scholarly journals Estimating driver-tissues by robust selective expression of genes associated with complex diseases or traits

2018 ◽  
Author(s):  
Lin Jiang ◽  
Chao Xue ◽  
Shangzhen Chen ◽  
Sheng Dai ◽  
Peikai Chen ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Large Scale ◽  
Genome Wide Association Study ◽  
Complex Diseases ◽  
Transcript Level ◽  
Cell Types ◽  
Z Score ◽  
Expression Of Genes ◽  
Selective Expression ◽  
Disease Associated Genes

AbstractThe driver tissues or cell-types of many human diseases, in which susceptibility genes cause the diseases, remain elusive. We developed a framework to detect the causal-tissues of complex diseases or traits according to selective expression of disease-associated genes in genome-wide association study (GWAS). The core method of the framework is a new robust z-score to estimate genes’ expression selectivity. Through extensive computing simulations and comparative analyses in a large-scale schizophrenia GWAS, we demonstrate the robust z-score is more sensitive than existing methods to detect multiple selectively expressed tissues, which further lead to the estimation of more biological sensible driver tissues. The effectiveness of this framework is further validated in five representative complex diseases with the usage of GWAS summary statistics and transcript-level expression in GTEx project. Finally, we also demonstrate that the prioritized tissues and the robust selective expression can enhance characterization of directly associated genes of a disease as well. Interesting results include the estimation of lung as a driver tissue of rheumatoid arthritis, consistent with clinical observations of morbidity between rheumatoid arthritis and lung diseases.

scholarly journals DESE: estimating driver tissues by selective expression of genes associated with complex diseases or traits

2019 ◽  
Vol 20 (1) ◽  
Author(s):  
Lin Jiang ◽  
Chao Xue ◽  
Sheng Dai ◽  
Shangzhen Chen ◽  
Peikai Chen ◽  
...  
Keyword(s):  
Association Studies ◽  
Complex Diseases ◽  
Cell Types ◽  
Genome Wide Association Studies ◽  
Summary Statistics ◽  
Unified Framework ◽  
Expression Of Genes ◽  
Genome Wide ◽  
Selective Expression ◽  
Disease Associated Genes

Abstract The driver tissues or cell types in which susceptibility genes initiate diseases remain elusive. We develop a unified framework to detect the causal tissues of complex diseases or traits according to selective expression of disease-associated genes in genome-wide association studies (GWASs). This framework consists of three components which run iteratively to produce a converged prioritization list of driver tissues. Additionally, this framework also outputs a list of prioritized genes as a byproduct. We apply the framework to six representative complex diseases or traits with GWAS summary statistics, which leads to the estimation of the lung as an associated tissue of rheumatoid arthritis.

scholarly journals Transcriptome-wide association study identifies susceptibility genes for rheumatoid arthritis

2021 ◽  
Vol 23 (1) ◽  
Author(s):  
Cuiyan Wu ◽  
Sijian Tan ◽  
Li Liu ◽  
Shiqiang Cheng ◽  
Peilin Li ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Association Study ◽  
Mrna Expression ◽  
Signaling Pathway ◽  
Large Scale ◽  
Genome Wide Association Study ◽  
Expression Profiles ◽  
Susceptibility Genes ◽  
Pathway Regulation ◽  
Gene Expression Profile Data

Abstract Objective To identify rheumatoid arthritis (RA)-associated susceptibility genes and pathways through integrating genome-wide association study (GWAS) and gene expression profile data. Methods A transcriptome-wide association study (TWAS) was conducted by the FUSION software for RA considering EBV-transformed lymphocytes (EL), transformed fibroblasts (TF), peripheral blood (NBL), and whole blood (YBL). GWAS summary data was driven from a large-scale GWAS, involving 5539 autoantibody-positive RA patients and 20,169 controls. The TWAS-identified genes were further validated using the mRNA expression profiles and made a functional exploration. Results TWAS identified 692 genes with PTWAS values < 0.05 for RA. CRIPAK (PEL = 0.01293, PTF = 0.00038, PNBL = 0.02839, PYBL = 0.0978), MUT (PEL = 0.00377, PTF = 0.00076, PNBL = 0.00778, PYBL = 0.00096), FOXRED1 (PEL = 0.03834, PTF = 0.01120, PNBL = 0.01280, PYBL = 0.00583), and EBPL (PEL = 0.00806, PTF = 0.03761, PNBL = 0.03540, PYBL = 0.04254) were collectively expressed in all the four tissues/cells. Eighteen genes, including ANXA5, AP4B1, ATIC (PTWAS = 0.0113, downregulated expression), C12orf65, CMAH, PDHB, RUNX3 (PTWAS = 0.0346, downregulated expression), SBF1, SH2B3, STK38, TMEM43, XPNPEP1, KIAA1530, NUFIP2, PPP2R3C, RAB24, STX6, and TLR5 (PTWAS = 0.04665, upregulated expression), were validated with integrative analysis of TWAS and mRNA expression profiles. TWAS-identified genes functionally involved in endoplasmic reticulum organization, regulation of cytokine production, TNF signaling pathway, immune response-regulating signaling pathway, regulation of autophagy, etc. Conclusion We identified multiple candidate genes and pathways, providing novel clues for the genetic mechanism of RA.

