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With the modern quality, quantity, and availability of genomic sequencing across species, as well as across the expanse of human populations, we can screen for shared signatures underlying longevity and lifespan. Knowledge of these mechanisms would be medically invaluable in combating aging and age-related diseases. The diversity of longevities across vertebrates is an opportunity to look for patterns of genetic variation that may signal how this life history property is regulated, and ultimately how it can be modulated. Variation in human longevity provides a unique window to look for cases of extreme lifespan within a population, as well as associations across populations for factors that influence capacity to live longer. Current large cohort studies support the use of population level analyses to identify key factors associating with human lifespan. These studies are powerful in concept, but have demonstrated limited ability to resolve signals from background variation. In parallel, the expanding catalog of sequencing and annotation from diverse species, some of which have evolved longevities well past a human lifespan, provides independent cases to look at the genomic signatures of longevity. Recent comparative genomic work has shown promise in finding shared mechanisms associating with longevity among distantly related vertebrate groups. Given the genetic constraints between vertebrates, we posit that a combination of approaches, of parallel meta-analysis of human longevity along with refined analysis of other vertebrate clades having exceptional longevity, will aid in resolving key regulators of enhanced lifespan that have proven to be elusive when analyzed in isolation.
Stephen Treaster; David Karasik; Matthew P. Harris. Footprints in the Sand: Deep Taxonomic Comparisons in Vertebrate Genomics to Unveil the Genetic Programs of Human Longevity. Frontiers in Genetics 2021, 12, 1 .
AMA StyleStephen Treaster, David Karasik, Matthew P. Harris. Footprints in the Sand: Deep Taxonomic Comparisons in Vertebrate Genomics to Unveil the Genetic Programs of Human Longevity. Frontiers in Genetics. 2021; 12 ():1.
Chicago/Turabian StyleStephen Treaster; David Karasik; Matthew P. Harris. 2021. "Footprints in the Sand: Deep Taxonomic Comparisons in Vertebrate Genomics to Unveil the Genetic Programs of Human Longevity." Frontiers in Genetics 12, no. : 1.
Genome‐wide association studies (GWAS) have improved our understanding of the genetic architecture of common, complex diseases such as osteoporosis. Nevertheless, to attribute functional skeletal contributions of candidate genes to osteoporosis‐related traits there is a need for efficient and cost‐effective in vivo functional testing. This can be achieved through CRISPR‐based reverse genetic screens, where phenotyping is traditionally performed in stable germline KO mutants. Recently it was shown that first‐generation (F0) mosaic mutant zebrafish (so‐called crispants) recapitulate the phenotype of germline KOs. To demonstrate feasibility of functional validation of osteoporosis candidate genes through crispant screening, we compared a crispant to a stable KO zebrafish model for the lrp5 gene. In humans, recessive loss‐of‐function mutations in LRP5, a co‐receptor in the Wnt signaling pathway, cause Osteoporosis‐pseudoglioma syndrome. In addition, several GWAS studies identified LRP5 as a major risk locus for osteoporosis‐related phenotypes. In this study, we showed that early stage lrp5 KO larvae display decreased notochord mineralization and malformations of the head cartilage. Quantitative micro‐computed tomography (microCT) scanning and mass‐spectrometry element analysis of the adult skeleton revealed decreased vertebral bone volume and bone mineralization, hallmark features of osteoporosis. Furthermore, regenerating fin tissue displayed reduced Wnt signaling activity in lrp5 KO adults. We next compared lrp5 mutants with crispants. Next‐generation sequencing analysis of adult crispant tissue revealed a mean out‐of‐frame mutation rate of 76%, resulting in strongly reduced levels of Lrp5 protein. These crispants generally showed a milder, but nonetheless highly comparable skeletal phenotype and a similarly reduced Wnt pathway response compared to lrp5 KO mutants. In conclusion, we show through faithful modeling of LRP5‐related primary osteoporosis, that crispant screening in zebrafish is a promising approach for rapid functional screening of osteoporosis candidate genes.
