المؤلفون: Luigi Ferrucci, Katrina N Estep, Thomas J. Butler, Robert W. Maul, David Schlessinger, Andrew R. Wood, Marcus A. Tuke, Joshua A. Sommers, Thomas A. Guilliam, Francesco Cucca, Daniel F. Bogenhagen, Alicia K. Byrd, Aidan J. Doherty, Stefania Bandinelli, Robert M. Brosh, Sanjay Kumar Bharti, Elena Yakubovskaya, Miguel Garcia-Diaz, Ann Zenobia Moore, Jun Ding, Kevin D. Raney

المصدر: Hum Mol Genet

مصطلحات موضوعية: DNA Replication, Mitochondrial DNA, Guanine, DNA Primase, DNA-Directed DNA Polymerase, DNA, Mitochondrial, Genome, DNA sequencing, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Genetics, Humans, Molecular Biology, Genetics (clinical), 030304 developmental biology, 0303 health sciences, Whole Genome Sequencing, biology, DNA synthesis, DNA Helicases, DNA replication, Helicase, General Medicine, Multifunctional Enzymes, DNA Polymerase gamma, Mitochondria, Cell biology, G-Quadruplexes, Italy, chemistry, Mutagenesis, Genome, Mitochondrial, Mutation, biology.protein, Nucleic Acid Conformation, General Article, 030217 neurology & neurosurgery, DNA, Mitochondrial DNA replication

الوصف: As the powerhouses of the eukaryotic cell, mitochondria must maintain their genomes which encode proteins essential for energy production. Mitochondria are characterized by guanine-rich DNA sequences that spontaneously form unusual three-dimensional structures known as G-quadruplexes (G4). G4 structures can be problematic for the essential processes of DNA replication and transcription because they deter normal progression of the enzymatic-driven processes. In this study, we addressed the hypothesis that mitochondrial G4 is a source of mutagenesis leading to base-pair substitutions. Our computational analysis of 2757 individual genomes from two Italian population cohorts (SardiNIA and InCHIANTI) revealed a statistically significant enrichment of mitochondrial mutations within sequences corresponding to stable G4 DNA structures. Guided by the computational analysis results, we designed biochemical reconstitution experiments and demonstrated that DNA synthesis by two known mitochondrial DNA polymerases (Pol γ, PrimPol) in vitro was strongly blocked by representative stable G4 mitochondrial DNA structures, which could be overcome in a specific manner by the ATP-dependent G4-resolving helicase Pif1. However, error-prone DNA synthesis by PrimPol using the G4 template sequence persisted even in the presence of Pif1. Altogether, our results suggest that genetic variation is enriched in G-quadruplex regions that impede mitochondrial DNA replication.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::5afb2d119be5d18078f77c07bad4b4f8Test
https://doi.org/10.1093/hmg/ddaa043Test