scholarly journals Exploring the overlap between rheumatoid arthritis susceptibility loci and long non-coding RNA annotations

2019 ◽  
Author(s):  
James Ding ◽  
Chenfu Shi ◽  
John Bowes ◽  
Stephen Eyre ◽  
Gisela Orozco
Keyword(s):  
Rheumatoid Arthritis ◽  
Complex Diseases ◽  
Cell Types ◽  
Protein Coding ◽  
Major Mechanism ◽  
Coding Regions ◽  
Functional Characterisation ◽  
Non Coding Rna ◽  
Significant Enrichment ◽  
Local Enrichment

ABSTRACTWhilst susceptibility variants for many complex diseases, such as rheumatoid arthritis (RA), have been well characterised, the mechanism by which risk is mediated is still unclear for many loci. This is especially true for the majority of variants that do not affect protein-coding regions. lncRNA represent a group of molecules that have been shown to be enriched amongst variants associated with RA and other complex diseases, compared to random variants. In order to establish to what degree direct disruption of lncRNA may represent a potential mechanism for mediating RA susceptibility, we chose to further explore this overlap. By testing the ability of annotated features to improve a model of disease susceptibility, we were able to demonstrate a local enrichment of enhancers from immune-relevant cell types amongst RA susceptibility variants (log2 enrichment 3.40). This was not possible for lncRNA annotations in general, however a small, but significant enrichment was observed for immune-enriched lncRNA (log2 enrichment 0.867002). This enrichment was no longer apparent when the model was conditioned on immune-relevant enhancers (log2 enrichment -0.372734), suggesting that direct disruption of lncRNA sequence, independent of enhancer disruption, does not represent a major mechanism by which susceptibility to complex diseases is mediated. Furthermore, we demonstrated that, in keeping with general lncRNA characteristics, immune-enriched lncRNA are expressed at low levels that may not be amenable to functional characterisation.

scholarly journals Trans-ancestry genome-wide association study identifies novel genetic mechanisms in rheumatoid arthritis

2021 ◽  
Author(s):  
Kazuyoshi Ishigaki ◽  
Saori Sakaue ◽  
Chikashi Terao ◽  
Yang Luo ◽  
Kyuto Sonehara ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Association Study ◽  
Fine Mapping ◽  
Large Scale ◽  
Genome Wide Association Study ◽  
Meta Analysis ◽  
Genetic Research ◽  
Genome Wide Association ◽  
Polygenic Risk Score ◽  
Genome Wide

AbstractTrans-ancestry genetic research promises to improve power to detect genetic signals, fine-mapping resolution, and performances of polygenic risk score (PRS). We here present a large-scale genome-wide association study (GWAS) of rheumatoid arthritis (RA) which includes 276,020 samples of five ancestral groups. We conducted a trans-ancestry meta-analysis and identified 124 loci (P < 5 × 10-8), of which 34 were novel. Candidate genes at the novel loci suggested essential roles of the immune system (e.g., TNIP2 and TNFRSF11A) and joint tissues (e.g., WISP1) in RA etiology. Trans-ancestry fine mapping identified putatively causal variants with biological insights (e.g., LEF1). Moreover, PRS based on trans-ancestry GWAS outperformed PRS based on single-ancestry GWAS and had comparable performance between European and East Asian populations. Our study provides multiple insights into the etiology of RA and improves genetic predictability of RA.

scholarly journals Rheumatoid Arthritis and Cardio-Cerebrovascular Disease: A Mendelian Randomization Study