Jan Willem Bek; Chen Shochat; Adelbert De Clercq; Hanna De Saffel; Annekatrien Boel; Juriaan Metz; Frans Rodenburg; David Karasik; Andy Willaert; Paul J. Coucke. Lrp5 Mutant and Crispant Zebrafish Faithfully Model Human Osteoporosis, Establishing the Zebrafish as a Platform for CRISPR ‐Based Functional Screening of Osteoporosis Candidate Genes. Journal of Bone and Mineral Research 2021, 1 .
AMA StyleJan Willem Bek, Chen Shochat, Adelbert De Clercq, Hanna De Saffel, Annekatrien Boel, Juriaan Metz, Frans Rodenburg, David Karasik, Andy Willaert, Paul J. Coucke. Lrp5 Mutant and Crispant Zebrafish Faithfully Model Human Osteoporosis, Establishing the Zebrafish as a Platform for CRISPR ‐Based Functional Screening of Osteoporosis Candidate Genes. Journal of Bone and Mineral Research. 2021; ():1.
Chicago/Turabian StyleJan Willem Bek; Chen Shochat; Adelbert De Clercq; Hanna De Saffel; Annekatrien Boel; Juriaan Metz; Frans Rodenburg; David Karasik; Andy Willaert; Paul J. Coucke. 2021. "Lrp5 Mutant and Crispant Zebrafish Faithfully Model Human Osteoporosis, Establishing the Zebrafish as a Platform for CRISPR ‐Based Functional Screening of Osteoporosis Candidate Genes." Journal of Bone and Mineral Research , no. : 1.
A Correction to this paper has been published: https://doi.org/10.1038/s41467-021-22613-2
Joris Deelen; Daniel S. Evans; Dan E. Arking; Niccolò Tesi; Marianne Nygaard; Xiaomin Liu; Mary K. Wojczynski; Mary L. Biggs; Ashley van der Spek; Gil Atzmon; Erin B. Ware; Chloé Sarnowski; Albert V. Smith; Ilkka Seppälä; Heather J. Cordell; Janina Dose; Najaf Amin; Alice M. Arnold; Kristin L. Ayers; Nir Barzilai; Elizabeth J. Becker; Marian Beekman; Hélène Blanché; Kaare Christensen; Lene Christiansen; Joanna C. Collerton; Sarah Cubaynes; Steven R. Cummings; Karen Davies; Birgit Debrabant; Jean-François Deleuze; Rachel Duncan; Jessica D. Faul; Claudio Franceschi; Pilar Galan; Vilmundur Gudnason; Tamara B. Harris; Martijn Huisman; Mikko A. Hurme; Carol Jagger; Iris Jansen; Marja Jylhä; Mika Kähönen; David Karasik; Sharon L. R. Kardia; Andrew Kingston; Thomas B. L. Kirkwood; Lenore J. Launer; Terho Lehtimäki; Wolfgang Lieb; Leo-Pekka Lyytikäinen; Carmen Martin-Ruiz; Junxia Min; Almut Nebel; Anne B. Newman; Chao Nie; Ellen A. Nohr; Eric S. Orwoll; Thomas T. Perls; Michael A. Province; Bruce M. Psaty; Olli T. Raitakari; Marcel J. T. Reinders; Jean-Marie Robine; Jerome I. Rotter; Paola Sebastiani; Jennifer Smith; Thorkild I. A. Sørensen; Kent D. Taylor; André G. Uitterlinden; Wiesje van der Flier; Sven J. van der Lee; Cornelia M. van Duijn; Diana van Heemst; James W. Vaupel; David Weir; Kenny Ye; Yi Zeng; Wanlin Zheng; Henne Holstege; Douglas P. Kiel; Kathryn L. Lunetta; P. Eline Slagboom; Joanne M. Murabito. Publisher Correction: A meta-analysis of genome-wide association studies identifies multiple longevity genes. Nature Communications 2021, 12, 1 -1.