المؤلفون: Jacob K. Kresovich, Jerome I. Rotter, James S. Pankow, Laura M. Raffield, André G. Uitterlinden, Hemant K. Tiwari, Dorret I. Boomsma, Marguerite R. Irvin, Kaare Christensen, Lili Milani, Jonas Mengel-From, Scott M. Ratliff, Peter Durda, James G. Wilson, Xiaochuan Wang, Rui Xia, Jordana T. Bell, Jenny van Dongen, Pamela R. Matias-Garcia, Alexander P. Reiner, Andrew M. McIntosh, Toshiko Tanaka, Sharon L.R. Kardia, Rebecca C Richmond, Konstantin Strauch, Rosie M. Walker, Dale P. Sandler, Amit Patki, Teemu Palviainen, Wei Chen, Pei-Chien Tsai, Medea Imboden, Stefania Bandinelli, Mika Kähönen, Xiuqing Guo, Stephen S. Rich, Oliver Robinson, Riccardo E. Marioni, Jie Yao, Debbie A Lawlor, Pierre Antoine Dugué, Roger L. Milne, Yunzhang Wang, Jennifer A. Smith, Nancy L. Pedersen, Matthijs D. van der Zee, Pashupati P. Mishra, Pei-Lun Kuo, Steve Horvath, Miina Ollikainen, Massimo Mangino, Melissa C. Southey, Ayoung Jeong, Linda Broer, Dianjianyi Sun, Tom G. Richardson, David Van Den Berg, Jack A. Taylor, Beate Ritz, Jeesun Jung, Caroline L Relton, Sarah E. Harris, Josine L. Min, Caroline Hayward, Eric Boerwinkle, Jaakko Kaprio, Melanie Waldenberger, David J. Porteous, Seyma Katrinli, Gibran Hemani, Olli T. Raitakari, Paolo Vineis, Silvia Polidoro, Karen N. Conneely, Christian Gieger, Donna K. Arnett, Marianne Nygaard, Maria K. Sobczyk, Therese Tillin, Falk W. Lohoff, Adolfo Correa, Wei Zhao, Elina Sillanpää, Zongli Xu, Joanne M. Murabito, John Wright, Gail Davies, Sara Hägg, Mette Soerensen, Alexandra M. Binder, Ann Zenobia Moore, Eco J. C. de Geus, Terho Lehtimäki, Dan Mason, Daniel L. McCartney, Myriam Fornage, Ian J. Deary, Alicia K. Smith, Joyce B. J. van Meurs, Ake T. Lu, Hannah R Elliott, Annette Peters, Silva Kasela, Idil Yet, Luigi Ferrucci, Shengxu Li, Nicole Probst-Hensch, Paul Elliott, Kathryn L. Lunetta

المساهمون: Tampere University, Department of Clinical Chemistry, Clinical Medicine, Department of Clinical Physiology and Nuclear Medicine, Institute for Molecular Medicine Finland, Genetic Epidemiology, Helsinki Institute of Life Science HiLIFE, Department of Public Health, Medical Research Council (MRC), Home Office, Imperial College Healthcare NHS Trust- BRC Funding, Internal Medicine, Epidemiology, Biological Psychology, APH - Mental Health, APH - Personalized Medicine, APH - Methodology

