated by H3K9ac and also elucidate patterns of H3K9ac-mediated regulation of gene expression during flag leaf aging in rice.

scholarly journals A compendium of uniformly processed human gene expression and splicing quantitative trait loci

2021 ◽  
Vol 53 (9) ◽  
pp. 1290-1299
Author(s):  
Nurlan Kerimov ◽  
James D. Hayhurst ◽  
Kateryna Peikova ◽  
Jonathan R. Manning ◽  
Peter Walter ◽  
...  
Keyword(s):  
Gene Expression ◽  
Quantitative Trait ◽  
Target Genes ◽  
Genome Wide Association Study ◽  
Cell Types ◽  
Summary Statistics ◽  
Genome Wide ◽  
Cell Type Specific ◽  
Trait Locus ◽  
Complex Human Traits

AbstractMany gene expression quantitative trait locus (eQTL) studies have published their summary statistics, which can be used to gain insight into complex human traits by downstream analyses, such as fine mapping and co-localization. However, technical differences between these datasets are a barrier to their widespread use. Consequently, target genes for most genome-wide association study (GWAS) signals have still not been identified. In the present study, we present the eQTL Catalogue (https://www.ebi.ac.uk/eqtl), a resource of quality-controlled, uniformly re-computed gene expression and splicing QTLs from 21 studies. We find that, for matching cell types and tissues, the eQTL effect sizes are highly reproducible between studies. Although most QTLs were shared between most bulk tissues, we identified a greater diversity of cell-type-specific QTLs from purified cell types, a subset of which also manifested as new disease co-localizations. Our summary statistics are freely available to enable the systematic interpretation of human GWAS associations across many cell types and tissues.

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