AMA StyleJoris Deelen, Daniel S. Evans, Dan E. Arking, Niccolò Tesi, Marianne Nygaard, Xiaomin Liu, Mary K. Wojczynski, Mary L. Biggs, Ashley van der Spek, Gil Atzmon, Erin B. Ware, Chloé Sarnowski, Albert V. Smith, Ilkka Seppälä, Heather J. Cordell, Janina Dose, Najaf Amin, Alice M. Arnold, Kristin L. Ayers, Nir Barzilai, Elizabeth J. Becker, Marian Beekman, Hélène Blanché, Kaare Christensen, Lene Christiansen, Joanna C. Collerton, Sarah Cubaynes, Steven R. Cummings, Karen Davies, Birgit Debrabant, Jean-François Deleuze, Rachel Duncan, Jessica D. Faul, Claudio Franceschi, Pilar Galan, Vilmundur Gudnason, Tamara B. Harris, Martijn Huisman, Mikko A. Hurme, Carol Jagger, Iris Jansen, Marja Jylhä, Mika Kähönen, David Karasik, Sharon L. R. Kardia, Andrew Kingston, Thomas B. L. Kirkwood, Lenore J. Launer, Terho Lehtimäki, Wolfgang Lieb, Leo-Pekka Lyytikäinen, Carmen Martin-Ruiz, Junxia Min, Almut Nebel, Anne B. Newman, Chao Nie, Ellen A. Nohr, Eric S. Orwoll, Thomas T. Perls, Michael A. Province, Bruce M. Psaty, Olli T. Raitakari, Marcel J. T. Reinders, Jean-Marie Robine, Jerome I. Rotter, Paola Sebastiani, Jennifer Smith, Thorkild I. A. Sørensen, Kent D. Taylor, André G. Uitterlinden, Wiesje van der Flier, Sven J. van der Lee, Cornelia M. van Duijn, Diana van Heemst, James W. Vaupel, David Weir, Kenny Ye, Yi Zeng, Wanlin Zheng, Henne Holstege, Douglas P. Kiel, Kathryn L. Lunetta, P. Eline Slagboom, Joanne M. Murabito. Publisher Correction: A meta-analysis of genome-wide association studies identifies multiple longevity genes. Nature Communications. 2021; 12 (1):1-1.
Chicago/Turabian StyleJoris Deelen; Daniel S. Evans; Dan E. Arking; Niccolò Tesi; Marianne Nygaard; Xiaomin Liu; Mary K. Wojczynski; Mary L. Biggs; Ashley van der Spek; Gil Atzmon; Erin B. Ware; Chloé Sarnowski; Albert V. Smith; Ilkka Seppälä; Heather J. Cordell; Janina Dose; Najaf Amin; Alice M. Arnold; Kristin L. Ayers; Nir Barzilai; Elizabeth J. Becker; Marian Beekman; Hélène Blanché; Kaare Christensen; Lene Christiansen; Joanna C. Collerton; Sarah Cubaynes; Steven R. Cummings; Karen Davies; Birgit Debrabant; Jean-François Deleuze; Rachel Duncan; Jessica D. Faul; Claudio Franceschi; Pilar Galan; Vilmundur Gudnason; Tamara B. Harris; Martijn Huisman; Mikko A. Hurme; Carol Jagger; Iris Jansen; Marja Jylhä; Mika Kähönen; David Karasik; Sharon L. R. Kardia; Andrew Kingston; Thomas B. L. Kirkwood; Lenore J. Launer; Terho Lehtimäki; Wolfgang Lieb; Leo-Pekka Lyytikäinen; Carmen Martin-Ruiz; Junxia Min; Almut Nebel; Anne B. Newman; Chao Nie; Ellen A. Nohr; Eric S. Orwoll; Thomas T. Perls; Michael A. Province; Bruce M. Psaty; Olli T. Raitakari; Marcel J. T. Reinders; Jean-Marie Robine; Jerome I. Rotter; Paola Sebastiani; Jennifer Smith; Thorkild I. A. Sørensen; Kent D. Taylor; André G. Uitterlinden; Wiesje van der Flier; Sven J. van der Lee; Cornelia M. van Duijn; Diana van Heemst; James W. Vaupel; David Weir; Kenny Ye; Yi Zeng; Wanlin Zheng; Henne Holstege; Douglas P. Kiel; Kathryn L. Lunetta; P. Eline Slagboom; Joanne M. Murabito. 2021. "Publisher Correction: A meta-analysis of genome-wide association studies identifies multiple longevity genes." Nature Communications 12, no. 1: 1-1.