المصدر: Genome Biology, Vol 22, Iss 1, Pp 1-25 (2021)
Genome Biology
Mccartney, D L, Min, J L, Richmond, R C, Lu, A T, Sobczyk, M K, Davies, G, Broer, L, Guo, X, Jeong, A, Jung, J, Kasela, S, Katrinli, S, Kuo, P, Matias-garcia, P R, Mishra, P P, Nygaard, M, Palviainen, T, Patki, A, Raffield, L M, Ratliff, S M, Richardson, T G, Robinson, O, Soerensen, M, Sun, D, Tsai, P, Van Der Zee, M D, Walker, R M, Wang, X, Wang, Y, Xia, R, Xu, Z, Yao, J, Zhao, W, Correa, A, Boerwinkle, E, Dugué, P, Durda, P, Elliott, H R, Gieger, C, De Geus, E J C, Harris, S E, Hemani, G, Imboden, M, Kähönen, M, Kardia, S L R, Kresovich, J K, Li, S, Lunetta, K L, Mangino, M, Mason, D, Mcintosh, A M, Mengel-from, J, Moore, A Z, Murabito, J M, Ollikainen, M, Pankow, J S, Pedersen, N L, Peters, A, Polidoro, S, Porteous, D J, Raitakari, O, Rich, S S, Sandler, D P, Sillanpää, E, Smith, A K, Southey, M C, Strauch, K, Tiwari, H, Tanaka, T, Tillin, T, Uitterlinden, A G, Van Den Berg, D J, Van Dongen, J, Wilson, J G, Wright, J, Yet, I, Arnett, D, Bandinelli, S, Bell, J T, Binder, A M, Boomsma, D I, Chen, W, Christensen, K, Conneely, K N, Elliott, P, Ferrucci, L, Fornage, M, Hägg, S, Hayward, C, Irvin, M, Kaprio, J, Lawlor, D A, Lehtimäki, T, Lohoff, F W, Milani, L, Milne, R L, Probst-hensch, N, Reiner, A P, Ritz, B, Rotter, J I, Smith, J A, Taylor, J A, Van Meurs, J B J, Vineis, P, Waldenberger, M, Deary, I J, Relton, C L, Horvath, S & Marioni, R E 2021, ' Genome-wide association studies identify 137 genetic loci for DNA methylation biomarkers of aging ', Genome Biology, vol. 22, no. 1 . https://doi.org/10.1186/s13059-021-02398-9Test
McCartney, D L, Min, J L, Richmond, R C, Lu, A T, Sobczyk, M K, Davies, G, Broer, L, Guo, X, Jeong, A, Jung, J, Kasela, S, Katrinli, S, Kuo, P L, Matias-Garcia, P R, Mishra, P P, Nygaard, M, Palviainen, T, Patki, A, Raffield, L M, Ratliff, S M, Richardson, T G, Robinson, O, Soerensen, M, Sun, D, Tsai, P C, van der Zee, M D, Walker, R M, Wang, X, Wang, Y, Xia, R, Xu, Z, Yao, J, Zhao, W, Correa, A, Boerwinkle, E, Dugué, P A, Durda, P, Elliott, H R, Gieger, C, de Geus, E J C, Harris, S E, Hemani, G, Imboden, M, Kähönen, M, Kardia, S L R, Kresovich, J K, Li, S, Lunetta, K L, Mengel-From, J, Christensen, K, The Genetics of DNA Methylation Consortium & NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium 2021, ' Genome-wide association studies identify 137 genetic loci for DNA methylation biomarkers of aging ', Genome Biology, vol. 22, 194 . https://doi.org/10.1186/s13059-021-02398-9Test
McCartney, D L, van der Zee, M D, de Geus, E J C, van Dongen, J, Boomsma, D I, Marioni, R E, The Genetics of DNA Methylation Consortium & NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium 2021, ' Genome-wide association studies identify 137 genetic loci for DNA methylation biomarkers of aging ', Genome Biology, vol. 22, no. 1, 194, pp. 1-25 . https://doi.org/10.1186/s13059-021-02398-9Test
Genome Biol. 22:194 (2021)
McCartney, D L, Min, J L, Richmond, R C, Lu, A T, Sobczyk, M K, Davies, G, Broer, L, Guo, X, Jeong, A, Jung, J, Kasela, S, Katrinli, S, Kuo, P-L, Matias-Garcia, P R, Mishra, P P, Nygaard, M, Palviainen, T, Patki, A, Raffield, L M, Ratliff, S M, Richardson, T G, Robinson, O, Soerensen, M, Sun, D, Tsai, P-C, van der Zee, M D, Walker, R M, Wang, X, Wang, Y, Xia, R, Xu, Z, Yao, J, Zhao, W, Correa, A, Boerwinkle, E, Dugué, P-A, Durda, P, Elliott, H R, Gieger, C, de Geus, E J C, Harris, S E, Hemani, G, Smith, A K, Wright, J, Lawlor, D A, Relton, C L, Horvath, S & Marioni, R E & et, A 2021, ' Genome-wide association studies identify 137 genetic loci for DNA methylation biomarkers of aging ', Genome Biology, vol. 22, no. 1, 194, pp. 194 . https://doi.org/10.1186/s13059-021-02398-9Test
Genome Biology, 22(1):194. BioMed Central Ltd.
Genome Biology, 22(1):194, 1-25. Springer Verlag

