scholarly journals A joint analysis of longevity and age-related disease variants for gene expression association

2021 ◽  
Author(s):  
Lu Zeng ◽  
Shouneng Peng ◽  
Seungsoo Kim ◽  
Jun Zhu ◽  
Bin Zhang ◽  
...  
Keyword(s):  
Gene Expression ◽  
Genetic Variants ◽  
Gene Expression Regulation ◽  
Human Longevity ◽  
Joint Analysis ◽  
Putative Gene ◽  
Related Disease ◽  
Age Related ◽  
Genome Wide

AbstractA large number of genetic variants associated with human longevity have been reported but how they play their functions remains elusive. We performed an integrative analysis on 113 genome-wide significant longevity and 14,529 age-related disease variants in the context of putative gene expression regulation. We found that most of the longevity allele types were different from the genotype of disease alleles when they were localized at the same chromosomal positions. Longevity variants were about eight times more likely to be associated with gene expression than randomly selected variants. The directions of the gene expression association were more likely to be opposite between longevity and disease variants when the association occurred to the same gene. Many longevity variants likely function through down-regulating inflammatory response and up-regulating healthy lipid metabolisms. In conclusion, this work helps to elucidate the potential mechanisms of longevity variants for follow-up studies to discover methods to extend human healthspan.

scholarly journals A Genome-Wide Scan Reveals Important Roles of DNA Methylation in Human Longevity by Regulating Age-Related Disease Genes

PLoS ONE ◽  
2015 ◽  
Vol 10 (3) ◽  
pp. e0120388 ◽  
Author(s):  
Fu-Hui Xiao ◽  
Yong-Han He ◽  
Qi-Gang Li ◽  
Huan Wu ◽  
Long-Hai Luo ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Human Longevity ◽  
Disease Genes ◽  
Related Disease ◽  
Age Related ◽  
Genome Wide ◽  
A Genome ◽  
Genome Wide Scan

scholarly journals Genome-Wide Scan Informed by Age-Related Disease Identifies Loci for Exceptional Human Longevity

PLoS Genetics ◽  
2015 ◽  
Vol 11 (12) ◽  
pp. e1005728 ◽  
Author(s):  
Kristen Fortney ◽  
Edgar Dobriban ◽  
Paolo Garagnani ◽  
Chiara Pirazzini ◽  
Daniela Monti ◽  
...  
Keyword(s):  
Human Longevity ◽  
Related Disease ◽  
Age Related ◽  
Genome Wide ◽  
Genome Wide Scan

scholarly journals A description of the relationship in healthy longevity and aging-related disease: from gene to protein

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Xiaolin Ni ◽  
Zhaoping Wang ◽  
Danni Gao ◽  
Huiping Yuan ◽  
Liang Sun ◽  
...  
Keyword(s):  
Gene Expression ◽  
Prolonged Exposure ◽  
Gene Expression Regulation ◽  
Regulation Of Gene Expression ◽  
Human Longevity ◽  
Form Complex ◽  
Genetic Characteristics ◽  
Age Related ◽  
The Relationship

AbstractHuman longevity is a complex phenotype influenced by both genetic and environmental factors. It is also known to be associated with various types of age-related diseases, such as Alzheimer’s disease (AD) and cardiovascular disease (CVD). The central dogma of molecular biology demonstrates the conversion of DNA to RNA to the encoded protein. These proteins interact to form complex cell signaling pathways, which perform various biological functions. With prolonged exposure to the environment, the in vivo homeostasis adapts to the changes, and finally, humans adopt the phenotype of longevity or aging-related diseases. In this review, we focus on two different states: longevity and aging-related diseases, including CVD and AD, to discuss the relationship between genetic characteristics, including gene variation, the level of gene expression, regulation of gene expression, the level of protein expression, both genetic and environmental influences and homeostasis based on these phenotypes shown in organisms.

scholarly journals Epistatic interactions of genetic loci associated with age-related macular degeneration

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Christina Kiel ◽  
Christoph A. Nebauer ◽  
Tobias Strunz ◽  
Simon Stelzl ◽  
Bernhard H. F. Weber
Keyword(s):  
Gene Expression ◽  
Macular Degeneration ◽  
Genetic Variants ◽  
Genome Wide Association Study ◽  
Age Related Macular Degeneration ◽  
Risk Scores ◽  
Cellular Processes ◽  
Age Related ◽  
Genome Wide ◽  
Extracellular Structures