The recently emerged SARS-CoV-2 virus is responsible for the ongoing COVID-19 pandemic that has rapidly developed into a global public health threat. Patients severely affected with COVID-19 present distinct clinical features, including acute respiratory disorder, neutrophilia, cytokine storm, and sepsis. In addition, multiple pro-inflammatory cytokines are found in the plasma of such patients. Transcriptome sequencing of different specimens obtained from patients suffering from severe episodes of COVID-19 shows dynamics in terms of their immune responses. However, those host factors required for SARS-CoV-2 propagation and the underlying molecular mechanisms responsible for dysfunctional immune responses during COVID-19 infection remain elusive. In the present study, we analyzed the mRNA-long non-coding RNA (lncRNA) co-expression network derived from publicly available SARS-CoV-2-infected transcriptome data of human lung epithelial cell lines and bronchoalveolar lavage fluid (BALF) from COVID-19 patients. Through co-expression network analysis, we identified four differentially expressed lncRNAs strongly correlated with genes involved in various immune-related pathways crucial for cytokine signaling. Our findings suggest that the aberrant expression of these four lncRNAs can be associated with cytokine storms and anti-viral responses during severe SARS-CoV-2 infection of the lungs. Thus, the present study uncovers molecular interactions behind the cytokine storm activation potentially responsible for hyper-inflammatory responses in critical COVID-19 patients.
Sumit Mukherjee; Bodhisattwa Banerjee; David Karasik; Milana Frenkel-Morgenstern. mRNA-lncRNA Co-Expression Network Analysis Reveals the Role of lncRNAs in Immune Dysfunction during Severe SARS-CoV-2 Infection. Viruses 2021, 13, 402 .
AMA StyleSumit Mukherjee, Bodhisattwa Banerjee, David Karasik, Milana Frenkel-Morgenstern. mRNA-lncRNA Co-Expression Network Analysis Reveals the Role of lncRNAs in Immune Dysfunction during Severe SARS-CoV-2 Infection. Viruses. 2021; 13 (3):402.
Chicago/Turabian StyleSumit Mukherjee; Bodhisattwa Banerjee; David Karasik; Milana Frenkel-Morgenstern. 2021. "mRNA-lncRNA Co-Expression Network Analysis Reveals the Role of lncRNAs in Immune Dysfunction during Severe SARS-CoV-2 Infection." Viruses 13, no. 3: 402.
Low muscle strength is an important heritable indicator of poor health linked to morbidity and mortality in older people. In a genome-wide association study meta-analysis of 256,523 Europeans aged 60 years and over from 22 cohorts we identify 15 loci associated with muscle weakness (European Working Group on Sarcopenia in Older People definition: n = 48,596 cases, 18.9% of total), including 12 loci not implicated in previous analyses of continuous measures of grip strength. Loci include genes reportedly involved in autoimmune disease (HLA-DQA1 p = 4 × 10−17), arthritis (GDF5 p = 4 × 10−13), cell cycle control and cancer protection, regulation of transcription, and others involved in the development and maintenance of the musculoskeletal system. Using Mendelian randomization we report possible overlapping causal pathways, including diabetes susceptibility, haematological parameters, and the immune system. We conclude that muscle weakness in older adults has distinct mechanisms from continuous strength, including several pathways considered to be hallmarks of ageing.