مصطلحات موضوعية: Aging, Multifactorial Inheritance, BLOOD, Epigenetic clock, 05 Environmental Sciences, biomarkkerit, Genome-wide association study, QH426-470, Epigenesis, Genetic, 0302 clinical medicine, Biomarkers of aging, GWAS, Biology (General), Adiposity, Genetics, 11832 Microbiology and virology, 0303 health sciences, 318 Medical biotechnology, DNA methylation, 1184 Genetics, developmental biology, physiology, genomiikka, Dna Methylation, Epigenetic Clock, Gwas, ddc, DNA-metylaatio, INSIGHTS, C-Reactive Protein, epigenetiikka, MENDELIAN RANDOMIZATION, Educational Status, ICEP, Genetic Markers, PROVIDES, SUSCEPTIBILITY LOCI, Bioinformatics, QH301-705.5, Genomics, Biology, 03 medical and health sciences, NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, AGE, SDG 3 - Good Health and Well-being, Plasminogen Activator Inhibitor 1, REGRESSION, Humans, Epigenetics, Gene, METAANALYSIS, 030304 developmental biology, Genome, Human, Research, Genetics of DNA Methylation Consortium, 06 Biological Sciences, Lipid Metabolism, Human genetics, Genetic architecture, Immunity, Innate, ikääntyminen, Genetic Loci, CpG Islands, 08 Information and Computing Sciences, 3111 Biomedicine, ENRICHMENT, epigenetic clock, 030217 neurology & neurosurgery, Biomarkers, Genome-Wide Association Study, Granulocytes

الوصف: Background Biological aging estimators derived from DNA methylation data are heritable and correlate with morbidity and mortality. Consequently, identification of genetic and environmental contributors to the variation in these measures in populations has become a major goal in the field. Results Leveraging DNA methylation and SNP data from more than 40,000 individuals, we identify 137 genome-wide significant loci, of which 113 are novel, from genome-wide association study (GWAS) meta-analyses of four epigenetic clocks and epigenetic surrogate markers for granulocyte proportions and plasminogen activator inhibitor 1 levels, respectively. We find evidence for shared genetic loci associated with the Horvath clock and expression of transcripts encoding genes linked to lipid metabolism and immune function. Notably, these loci are independent of those reported to regulate DNA methylation levels at constituent clock CpGs. A polygenic score for GrimAge acceleration showed strong associations with adiposity-related traits, educational attainment, parental longevity, and C-reactive protein levels. Conclusion This study illuminates the genetic architecture underlying epigenetic aging and its shared genetic contributions with lifestyle factors and longevity.

وصف الملف: fulltext; application/pdf

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::7d4c22aaef8ad6a80ac07f88cd86c101Test
https://trepo.tuni.fi/handle/10024/133417Test

المؤلفون: Stefania Bandinelli, Julián Candia, Birgit Schilling, Nathan Basisty, Luigi Ferrucci, Angelique Biancotto, Giovanna Fantoni, Toshiko Tanaka, Ann Zenobia Moore

المصدر: eLife
eLife, Vol 9 (2020)

مصطلحات موضوعية: Adult, Male, Proteomics, 0301 basic medicine, Aging, medicine.medical_specialty, QH301-705.5, Science, Inflammation, healthspan, Disease, Bioinformatics, General Biochemistry, Genetics and Molecular Biology, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Risk Factors, Epidemiology, medicine, Humans, Biology (General), Risk factor, Aged, Aged, 80 and over, General Immunology and Microbiology, business.industry, General Neuroscience, Blood Proteins, General Medicine, Middle Aged, Blood proteins, Epidemiology and Global Health, 030104 developmental biology, Secretory protein, Medicine, biomarker, Biomarker (medicine), Female, medicine.symptom, business, Biomarkers, 030217 neurology & neurosurgery, Research Article, Computational and Systems Biology, Human

الوصف: Older age is a strong shared risk factor for many chronic diseases, and there is increasing interest in identifying aging biomarkers. Here, a proteomic analysis of 1301 plasma proteins was conducted in 997 individuals between 21 and 102 years of age. We identified 651 proteins associated with age (506 over-represented, 145 underrepresented with age). Mediation analysis suggested a role for partialcis-epigenetic control of protein expression with age. Of the age-associated proteins, 33.5% and 45.3%, were associated with mortality and multimorbidity, respectively. There was enrichment of proteins associated with inflammation and extracellular matrix as well as senescence-associated secretory proteins. A 76-protein proteomic age signature predicted accumulation of chronic diseases and all-cause mortality. These data support the use of proteomic biomarkers to monitor aging trajectories and to identify individuals at higher risk of disease to be targeted for in depth diagnostic procedures and early interventions.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::e694d300976a96e51a5b8fec74ad3abfTest
https://doi.org/10.7554/elife.61073Test