2021 ◽  
Vol 12 ◽  
Author(s):  
Shizheng Qiu ◽  
Meijie Li ◽  
Shunshan Jin ◽  
Haoyu Lu ◽  
Yang Hu
Keyword(s):  
Rheumatoid Arthritis ◽  
Cardiovascular Disease ◽  
Coronary Heart Disease ◽  
Heart Disease ◽  
Cerebrovascular Disease ◽  
Heart Attack ◽  
Large Scale ◽  
Genome Wide Association Study ◽  
Mendelian Randomization ◽  
Sensitivity Analyses

Significant genetic association exists between rheumatoid arthritis (RA) and cardiovascular disease. The associated mechanisms include common inflammatory mediators, changes in lipoprotein composition and function, immune responses, etc. However, the causality of RA and vascular/heart problems remains unknown. Herein, we performed Mendelian randomization (MR) analysis using a large-scale RA genome-wide association study (GWAS) dataset (462,933 cases and 457,732 controls) and six cardio-cerebrovascular disease GWAS datasets, including age angina (461,880 cases and 447,052 controls), hypertension (461,880 cases and 337,653 controls), age heart attack (10,693 cases and 451,187 controls), abnormalities of heartbeat (461,880 cases and 361,194 controls), stroke (7,055 cases and 454,825 controls), and coronary heart disease (361,194 cases and 351,037 controls) from United Kingdom biobank. We further carried out heterogeneity and sensitivity analyses. We confirmed the causality of RA with age angina (OR = 1.17, 95% CI: 1.04–1.33, p = 1.07E−02), hypertension (OR = 1.45, 95% CI: 1.20–1.75, p = 9.64E−05), age heart attack (OR = 1.15, 95% CI: 1.05–1.26, p = 3.56E−03), abnormalities of heartbeat (OR = 1.07, 95% CI: 1.01–1.12, p = 1.49E−02), stroke (OR = 1.06, 95% CI: 1.01–1.12, p = 2.79E−02), and coronary heart disease (OR = 1.19, 95% CI: 1.01–1.39, p = 3.33E−02), contributing to the understanding of the overlapping genetic mechanisms and therapeutic approaches between RA and cardiovascular disease.

scholarly journals Transcriptome-wide association study identifies susceptibility genes for rheumatoid arthritis

2020 ◽  
Author(s):  
Cuiyan Wu ◽  
Sijia Tan ◽  
Li Liu ◽  
Shiqiang Cheng ◽  
Peilin Li ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Association Study ◽  
Mrna Expression ◽  
Large Scale ◽  
Genome Wide Association Study ◽  
Expression Profiles ◽  
Susceptibility Genes ◽  
Genome Wide ◽  
Regulated Expression ◽  
Gene Expression Profile Data

Abstract ObjectiveTo identify rheumatoid arthritis (RA) associated susceptibility genes and pathways through integrating genome-wide association study (GWAS) and gene expression profile data. MethodsA transcriptome-wide association study (TWAS) was conducted by the FUSION software for RA considering EBV-transformed lymphocytes (EL), transformed fibroblasts (TF), peripheral blood (NBL) and whole blood (YBL). GWAS summary data was driven from a large-scale GWAS, involving 5,539 autoantibody-positive RA patients and 20,169 controls. The TWAS-identified genes were further validated using the mRNA expression profiles and made a functional exploration. ResultsTWAS identified 692 genes with PTWAS values < 0.05 for RA. CRIPAK (PEL = 0.01293, PTF = 0.00038, PNBL = 0.02839, PYBL = 0.0978), MUT (PEL = 0.00377, PTF = 0.00076, PNBL = 0.00778, PYBL = 0.00096), FOXRED1 (PEL = 0.03834, PTF = 0.01120, PNBL = 0.01280, PYBL = 0.00583) and EBPL (PEL = 0.00806, PTF = 0.03761, PNBL = 0.03540, PYBL = 0.04254) were collectively expressed in all the four tissues/cells. 18 genes, including ANXA5, AP4B1, ATIC (PTWAS = 0.0113, down-regulated expression), C12orf65, CMAH, PDHB, RUNX3 (PTWAS = 0.0346, down-regulated expression), SBF1, SH2B3, STK38, TMEM43, XPNPEP1, KIAA1530, NUFIP2, PPP2R3C, RAB24, STX6, TLR5 (PTWAS = 0.04665, up-regulated expression), were validated with integrative analysis of TWAS and mRNA expression profiles. TWAS-identified genes functionally involved in endomembrane system organization, endoplasmic reticulum organization, regulation of cytokine production, TNF signaling pathway, etc. ConclusionWe identified multiple candidate genes and pathways, providing novel clues for the genetic mechanism of RA.