Garan Jones; Katerina Trajanoska; Adam J. Santanasto; Najada Stringa; Chia-Ling Kuo; Janice L. Atkins; Joshua R. Lewis; Thuyvy Duong; Shengjun Hong; Mary L. Biggs; Jian’An Luan; Chloe Sarnowski; Kathryn L. Lunetta; Toshiko Tanaka; Mary K. Wojczynski; Ryan Cvejkus; Maria Nethander; Sahar Ghasemi; Jingyun Yang; M. Carola Zillikens; Stefan Walter; Kamil Sicinski; Erika Kague; Cheryl L. Ackert-Bicknell; Dan E. Arking; B. Gwen Windham; Eric Boerwinkle; Megan L. Grove; Misa Graff; Dominik Spira; Ilja Demuth; Nathalie van der Velde; Lisette C. P. G. M. de Groot; Bruce M. Psaty; Michelle C. Odden; Alison E. Fohner; Claudia Langenberg; Nicholas J. Wareham; Stefania Bandinelli; Natasja M. van Schoor; Martijn Huisman; Qihua Tan; Joseph Zmuda; Dan Mellström; Magnus Karlsson; David A. Bennett; Aron S. Buchman; Philip L. De Jager; Andre G. Uitterlinden; Uwe Völker; Thomas Kocher; Alexander Teumer; Leocadio Rodriguéz-Mañas; Francisco J. García; José A. Carnicero; Pamela Herd; Lars Bertram; Claes Ohlsson; Joanne M. Murabito; David Melzer; George A. Kuchel; Luigi Ferrucci; David Karasik; Fernando Rivadeneira; Douglas P. Kiel; Luke C. Pilling. Genome-wide meta-analysis of muscle weakness identifies 15 susceptibility loci in older men and women. Nature Communications 2021, 12, 1 -11.
AMA StyleGaran Jones, Katerina Trajanoska, Adam J. Santanasto, Najada Stringa, Chia-Ling Kuo, Janice L. Atkins, Joshua R. Lewis, Thuyvy Duong, Shengjun Hong, Mary L. Biggs, Jian’An Luan, Chloe Sarnowski, Kathryn L. Lunetta, Toshiko Tanaka, Mary K. Wojczynski, Ryan Cvejkus, Maria Nethander, Sahar Ghasemi, Jingyun Yang, M. Carola Zillikens, Stefan Walter, Kamil Sicinski, Erika Kague, Cheryl L. Ackert-Bicknell, Dan E. Arking, B. Gwen Windham, Eric Boerwinkle, Megan L. Grove, Misa Graff, Dominik Spira, Ilja Demuth, Nathalie van der Velde, Lisette C. P. G. M. de Groot, Bruce M. Psaty, Michelle C. Odden, Alison E. Fohner, Claudia Langenberg, Nicholas J. Wareham, Stefania Bandinelli, Natasja M. van Schoor, Martijn Huisman, Qihua Tan, Joseph Zmuda, Dan Mellström, Magnus Karlsson, David A. Bennett, Aron S. Buchman, Philip L. De Jager, Andre G. Uitterlinden, Uwe Völker, Thomas Kocher, Alexander Teumer, Leocadio Rodriguéz-Mañas, Francisco J. García, José A. Carnicero, Pamela Herd, Lars Bertram, Claes Ohlsson, Joanne M. Murabito, David Melzer, George A. Kuchel, Luigi Ferrucci, David Karasik, Fernando Rivadeneira, Douglas P. Kiel, Luke C. Pilling. Genome-wide meta-analysis of muscle weakness identifies 15 susceptibility loci in older men and women. Nature Communications. 2021; 12 (1):1-11.