المؤلفون: Nicole Probst-Hensch, Idil Yet, Rui Xia, Jordana T. Bell, Luigi Ferrucci, Hannah R Elliott, Jaakko Kaprio, Melanie Waldenberger, Mika Kähönen, Seyma Katrinli, Paul Elliott, Kathryn L. Lunetta, Josine L. Min, Teemu Palviainen, Scott M. Ratliff, Dan Mason, Xiaochuan Wang, Donna K. Arnett, Paolo Vineis, Stefania Bandinelli, Linda Broer, Toshiko Tanaka, Daniel L. McCartney, Falk W. Lohoff, Pei-Lun Kuo, Roger L. Milne, Ake T. Lu, Stephen S. Rich, Silvia Polidoro, Karen N. Conneely, Andrew M. McIntosh, Jeesun Jung, David Van Den Berg, Yunzhang Wang, Marianne Nygaard, Ayoung Jeong, Konstantin Strauch, Eric Boerwinkle, Massimo Mangino, Melissa C. Southey, Caroline Hayward, Jack A. Taylor, Eco J. C. de Geus, Therese Tillin, Steve Horvath, Beate Ritz, Peter Durda, Ann Zenobia Moore, André G. Uitterlinden, Annette Peters, Silva Kasela, David J. Porteous, James G. Wilson, Wei Zhao, Terho Lehtimäki, Maria K. Sobczyk, Elina Sillanpää, Adolfo Correa, Rebecca C. Richmond, Zongli Xu, Myriam Fornage, Pamela R. Matias-Garcia, Medea Imboden, Ian J. Deary, Alicia K. Smith, Jie Yao, John Wright, Dorret I. Boomsma, Joanne M. Murabito, Mette Soerensen, Gail Davies, James S. Pankow, Pashupati P. Mishra, Alexandra M. Binder, Jennifer A. Smith, Sara Hägg, Gibran Hemani, Joyce B. J. van Meurs, Christian Gieger, Miina Ollikainen, Jenny van Dongen, Oliver Robinson, Marguerite R. Irvin, Wei Chen, Pei-Chien Tsai, Caroline L. Relton, Shengxu Li, Jacob K. Kresovich, Riccardo E. Marioni, Jonas Mengel-From, Deborah A. Lawlor, Xiuqing Guo, Matthijs D. van der Zee, Nancy L. Pedersen, Sarah E. Harris, Dianjianyi Sun, Rosie M. Walker, Pierre Antoine Dugué, Olli T. Raitakari, Laura M. Raffield, Kaare Christensen, Hemant K. Tiwari, Dale P. Sandler, Alexander P. Reiner, Amit Patki, Lili Milani, Jerome I. Rotter, Tom G. Richardson, Sharon L.R. Kardia

مصطلحات موضوعية: African american, Genetics, 0303 health sciences, dNaM, Genome-wide association study, Biology, Genome, 3. Good health, 03 medical and health sciences, 0302 clinical medicine, Ageing, DNA methylation, Parental longevity, Epigenetics, 030217 neurology & neurosurgery, 030304 developmental biology

الوصف: Biological ageing estimators derived from DNA methylation (DNAm) data are heritable and correlate with morbidity and mortality. Leveraging DNAm and SNP data from >41,000 individuals, we identify 137 genome-wide significant loci (113 novel) from meta-analyses of four epigenetic clocks and epigenetic surrogate markers for granulocyte proportions and plasminogen activator inhibitor 1 levels, respectively. We report strong genetic correlations with longevity and lifestyle factors such as smoking, education, and obesity. Significant associations are observed in polygenic risk score analysis and to a lesser extent in Mendelian randomization analyses. This study illuminates the genetic architecture underlying epigenetic ageing and its shared genetic contributions with lifestyle factors and longevity.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_________::bb2c1881dadc6c863e5931c8f31b752dTest
https://doi.org/10.1101/2020.06.29.133702Test

