scholarly journals Common genes underlying asthma and COPD? Genome-wide analysis on the Dutch hypothesis

2014 ◽  
Vol 44 (4) ◽  
pp. 860-872 ◽  
Author(s):  
Joanna Smolonska ◽  
Gerard H. Koppelman ◽  
Cisca Wijmenga ◽  
Judith M. Vonk ◽  
Pieter Zanen ◽  
...  
Keyword(s):  
Gene Expression ◽  
Lung Tissue ◽  
Blood Cells ◽  
Association Studies ◽  
Chronic Obstructive ◽  
Eqtl Analysis ◽  
Genome Wide Association Studies ◽  
Genome Wide ◽  
Replication Phase ◽  
Genome Wide Significance

Asthma and chronic obstructive pulmonary disease (COPD) are thought to share a genetic background (“Dutch hypothesis”).We investigated whether asthma and COPD have common underlying genetic factors, performing genome-wide association studies for both asthma and COPD and combining the results in meta-analyses.Three loci showed potential involvement in both diseases: chr2p24.3, chr5q23.1 and chr13q14.2, containing DDX1, COMMD10 (both participating in the nuclear factor (NF) κβ pathway) and GNG5P5, respectively. Single nucleotide polymorphisms (SNPs) rs9534578 in GNG5P5 reached genome-wide significance after first replication phase (p=9.96×10−9). The second replication phase, in seven independent cohorts, provided no significant replication. Expression quantitative trait loci (eQTL) analysis in blood cells and lung tissue on the top 20 associated SNPs identified two SNPs in COMMD10 that influenced gene expression.Inflammatory processes differ in asthma and COPD and are mediated by NF-κβ, which could be driven by the same underlying genes, COMMD10 and DDX1. None of the SNPs reached genome-wide significance. Our eQTL studies support a functional role for two COMMD10 SNPs, since they influence gene expression in both blood cells and lung tissue. Our findings suggest that there is either no common genetic component in asthma and COPD or, alternatively, different environmental factors, e.g. lifestyle and occupation in different countries and continents, which may have obscured the genetic common contribution.

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 Transcriptome-wide Mendelian randomization study prioritising novel tissue-dependent genes for glioma susceptibility

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Jamie W. Robinson ◽  
Richard M. Martin ◽  
Spiridon Tsavachidis ◽  
Amy E. Howell ◽  
Caroline L. Relton ◽  
...  
Keyword(s):  
Gene Expression ◽  
Association Studies ◽  
Tissue Expression ◽  
Tissue Type ◽  
Mendelian Randomisation ◽  
Genome Wide Association Studies ◽  
Causal Pathways ◽  
Genome Wide ◽  
Glioma Risk ◽  
Brain Tissues

AbstractGenome-wide association studies (GWAS) have discovered 27 loci associated with glioma risk. Whether these loci are causally implicated in glioma risk, and how risk differs across tissues, has yet to be systematically explored. We integrated multi-tissue expression quantitative trait loci (eQTLs) and glioma GWAS data using a combined Mendelian randomisation (MR) and colocalisation approach. We investigated how genetically predicted gene expression affects risk across tissue type (brain, estimated effective n = 1194 and whole blood, n = 31,684) and glioma subtype (all glioma (7400 cases, 8257 controls) glioblastoma (GBM, 3112 cases) and non-GBM gliomas (2411 cases)). We also leveraged tissue-specific eQTLs collected from 13 brain tissues (n = 114 to 209). The MR and colocalisation results suggested that genetically predicted increased gene expression of 12 genes were associated with glioma, GBM and/or non-GBM risk, three of which are novel glioma susceptibility genes (RETREG2/FAM134A, FAM178B and MVB12B/FAM125B). The effect of gene expression appears to be relatively consistent across glioma subtype diagnoses. Examining how risk differed across 13 brain tissues highlighted five candidate tissues (cerebellum, cortex, and the putamen, nucleus accumbens and caudate basal ganglia) and four previously implicated genes (JAK1, STMN3, PICK1 and EGFR). These analyses identified robust causal evidence for 12 genes and glioma risk, three of which are novel. The correlation of MR estimates in brain and blood are consistently low which suggested that tissue specificity needs to be carefully considered for glioma. Our results have implicated genes yet to be associated with glioma susceptibility and provided insight into putatively causal pathways for glioma risk.

scholarly journals A description of large-scale metabolomics studies: increasing value by combining metabolomics with genome-wide SNP genotyping and transcriptional profiling

2012 ◽  
Vol 215 (1) ◽  
pp. 17-28 ◽  
Author(s):  
Georg Homuth ◽  
Alexander Teumer ◽  
Uwe Völker ◽  
Matthias Nauck
Keyword(s):  
Blood Cells ◽  
Large Scale ◽  
Genetic Factors ◽  
Association Studies ◽  
Transcriptional Profiling ◽  
Genome Wide Association Studies ◽  
Protein Levels ◽  
Future Developments ◽  
Genome Wide ◽  
Metabolome Data