Chicago/Turabian StyleGaran Jones; Katerina Trajanoska; Adam J. Santanasto; Najada Stringa; Chia-Ling Kuo; Janice L. Atkins; Joshua R. Lewis; Thuyvy Duong; Shengjun Hong; Mary L. Biggs; Jian’An Luan; Chloe Sarnowski; Kathryn L. Lunetta; Toshiko Tanaka; Mary K. Wojczynski; Ryan Cvejkus; Maria Nethander; Sahar Ghasemi; Jingyun Yang; M. Carola Zillikens; Stefan Walter; Kamil Sicinski; Erika Kague; Cheryl L. Ackert-Bicknell; Dan E. Arking; B. Gwen Windham; Eric Boerwinkle; Megan L. Grove; Misa Graff; Dominik Spira; Ilja Demuth; Nathalie van der Velde; Lisette C. P. G. M. de Groot; Bruce M. Psaty; Michelle C. Odden; Alison E. Fohner; Claudia Langenberg; Nicholas J. Wareham; Stefania Bandinelli; Natasja M. van Schoor; Martijn Huisman; Qihua Tan; Joseph Zmuda; Dan Mellström; Magnus Karlsson; David A. Bennett; Aron S. Buchman; Philip L. De Jager; Andre G. Uitterlinden; Uwe Völker; Thomas Kocher; Alexander Teumer; Leocadio Rodriguéz-Mañas; Francisco J. García; José A. Carnicero; Pamela Herd; Lars Bertram; Claes Ohlsson; Joanne M. Murabito; David Melzer; George A. Kuchel; Luigi Ferrucci; David Karasik; Fernando Rivadeneira; Douglas P. Kiel; Luke C. Pilling. 2021. "Genome-wide meta-analysis of muscle weakness identifies 15 susceptibility loci in older men and women." Nature Communications 12, no. 1: 1-11.
Genetic studies of bone mineral density (BMD) largely have been conducted in European populations. We therefore conducted a meta‐analysis of six independent African ancestry cohorts to determine whether previously reported BMD loci identified in European populations were transferable to African ancestry populations. We included nearly 5,000 individuals with both genetic data and assessments of BMD. Genotype imputation was conducted using the 1000G reference panel. We assessed SNP associations with femoral neck and lumbar spine BMD in each cohort separately, then combined results in fixed effects (or random effects if study heterogeneity was high, I2 index > 60) inverse variance weighted meta‐analyses. In secondary analyses, we conducted locus‐based analyses of rare variants using SKAT‐O. Mean age ranged from 12 to 68 years. One cohort included only men and another cohort included only women; proportion of women in the other four cohorts ranged from 52% to 63%. Of 56 BMD loci tested, one locus, 6q25 (C6orf97, P‐value=8.87×10‐4) was associated with lumbar spine BMD and two loci, 7q21 (SLC25A13, P‐value=2.84×10‐4) and 7q31 (WNT16, P‐value=2.96×10‐5) were associated with femoral neck BMD. Effects were in the same direction as previously reported in European ancestry studies and met a Bonferroni‐adjusted P‐value threshold, the criteria for transferability to African ancestry populations. We also found associations that met locus‐specific Bonferroni‐adjusted P‐value thresholds in 11q13 (LRP5, P‐values<2.23×10‐4), 11q14 (DCDC5, P‐values<5.35×10‐5), and 17p13 (SMG6, P‐values<6.78×10‐5) that were not tagged by European ancestry index SNPs. Rare single nucleotide variants in AKAP11 (P‐value=2.32×10‐2), MBL2 (P‐value=4.09×10‐2), MEPE (P‐value=3.15×10‐2), SLC25A13 (P‐value=3.03×10‐2), STARD3NL (P‐value=3.35×10‐2), and TNFRSF11A (P‐value=3.18×10‐3) were also associated with BMD. The majority of known BMD loci were not transferable. Larger genetic studies of BMD in African ancestry populations will be needed to overcome limitations in statistical power, and to identify both other loci that are transferable across populations and novel population‐specific variants. This article is protected by copyright. All rights reserved.