AbstractThe currently largest genome-wide association study (GWAS) for age-related macular degeneration (AMD) defines disease association with genome-wide significance for 52 independent common and rare genetic variants across 34 chromosomal loci. Overall, these loci contain over 7200 variants and are enriched for genes with functions indicating several shared cellular processes. Still, the precise mechanisms leading to AMD pathology are largely unknown. Here, we exploit the phenomenon of epistatic interaction to identify seemingly independent AMD-associated variants that reveal joint effects on gene expression. We focus on genetic variants associated with lipid metabolism, organization of extracellular structures, and innate immunity, specifically the complement cascade. Multiple combinations of independent variants were used to generate genetic risk scores allowing gene expression in liver to be compared between low and high-risk AMD. We identified genetic variant combinations correlating significantly with expression of 26 genes, of which 19 have not been associated with AMD before. This study defines novel targets and allows prioritizing further functional work into AMD pathobiology.

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 Differential evolution in 3′UTRs leads to specific gene expression in Staphylococcus

2020 ◽  
Vol 48 (5) ◽  
pp. 2544-2563 ◽  
Author(s):  
Pilar Menendez-Gil ◽  
Carlos J Caballero ◽  
Arancha Catalan-Moreno ◽  
Naiara Irurzun ◽  
Inigo Barrio-Hernandez ◽  
...  
Keyword(s):  
Gene Expression ◽  
Gene Expression Regulation ◽  
Bacterial Species ◽  
Regulatory Elements ◽  
Specific Gene ◽  
Species Differentiation ◽  
Orthologous Genes ◽  
Genome Wide ◽  
Sequence Variations ◽  
Species Specific

Abstract The evolution of gene expression regulation has contributed to species differentiation. The 3′ untranslated regions (3′UTRs) of mRNAs include regulatory elements that modulate gene expression; however, our knowledge of their implications in the divergence of bacterial species is currently limited. In this study, we performed genome-wide comparative analyses of mRNAs encoding orthologous proteins from the genus Staphylococcus and found that mRNA conservation was lost mostly downstream of the coding sequence (CDS), indicating the presence of high sequence diversity in the 3′UTRs of orthologous genes. Transcriptomic mapping of different staphylococcal species confirmed that 3′UTRs were also variable in length. We constructed chimeric mRNAs carrying the 3′UTR of orthologous genes and demonstrated that 3′UTR sequence variations affect protein production. This suggested that species-specific functional 3′UTRs might be specifically selected during evolution. 3′UTR variations may occur through different processes, including gene rearrangements, local nucleotide changes, and the transposition of insertion sequences. By extending the conservation analyses to specific 3′UTRs, as well as the entire set of Escherichia coli and Bacillus subtilis mRNAs, we showed that 3′UTR variability is widespread in bacteria. In summary, our work unveils an evolutionary bias within 3′UTRs that results in species-specific non-coding sequences that may contribute to bacterial diversity.

The COP9 signalosome influences the epigenetic landscape of Arabidopsis thaliana

2018 ◽  
Vol 35 (16) ◽  
pp. 2718-2723 ◽  
Author(s):  
Tamir Tuller ◽  
Alon Diament ◽  
Avital Yahalom ◽  
Assaf Zemach ◽  
Shimshi Atar ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Arabidopsis Thaliana ◽  
Gene Expression Regulation ◽  
Developmental Pathways ◽  
Cop9 Signalosome ◽  
Supplementary Information ◽  
Loss Of Function ◽  
Genome Wide ◽  
High Level

Abstract Motivation The COP9 signalosome is a highly conserved multi-protein complex consisting of eight subunits, which influences key developmental pathways through its regulation of protein stability and transcription. In Arabidopsis thaliana, mutations in the COP9 signalosome exhibit a number of diverse pleiotropic phenotypes. Total or partial loss of COP9 signalosome function in Arabidopsis leads to misregulation of a number of genes involved in DNA methylation, suggesting that part of the pleiotropic phenotype is due to global effects on DNA methylation. Results We determined and analyzed the methylomes and transcriptomes of both partial- and total-loss-of-function Arabidopsis mutants of the COP9 signalosome. Our results support the hypothesis that the COP9 signalosome has a global genome-wide effect on methylation and that this effect is at least partially encoded in the DNA. Our analyses suggest that COP9 signalosome-dependent methylation is related to gene expression regulation in various ways. Differentially methylated regions tend to be closer in the 3D conformation of the genome to differentially expressed genes. These results suggest that the COP9 signalosome has a more comprehensive effect on gene expression than thought before, and this is partially related to regulation of methylation. The high level of COP9 signalosome conservation among eukaryotes may also suggest that COP9 signalosome regulates methylation not only in plants but also in other eukaryotes, including humans. Supplementary information Supplementary data are available at Bioinformatics online.

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