The metabolome, defined as the reflection of metabolic dynamics derived from parameters measured primarily in easily accessible body fluids such as serum, plasma, and urine, can be considered as the omics data pool that is closest to the phenotype because it integrates genetic influences as well as nongenetic factors. Metabolic traits can be related to genetic polymorphisms in genome-wide association studies, enabling the identification of underlying genetic factors, as well as to specific phenotypes, resulting in the identification of metabolome signatures primarily caused by nongenetic factors. Similarly, correlation of metabolome data with transcriptional or/and proteome profiles of blood cells also produces valuable data, by revealing associations between metabolic changes and mRNA and protein levels. In the last years, the progress in correlating genetic variation and metabolome profiles was most impressive. This review will therefore try to summarize the most important of these studies and give an outlook on future developments.

scholarly journals A transcriptome-wide Mendelian randomization study to uncover tissue-dependent regulatory mechanisms across the human phenome

2019 ◽  
Author(s):  
Tom G Richardson ◽  
Gibran Hemani ◽  
Tom R Gaunt ◽  
Caroline L Relton ◽  
George Davey Smith
Keyword(s):  
Gene Expression ◽  
Genetic Variants ◽  
Complex Traits ◽  
Mendelian Randomization ◽  
Drug Repositioning ◽  
Association Studies ◽  
Thyroid Tissue ◽  
Genome Wide Association Studies ◽  
Tissue Specific ◽  
Genome Wide

AbstractBackgroundDeveloping insight into tissue-specific transcriptional mechanisms can help improve our understanding of how genetic variants exert their effects on complex traits and disease. By applying the principles of Mendelian randomization, we have undertaken a systematic analysis to evaluate transcriptome-wide associations between gene expression across 48 different tissue types and 395 complex traits.ResultsOverall, we identified 100,025 gene-trait associations based on conventional genome-wide corrections (P < 5 × 10−08) that also provided evidence of genetic colocalization. These results indicated that genetic variants which influence gene expression levels in multiple tissues are more likely to influence multiple complex traits. We identified many examples of tissue-specific effects, such as genetically-predicted TPO, NR3C2 and SPATA13 expression only associating with thyroid disease in thyroid tissue. Additionally, FBN2 expression was associated with both cardiovascular and lung function traits, but only when analysed in heart and lung tissue respectively.We also demonstrate that conducting phenome-wide evaluations of our results can help flag adverse on-target side effects for therapeutic intervention, as well as propose drug repositioning opportunities. Moreover, we find that exploring the tissue-dependency of associations identified by genome-wide association studies (GWAS) can help elucidate the causal genes and tissues responsible for effects, as well as uncover putative novel associations.ConclusionsThe atlas of tissue-dependent associations we have constructed should prove extremely valuable to future studies investigating the genetic determinants of complex disease. The follow-up analyses we have performed in this study are merely a guide for future research. Conducting similar evaluations can be undertaken systematically at http://mrcieu.mrsoftware.org/Tissue_MR_atlas/.

scholarly journals Heritability and genome-wide association study of diffusing capacity of the lung

2018 ◽  
Vol 52 (3) ◽  
pp. 1800647 ◽  
Author(s):  
Natalie Terzikhan ◽  
Fangui Sun ◽  
Fien M. Verhamme ◽  
Hieab H.H. Adams ◽  
Daan Loth ◽  
...  
Keyword(s):  
Genome Wide Association Study ◽  
Association Studies ◽  
Genome Wide Association ◽  
Considerable Proportion ◽  
Chronic Obstructive ◽  
Genome Wide Association Studies ◽  
Diffusing Capacity ◽  
Human Lung Tissue ◽  
Alveolar Volume ◽  
Genome Wide

Although several genome-wide association studies (GWAS) have investigated the genetics of pulmonary ventilatory function, little is known about the genetic factors that influence gas exchange. The aim of the study was to investigate the heritability of, and genetic variants associated with the diffusing capacity of the lung.GWAS was performed on diffusing capacity of the lung measured by carbon monoxide uptake (DLCO) and per alveolar volume (VA) using the single-breath technique, in 8372 individuals from two population-based cohort studies, the Rotterdam Study and the Framingham Heart Study. Heritability was estimated in related (n=6246) and unrelated (n=3286) individuals.Heritability of DLCO and DLCO/VA ranged between 23% and 28% in unrelated individuals and between 45% and 49% in related individuals. Meta-analysis identified a genetic variant in ADGRG6 that is significantly associated with DLCO/VA. Gene expression analysis of ADGRG6 in human lung tissue revealed a decreased expression in patients with chronic obstructive pulmonary disease (COPD) and subjects with decreased DLCO/VA.DLCO and DLCO/VA are heritable traits, with a considerable proportion of variance explained by genetics. A functional variant in ADGRG6 gene region was significantly associated with DLCO/VA. Pulmonary ADGRG6 expression was decreased in patients with COPD.