Michelle S. Yau; Allison L. Kuipers; Ryan Price; Aude Nicolas; Salman M. Tajuddin; Samuel K. Handelman; Liubov Arbeeva; Alessandra Chesi; Yi‐Hsiang Hsu; Ching‐Ti Liu; David Karasik; Babette S. Zemel; Struan F.A. Grant; Joanne M. Jordan; Rebecca D. Jackson; Michele K. Evans; Tamara B. Harris; Joseph M. Zmuda; Douglas P. Kiel. A Meta‐Analysis of the Transferability of Bone Mineral Density Genetic Loci Associations From European to African Ancestry Populations. Journal of Bone and Mineral Research 2020, 36, 469 -479.
AMA StyleMichelle S. Yau, Allison L. Kuipers, Ryan Price, Aude Nicolas, Salman M. Tajuddin, Samuel K. Handelman, Liubov Arbeeva, Alessandra Chesi, Yi‐Hsiang Hsu, Ching‐Ti Liu, David Karasik, Babette S. Zemel, Struan F.A. Grant, Joanne M. Jordan, Rebecca D. Jackson, Michele K. Evans, Tamara B. Harris, Joseph M. Zmuda, Douglas P. Kiel. A Meta‐Analysis of the Transferability of Bone Mineral Density Genetic Loci Associations From European to African Ancestry Populations. Journal of Bone and Mineral Research. 2020; 36 (3):469-479.
Chicago/Turabian StyleMichelle S. Yau; Allison L. Kuipers; Ryan Price; Aude Nicolas; Salman M. Tajuddin; Samuel K. Handelman; Liubov Arbeeva; Alessandra Chesi; Yi‐Hsiang Hsu; Ching‐Ti Liu; David Karasik; Babette S. Zemel; Struan F.A. Grant; Joanne M. Jordan; Rebecca D. Jackson; Michele K. Evans; Tamara B. Harris; Joseph M. Zmuda; Douglas P. Kiel. 2020. "A Meta‐Analysis of the Transferability of Bone Mineral Density Genetic Loci Associations From European to African Ancestry Populations." Journal of Bone and Mineral Research 36, no. 3: 469-479.
Through a genome-wide analysis of bone mineral density (BMD) and muscle mass, identification of a signaling pattern on 17p11.2 recognized the presence of sterol regulatory element-binding factor 1 (SREBF1), a gene responsible for the regulation of lipid homeostasis. In conjunction with lipid-based metabolic functions, SREBF1 also codes for the protein, SREBP-1, a transcription factor known for its role in adipocyte differentiation. We conducted a quantitative correlational study. We established a zebrafish (ZF) SREBF1 knockout (KO) model and used a targeted customized lipidomics approach to analyze the extent of SREBF1 capabilities. For lipidomics profiling, we isolated the dorsal muscles of wild type (WT) and KO fishes, and we performed liquid chromatography-tandem mass spectrometry screening assays of these samples. In our analysis, we profiled 48 lipid mediators (LMs) derived from various essential polyunsaturated fatty acids to determine potential targets regulated by SREBF1, and we found that the levels of 11,12 epoxyeicosatrienoic acid (11,12-EET) were negatively associated with the number of SREBF1 alleles (P = 0.006 for a linear model). We also compared gene expression between KO and WT ZF by genome-wide RNA-sequencing. Significantly enriched pathways included fatty acid elongation, linoleic acid metabolism, arachidonic acid metabolism, adipocytokine signaling, and DNA replication. We discovered trends indicating that BMD in adult fish was significantly lower in the KO than in the WT population (P < 0.03). These studies reinforce the importance of lipidomics investigation by detailing how the KO of SREBF1 affects both BMD and lipid-signaling mediators, thus confirming the importance of SREBF1 for musculoskeletal homeostasis.
Chen Shochat; Zhiying Wang; Chenglin Mo; Sarah Nelson; Rajashekar Donaka; Jian Huang; David Karasik; Marco Brotto. Deletion of SREBF1, a Functional Bone-Muscle Pleiotropic Gene, Alters Bone Density and Lipid Signaling in Zebrafish. Endocrinology 2020, 162, 1 .