Large Scale Discoveries of Genes and Polymorphisms Associated with Variation in Hematologic Traits

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. SCI-40-SCI-40
Author(s):  
Nicole Soranzo
Keyword(s):  
Blood Cell ◽  
Genetic Variants ◽  
Blood Cells ◽  
Large Scale ◽  
Genome Wide Association Study ◽  
Conflicts Of Interest ◽  
Cell Types ◽  
The Novel ◽  
Hematopoietic Stem ◽  
Genome Wide

Abstract Hematopoiesis generates mature blood cells from hematopoietic stem cells (HSC) in distinct lineages to release of trillions of mature cells each day into the peripheral blood stream to perform essential functions such as oxygen transport, hemostasis and host defense. The formation and turnover of blood cells are tightly controlled and so the properties of blood cells, including their volume and count, have large heritabilities and are easily influenced by genetic variation. Here we describe the most statistically powerful genome wide association study (GWAS) of blood cell indices to date. We tested associations of 29.5 million polymorphic DNA sequence variants derived using the the Affymetrix axiom array with interpolation of 20 million variants using the UK 10000 genome data with 36 different hematological indices of red cells, white cells and platelets, some of which, such as the reticulocyte count, have been explored for the first time. We discovered significant associations at thousands of associated genetic variants, including hundreds of associations for low frequency genetic variants, thus identifying associations with larger effects on indices than those reported for common variants by previous discovery studies. We have described detailed follow-up studies of the novel associations. Using cell type-specific epigenome and gene expression data generated by the BLUEPRINT project and results from chromatin conformation capture in major blood cell types, we can identify the likely causal variants and their functional impact at a large number of the novel loci. Finally, we have evaluated the contribution of genetic variants to common and complex diseases. In conclusion, we have interrogated phenotypes across the whole hematopoietic tree and increased the number of traits associated with blood cell phenotypes by an order of magnitude. Overall, our results demonstrate widespread and powerful genetic influences on the formation and regulation of the major human blood cell types, identifying many novel genes involved and show the value of genome-wide functional annotation from relevant primary cell populations for interpreting genetic association results. Disclosures No relevant conflicts of interest to declare.

scholarly journals Contribution of Ionotropic Glutamatergic Receptors to Excitability and Attentional Signals in Macaque Frontal Eye Field

2021 ◽  
Author(s):  
Miguel Dasilva ◽  
Christian Brandt ◽  
Marc Alwin Gieselmann ◽  
Claudia Distler ◽  
Alexander Thiele
Keyword(s):  
Attentional Control ◽  
Large Scale ◽  
Neuronal Excitability ◽  
Cell Types ◽  
Receptor Activation ◽  
Frontal Eye Field ◽  
Control Signals ◽  
Cognitive Operations ◽  
Eye Field ◽  
Large Scale Networks

Abstract Top-down attention, controlled by frontal cortical areas, is a key component of cognitive operations. How different neurotransmitters and neuromodulators flexibly change the cellular and network interactions with attention demands remains poorly understood. While acetylcholine and dopamine are critically involved, glutamatergic receptors have been proposed to play important roles. To understand their contribution to attentional signals, we investigated how ionotropic glutamatergic receptors in the frontal eye field (FEF) of male macaques contribute to neuronal excitability and attentional control signals in different cell types. Broad-spiking and narrow-spiking cells both required N-methyl-D-aspartic acid and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor activation for normal excitability, thereby affecting ongoing or stimulus-driven activity. However, attentional control signals were not dependent on either glutamatergic receptor type in broad- or narrow-spiking cells. A further subdivision of cell types into different functional types using cluster-analysis based on spike waveforms and spiking characteristics did not change the conclusions. This can be explained by a model where local blockade of specific ionotropic receptors is compensated by cell embedding in large-scale networks. It sets the glutamatergic system apart from the cholinergic system in FEF and demonstrates that a reduction in excitability is not sufficient to induce a reduction in attentional control signals.

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