المؤلفون: Amy R. Vandiver, Toshiko Tanaka, Leonid Padyukov, Xin Li, Andrew P. Feinberg, Yun Liu, Luigi Ferrucci, Martin J. Aryee, Ann Zenobia Moore, Tomas J. Ekström, M. Daniele Fallin, Lars Klareskog

المصدر: American journal of human genetics. 94(4)

مصطلحات موضوعية: Linkage disequilibrium, Genome-wide association study, Quantitative trait locus, Biology, Polymorphism, Single Nucleotide, Linkage Disequilibrium, Article, Epigenesis, Genetic, 03 medical and health sciences, 0302 clinical medicine, Genetics, Humans, Genetics(clinical), Genetic Predisposition to Disease, Epigenetics, RNA-Directed DNA Methylation, Genetics (clinical), 030304 developmental biology, Genetic association, 0303 health sciences, Smoking, Methylation, DNA Methylation, DNA methylation, 030217 neurology & neurosurgery, Genome-Wide Association Study

الوصف: Epigenetic marks such as DNA methylation have generated great interest in the study of human disease. However, studies of DNA methylation have not established population-epigenetics principles to guide design, efficient statistics, or interpretation. Here, we show that the clustering of correlated DNA methylation at CpGs was similar to that of linkage-disequilibrium (LD) correlation in genetic SNP variation but for much shorter distances. Some clustering of methylated CpGs appeared to be genetically driven. Further, a set of correlated methylated CpGs related to a single SNP-based LD block was not always physically contiguous—segments of uncorrelated methylation as long as 300 kb could be interspersed in the cluster. Thus, we denoted these sets of correlated CpGs as GeMes, defined as potentially noncontiguous methylation clusters under the control of one or more methylation quantitative trait loci. This type of correlated methylation structure has implications for both biological functions of DNA methylation and for the design, analysis, and interpretation of epigenome-wide association studies.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::8e4521f689812a498d64a59cd894a6efTest
https://pubmed.ncbi.nlm.nih.gov/24656863Test

المؤلفون: Kenneth W. Fishbein, Ann Zenobia Moore, Luigi Ferrucci, Richard G. Spencer, Sokratis Makrogiannis

المصدر: IEEE Transactions on Biomedical Engineering. :1-1

مصطلحات موضوعية: Computer science, Biomedical Engineering, Adipose tissue, Predictive capability, Thigh, Muscle mass, computer.software_genre, Article, 030218 nuclear medicine & medical imaging, 03 medical and health sciences, 0302 clinical medicine, Voxel, Image Processing, Computer-Assisted, medicine, Humans, Tissue distribution, Muscle, Skeletal, Aged, Models, Statistical, medicine.diagnostic_test, Skeletal muscle, Magnetic resonance imaging, Middle Aged, Magnetic Resonance Imaging, Characterization (materials science), medicine.anatomical_structure, Female, Functional status, computer, Algorithms, 030217 neurology & neurosurgery, Image based, Biomedical engineering

الوصف: The identification and characterization of regional body tissues is essential to understand changes that occur with aging and age-related metabolic diseases such as diabetes and obesity and how these diseases affect trajectories of health and functional status. Imaging technologies are frequently used to derive volumetric, area, and density measurements of different tissues. Despite the significance and direct applicability of automated tissue quantification and characterization techniques, these topics have remained relatively under-explored in the medical image analysis literature. We present a method for identification and characterization of muscle and adipose tissue in the mid-thigh region using MRI. We propose an image-based muscle quality prediction technique that estimates tissue-specific probability density models and their eigenstructures in the joint domain of water- and fat-suppressed voxel signal intensities along with volumetric and intensity-based tissue characteristics computed during the quantification stage. We evaluated the predictive capability of our approach against reference biomechanical muscle quality measurements using statistical tests and classification performance experiments. The reference standard for muscle quality is defined as the ratio of muscle strength to muscle mass. The results show promise for the development of non-invasive image-based muscle quality descriptors.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::6ec228532620b3053a12dfca3408ddf2Test
https://doi.org/10.1109/tbme.2015.2474305Test