GWAS contribution to atrial fibrillation and atrial fibrillation-related stroke: pathophysiological implications

2019 ◽  
Vol 20 (10) ◽  
pp. 765-780 ◽  
Author(s):  
Diana Cruz ◽  
Ricardo Pinto ◽  
Margarida Freitas-Silva ◽  
José Pedro Nunes ◽  
Rui Medeiros
Keyword(s):  
Atrial Fibrillation ◽  
Genetic Variants ◽  
Complex Traits ◽  
Association Studies ◽  
Cardioembolic Stroke ◽  
Risk Scores ◽  
Genome Wide Association Studies ◽  
Genetic Determinants ◽  
Genome Wide ◽  
Genome Wide Significance

Atrial fibrillation (AF) and stroke are included in a group of complex traits that have been approached regarding of their study by susceptibility genetic determinants. Since 2007, several genome-wide association studies (GWAS) aiming to identify genetic variants modulating AF risk have been conducted. Thus, 11 GWAS have identified 26 SNPs (p < 5 × 10-2), of which 19 reached genome-wide significance (p < 5 × 10-8). From those variants, seven were also associated with cardioembolic stroke and three reached genome-wide significance in stroke GWAS. These associations may shed a light on putative shared etiologic mechanisms between AF and cardioembolic stroke. Additionally, some of these identified variants have been incorporated in genetic risk scores in order to elucidate new approaches of stroke prediction, prevention and treatment.

scholarly journals Genetics of COPD

2020 ◽  
Vol 82 (1) ◽  
pp. 413-431 ◽  
Author(s):  
Edwin K. Silverman
Keyword(s):  
Association Studies ◽  
Chronic Obstructive ◽  
Genome Wide Association Studies ◽  
Obstructive Pulmonary Disease ◽  
Functional Variants ◽  
Genome Wide ◽  
Antitrypsin Deficiency ◽  
Alpha 1 Antitrypsin Deficiency ◽  
Alpha 1 Antitrypsin ◽  
Genomic Regions

Although chronic obstructive pulmonary disease (COPD) risk is strongly influenced by cigarette smoking, genetic factors are also important determinants of COPD. In addition to Mendelian syndromes such as alpha-1 antitrypsin deficiency, many genomic regions that influence COPD susceptibility have been identified in genome-wide association studies. Similarly, multiple genomic regions associated with COPD-related phenotypes, such as quantitative emphysema measures, have been found. Identifying the functional variants and key genes within these association regions remains a major challenge. However, newly identified COPD susceptibility genes are already providing novel insights into COPD pathogenesis. Network-based approaches that leverage these genetic discoveries have the potential to assist in decoding the complex genetic architecture of COPD.

scholarly journals Genome wide association study of passive immunity and disease traits in beef-suckler and dairy calves on Irish farms

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Dayle Johnston ◽  
Robert Mukiibi ◽  
Sinéad M. Waters ◽  
Mark McGee ◽  
Carla Surlis ◽  
...  
Keyword(s):  
Genome Wide Association Study ◽  
Association Studies ◽  
Dairy Calves ◽  
Genome Wide Association ◽  
Passive Immunity ◽  
Genome Wide Association Studies ◽  
Serum Igg ◽  
Genome Wide ◽  
Beef Suckler ◽  
Genome Wide Significance

Abstract Calves with lower concentrations of immunoglobulin G (IgG) in their blood, have a greater risk of developing diseases. There is a lack of knowledge on genetic markers known to be associated with immunological variability or disease resistance. Therefore, the objective of this study was to identify SNP markers associated with passive immunity measures (serum IgG, serum protein, albumin, globulin and total protein concentrations, total solids Brix percentage, zinc sulphate turbidity units) and disease (pneumonia, diarrhoea, crude illness) traits in Irish commercial beef-suckler and dairy calves through genome wide association studies (GWAS). Genotyping was performed on DNA samples from beef-suckler (n = 698) and dairy (n = 1178) calves, using the IDBv3 chip. Heritability of passive immunity associated traits (range 0.02–0.22) and the disease traits (range 0.03–0.20) were low-to-moderate. Twenty-five and fifteen SNPs approached genome wide significance (P < 5 × 10−5) for the passive immunity and the disease traits, respectively. One SNP “ARS-BFGL-BAC-27914” reached Bonferroni genome wide significance (P < 1.15 × 10−6) for an association with serum IgG concentration in beef calves. Further work will evaluate these SNPs in larger cattle populations and assess their contribution to genomic selection breeding strategies, aimed towards producing more disease resistant livestock.

Sign in / Sign up

Export Citation Format

Share Document