AMA StyleChen Shochat, Zhiying Wang, Chenglin Mo, Sarah Nelson, Rajashekar Donaka, Jian Huang, David Karasik, Marco Brotto. Deletion of SREBF1, a Functional Bone-Muscle Pleiotropic Gene, Alters Bone Density and Lipid Signaling in Zebrafish. Endocrinology. 2020; 162 (1):1.
Chicago/Turabian StyleChen Shochat; Zhiying Wang; Chenglin Mo; Sarah Nelson; Rajashekar Donaka; Jian Huang; David Karasik; Marco Brotto. 2020. "Deletion of SREBF1, a Functional Bone-Muscle Pleiotropic Gene, Alters Bone Density and Lipid Signaling in Zebrafish." Endocrinology 162, no. 1: 1.
Both extrinsic and intrinsic factors predispose older people to fall. We performed a genome-wide association analysis to investigate how much of an individual’s fall susceptibility can be attributed to genetics in 89,076 cases and 362,103 controls from the UK Biobank Study. The analysis revealed a small, but significant SNP-based heritability (2.7%) and identified three novel fall-associated loci (Pcombined ≤ 5 × 10−8). Polygenic risk scores in two independent settings showed patterns of polygenic inheritance. Risk of falling had positive genetic correlations with fractures, identifying for the first time a pathway independent of bone mineral density. There were also positive genetic correlations with insomnia, neuroticism, depressive symptoms, and different medications. Negative genetic correlations were identified with muscle strength, intelligence and subjective well-being. Brain, and in particular cerebellum tissue, showed the highest gene expression enrichment for fall-associated variants. Overall, despite the highly heterogenic nature underlying fall risk, a proportion of the susceptibility can be attributed to genetics.
Katerina Trajanoska; Lotta J. Seppala; Carolina Medina-Gomez; Yi-Hsiang Hsu; Sirui Zhou; Natasja M. Van Schoor; Lisette C. P. G. M. De Groot; David Karasik; J. Brent Richards; Douglas P. Kiel; Andre G. Uitterlinden; John R. B. Perry; Nathalie Van Der Velde; Felix R. Day; Fernando Rivadeneira. Genetic basis of falling risk susceptibility in the UK Biobank Study. Communications Biology 2020, 3, 1 -10.
AMA StyleKaterina Trajanoska, Lotta J. Seppala, Carolina Medina-Gomez, Yi-Hsiang Hsu, Sirui Zhou, Natasja M. Van Schoor, Lisette C. P. G. M. De Groot, David Karasik, J. Brent Richards, Douglas P. Kiel, Andre G. Uitterlinden, John R. B. Perry, Nathalie Van Der Velde, Felix R. Day, Fernando Rivadeneira. Genetic basis of falling risk susceptibility in the UK Biobank Study. Communications Biology. 2020; 3 (1):1-10.
Chicago/Turabian StyleKaterina Trajanoska; Lotta J. Seppala; Carolina Medina-Gomez; Yi-Hsiang Hsu; Sirui Zhou; Natasja M. Van Schoor; Lisette C. P. G. M. De Groot; David Karasik; J. Brent Richards; Douglas P. Kiel; Andre G. Uitterlinden; John R. B. Perry; Nathalie Van Der Velde; Felix R. Day; Fernando Rivadeneira. 2020. "Genetic basis of falling risk susceptibility in the UK Biobank Study." Communications Biology 3, no. 1: 1-10.
We summarize recent evidence on the shared genetics within and outside the musculoskeletal system (mostly related to bone density and osteoporosis). Osteoporosis is determined by an interplay between multiple genetic and environmental factors. Significant progress has been made regarding its genetic background revealing a number of robustly validated loci and respective pathways. However, pleiotropic factors affecting bone and other tissues are not well understood. The analytical methods proposed to test for potential associations between genetic variants and multiple phenotypes can be applied to bone-related data. A number of recent genetic studies have shown evidence of pleiotropy between bone density and other different phenotypes (traits, conditions, or diseases), within and outside the musculoskeletal system. Power benefits of combining correlated phenotypes, as well as unbiased discovery, make these studies promising. