scholarly journals Genetic Regulation of Biomarkers as Stress Proxies in Dairy Cows

Genes ◽  
2021 ◽  
Vol 12 (4) ◽  
pp. 534
Author(s):  
Marco Milanesi ◽  
Matilde Maria Passamonti ◽  
Katia Cappelli ◽  
Andrea Minuti ◽  
Valentino Palombo ◽  
...  
Keyword(s):  
Inflammatory Responses ◽  
Bos Taurus ◽  
Association Studies ◽  
Meta Analysis ◽  
Genetic Regulation ◽  
Chromosome 1 ◽  
Genome Wide Association Studies ◽  
Genetic Associations ◽  
Physiological Level ◽  
Glutamyl Transferase

Stress in livestock reduces productivity and is a welfare concern. At a physiological level, stress is associated with the activation of inflammatory responses and increased levels of harmful reactive oxygen species. Biomarkers that are indicative of stress could facilitate the identification of more stress-resilient animals. We examined twenty-one metabolic, immune response, and liver function biomarkers that have been associated with stress in 416 Italian Simmental and 436 Italian Holstein cows which were genotyped for 150K SNPs. Single-SNP and haplotype-based genome-wide association studies were carried out to assess whether the variation in the levels in these biomarkers is under genetic control and to identify the genomic loci involved. Significant associations were found for the plasma levels of ceruloplasmin (Bos taurus chromosome 1—BTA1), paraoxonase (BTA4) and γ-glutamyl transferase (BTA17) in the individual breed analysis that coincided with the position of the genes coding for these proteins, suggesting that their expression is under cis-regulation. A meta-analysis of both breeds identified additional significant associations with paraoxonase on BTA 16 and 26. Finding genetic associations with variations in the levels of these biomarkers suggests that the selection for high or low levels of expression could be achieved rapidly. Whether the level of expression of the biomarkers correlates with the response to stressful situations has yet to be determined.

scholarly journals Protein QTL analysis of IGF-I and its binding proteins provides insights into growth biology

2020 ◽  
Author(s):  
Eric Bartell ◽  
Masanobu Fujimoto ◽  
Jane C. Khoury ◽  
Philip R. Khoury ◽  
Sailaja Vedantam ◽  
...  
Keyword(s):  
Birth Weight ◽  
Association Studies ◽  
Genetic Regulation ◽  
Human Growth ◽  
Serum Levels ◽  
Genome Wide Association Studies ◽  
Genetic Associations ◽  
Protein Levels ◽  
Igf I ◽  
Igfbp 3

AbstractThe growth hormone and insulin-like growth factor (IGF) system is integral to human growth. Genome-wide association studies (GWAS) have identified variants associated with height and located near the genes in this pathway. However, mechanisms underlying these genetic associations are not understood. To investigate the regulation of the genes in this pathway and mechanisms by which regulation could affect growth, we performed GWAS of measured serum protein levels of IGF-I, IGFBP-3, PAPP-A2, IGF-II, and IGFBP-5 in 839 children (3-18 years) from the Cincinnati Genomic Control Cohort. We identified variants associated with protein levels near IGFBP3 and IGFBP5 genes, which contain multiple signals of association with height and other skeletal growth phenotypes. Surprisingly, variants that associate with protein levels at these two loci do not colocalize with height associations, confirmed through conditional analysis. Rather, the IGFBP3 signal (associated with total IGFBP-3 and IGF-II levels) colocalizes with an association with sitting height ratio (SHR); the IGFBP5 signal (associated with IGFBP-5 levels) colocalizes with birth weight. Indeed, height-associated SNPs near genes encoding other proteins in this pathway are not associated with serum levels, possibly excluding PAPP-A2. Mendelian randomization supports a stronger relationship of measured serum levels with SHR (for IGFBP-3) and birth weight (for IGFBP-5) than with height. In conclusion, we begin to characterize the genetic regulation of serum levels of IGF-related proteins in childhood. Furthermore, our data strongly suggest the existence of growth-regulating mechanisms acting through IGF-related genes in ways that are not reflected in measured serum levels of the corresponding proteins.

scholarly journals Novel susceptibility loci and genetic regulation mechanisms for type 2 diabetes

2018 ◽  
Author(s):  
Angli Xue ◽  
Yang Wu ◽  
Zhihong Zhu ◽  
Futao Zhang ◽  
Kathryn E Kemper ◽  
...  
Keyword(s):  
Gene Expression ◽  
Type 2 Diabetes ◽  
Rare Variants ◽  
Association Studies ◽  
Meta Analysis ◽  
Genetic Regulation ◽  
Regulation Of Gene Expression ◽  
European Ancestry ◽  
Genome Wide Association Studies

AbstractWe conducted a meta-analysis of genome-wide association studies (GWAS) with ∼16 million genotyped/imputed genetic variants in 62,892 type 2 diabetes (T2D) cases and 596,424 controls of European ancestry. We identified 139 common and 4 rare (minor allele frequency < 0.01) variants associated with T2D, 42 of which (39 common and 3 rare variants) were independent of the known variants. Integration of the gene expression data from blood (n = 14,115 and 2,765) and other T2D-relevant tissues (n = up to 385) with the GWAS results identified 33 putative functional genes for T2D, three of which were targeted by approved drugs. A further integration of DNA methylation (n = 1,980) and epigenomic annotations data highlighted three putative T2D genes (CAMK1D, TP53INP1 and ATP5G1) with plausible regulatory mechanisms whereby a genetic variant exerts an effect on T2D through epigenetic regulation of gene expression. We further found evidence that the T2D-associated loci have been under purifying selection.

scholarly journals EnigmaVis: Online Interactive Visualization of Genome-Wide Association Studies of the Enhancing NeuroImaging Genetics through Meta-Analysis (ENIGMA) Consortium

2012 ◽  
Vol 15 (3) ◽  
pp. 414-418 ◽  
Author(s):  
Nic M. Novak ◽  
Jason L. Stein ◽  
Sarah E. Medland ◽  
Derrek P. Hibar ◽  
Paul M. Thompson ◽  
...  
Keyword(s):  
Large Scale ◽  
Association Studies ◽  
Meta Analysis ◽  
Genome Wide Association ◽  
Intracranial Volume ◽  
Genome Wide Association Studies ◽  
Genetic Associations ◽  
Genome Wide ◽  
Neuroimaging Data ◽  
Neuroimaging Genetics

In an attempt to increase power to detect genetic associations with brain phenotypes derived from human neuroimaging data, we recently conducted a large-scale, genome-wide association meta-analysis of hippocampal, brain, and intracranial volume through the Enhancing NeuroImaging Genetics through Meta-Analysis (ENIGMA) consortium. Here, we present a freely available online interactive tool, EnigmaVis, which makes it easy to visualize the association results generated by the consortium alongside allele frequency, genes, and functional annotations. EnigmaVis runs natively within the web browser, and generates plots that show the level of association between brain phenotypes at user-specified genomic positions. Uniquely, EnigmaVis is dynamic; users can interact with elements on the plot in real time. This software will be useful when exploring the effect on brain structure of particular genetic variants influencing neuropsychiatric illness and cognitive function. Future projects of the consortium and updates to EnigmaVis will also be displayed on the site. EnigmaVis is freely available online at http://enigma.loni.ucla.edu/enigma-vis/

scholarly journals Loss-of-function of MFGE8 and protection against coronary atherosclerosis

2021 ◽  
Author(s):  
Sanni E Ruotsalainen ◽  
Ida Surakka ◽  
Nina Mars ◽  
Juha Karjalainen ◽  
Mitja Kurki ◽  
...  
Keyword(s):  
Cardiovascular Diseases ◽  
Coronary Atherosclerosis ◽  
Association Studies ◽  
Meta Analysis ◽  
Significant Risk ◽  
Premature Death ◽  
Population History ◽  
Genome Wide Association Studies ◽  
Genetic Associations ◽  
Loss Of Function

Cardiovascular diseases are the leading cause of premature death and disability worldwide, with both genetic and environmental determinants. While genome-wide association studies have identified multiple genetic loci associated with cardiovascular diseases, exact genes driving these associations remain mostly uncovered. Due to Finland's population history, many deleterious and high-impact variants are enriched in the Finnish population giving a possibility to find genetic associations for protein-truncating variants that likely tie the association to a gene and that would not be detected elsewhere. In FinnGen, a large Finnish biobank study, we identified an inframe insertion rs534125149 in MFGE8 to have protective effect against coronary atherosclerosis (OR = 0.75, p = 2.63E-16) and related endpoints. This variant is highly enriched in Finland (70-fold compared to Non-Finnish Europeans) with allele frequency of 3% in Finland. The protective association was replicated in meta-analysis of biobanks of Japan and Estonian (OR = 0.75, p = 5.41E-7). Additionally, we identified a splice acceptor variant rs201988637 in MFGE8, independent of the rs534125149 and similarly protective in relation to coronary atherosclerosis (OR = 0.72, p = 7.94E-06) and related endpoints, with no significant risk-increasing associations. The protein-truncating variant was also associated with lower pulse pressure, pointing towards a function of MFGE8 in arterial stiffness and aging also in humans in addition to previous evidence in mice. In conclusion, our results show that inhibiting the production of lactadherin could lower the risk for coronary heart disease substantially.

scholarly journals Identifying Risk Genes and Interpreting Pathogenesis for Parkinson’s Disease by a Multiomics Analysis

Genes ◽  
2020 ◽  
Vol 11 (9) ◽  
pp. 1100
Author(s):  
Wen-Wen Cheng ◽  
Qiang Zhu ◽  
Hong-Yu Zhang
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Genetic Variants ◽  
Association Studies ◽  
Meta Analysis ◽  
Genetic Regulation ◽  
Regulation Of Transcription ◽  
Genome Wide Association Studies ◽  
Risk Genes ◽  
Dna Elements

Genome-wide association studies (GWAS) have identified tens of genetic variants associated with Parkinson’s disease (PD). Nevertheless, the genes or DNA elements that affect traits through these genetic variations are usually undiscovered. This study was the first to combine meta-analysis GWAS data and expression data to identify PD risk genes. Four known genes, CRHR1, KANSL1, NSF and LRRC37A, and two new risk genes, STX4 and BST1, were identified. Among them, CRHR1 is a known drug target, indicating that hydrocortisone may become a potential drug for the treatment of PD. Furthermore, the potential pathogenesis of CRHR1 and LRRC37A was explored by applying DNA methylation (DNAm) data, indicating a pathogenesis whereby the effect of a genetic variant on PD is mediated by genetic regulation of transcription through DNAm. Overall, this research identified the risk genes and pathogenesis that affect PD through genetic variants, which has significance for the diagnosis and treatment of PD.

scholarly journals Protein QTL analysis of IGF-I and its binding proteins provides insights into growth biology

2020 ◽  
Vol 29 (15) ◽  
pp. 2625-2636
Author(s):  
Eric Bartell ◽  
Masanobu Fujimoto ◽  
Jane C Khoury ◽  
Philip R Khoury ◽  
Sailaja Vedantam ◽  
...  
Keyword(s):  
Birth Weight ◽  
Association Studies ◽  
Genetic Regulation ◽  
Serum Levels ◽  
Genome Wide Association Studies ◽  
Nucleotide Polymorphisms ◽  
Genetic Associations ◽  
Protein Levels ◽  
Igf I ◽  
Igfbp 3

Abstract The growth hormone and insulin-like growth factor (IGF) system is integral to human growth. Genome-wide association studies (GWAS) have identified variants associated with height and located near the genes in this pathway. However, mechanisms underlying these genetic associations are not understood. To investigate the regulation of the genes in this pathway and mechanisms by which regulation could affect growth, we performed GWAS of measured serum protein levels of IGF-I, IGF binding protein-3 (IGFBP-3), pregnancy-associated plasma protein A (PAPP-A2), IGF-II and IGFBP-5 in 838 children (3–18 years) from the Cincinnati Genomic Control Cohort. We identified variants associated with protein levels near IGFBP3 and IGFBP5 genes, which contain multiple signals of association with height and other skeletal growth phenotypes. Surprisingly, variants that associate with protein levels at these two loci do not colocalize with height associations, confirmed through conditional analysis. Rather, the IGFBP3 signal (associated with total IGFBP-3 and IGF-II levels) colocalizes with an association with sitting height ratio (SHR); the IGFBP5 signal (associated with IGFBP-5 levels) colocalizes with birth weight. Indeed, height-associated single nucleotide polymorphisms near genes encoding other proteins in this pathway are not associated with serum levels, possibly excluding PAPP-A2. Mendelian randomization supports a stronger causal relationship of measured serum levels with SHR (for IGFBP-3) and birth weight (for IGFBP-5) than with height. In conclusion, we begin to characterize the genetic regulation of serum levels of IGF-related proteins in childhood. Furthermore, our data strongly suggest the existence of growth-regulating mechanisms acting through IGF-related genes in ways that are not reflected in measured serum levels of the corresponding proteins.

scholarly journals Best practices of multi-ancestry, meta-analytic transcriptome-wide association studies: lessons from the Global Biobank Meta-analysis Initiative

2021 ◽  
Author(s):  
Arjun Bhattacharya ◽  
Jibril B Hirbo ◽  
Dan Zhou ◽  
Wei Zhou ◽  
Jie Zheng ◽  
...  
Keyword(s):  
Gene Expression ◽  
Association Studies ◽  
Meta Analysis ◽  
Genomic Medicine ◽  
Genetic Association Studies ◽  
Specific Gene ◽  
Genome Wide Association Studies ◽  
Genetic Associations ◽  
Genome Wide ◽  
Study Population

The Global Biobank Meta-analysis Initiative (GBMI), through its genetic and demographic diversity, provides a valuable opportunity to study population-wide and ancestry-specific genetic associations. However, with multiple ascertainment strategies and multi-ethnic study populations across biobanks, the GBMI provides a distinct set of challenges in implementing statistical genetics methods. Transcriptome-wide association studies (TWAS) are a popular tool to boost detection power for and provide biological context to genetic associations by integrating single nucleotide polymorphism to trait (SNP-trait) associations from genome-wide association studies (GWAS) with SNP-based predictive models of gene expression. TWAS presents unique challenges beyond GWAS, especially in a multi-biobank and meta-analytic setting like the GBMI. In this work, we present the GBMI TWAS pipeline, outlining practical considerations for ancestry and tissue specificity and meta-analytic strategies, as well as open challenges at every step of the framework. Our work provides a strong foundation for adding tissue-specific gene expression context to biobank-linked genetic association studies, allowing for ancestry-aware discovery to accelerate genomic medicine.

scholarly journals Metanalysis of genome-wide association studies for panic disorder suggest pathways and mechanisms of pathogenesis

2018 ◽  
Author(s):  
Rhayra Xavier do Carmo Silva ◽  
Sueslene Prado Rocha ◽  
Dainara Pereira dos Santos Souza ◽  
Monica Gomes Lima-Maximino ◽  
Caio Maximino
Keyword(s):  
Panic Disorder ◽  
Inflammatory Responses ◽  
Drug Repositioning ◽  
Association Studies ◽  
Meta Analysis ◽  
Genome Wide Association ◽  
Mouse Strains ◽  
Genome Wide Association Studies ◽  
Nucleotide Polymorphisms ◽  
Genome Wide

AbstractPanic disorder (PD) is characterized by abrupt surges of intense fear and distress. There is evidence for a genetic component in this disorder. We ran a meta-analysis of genome-wide association studies of patients with PD, and found 25 single-nucleotide polymorphisms that were associated with the disorder. Causal gene prediction based on these polymorphisms uncovered 20 hits. Exploratory analyses suggested that these genes formed interactor networks, which was enriched in signaling pathways associated with immune and inflammatory responses, as well as growth factors and other developmental mediators. A subset of genes is enriched in limbic regions of the human brain and in microglia and myelinating oligodendrocytes of mice. While these genes were not associated with relevant neurobehavioral phenotypes in mutant mice, expression levels of several causal genes in the amygdala, prefrontal cortex, hippocampus, hypothalamus, and adrenal gland of recombinant mouse strains was associated with endophenotypes of fear conditioning. Drug repositioning prediction was unsuccessful, but this does not discard these genes and pathways as targets for investigational drugs. In general,ASB3,EIF2S2, RASGRF2, andTRMT2B(and its coded proteins) emerged as interesting targets for mechanistic research on PD. These exploratory findings point towards hypotheses of pathogenesis and neuropharmacology that need to be further investigated.

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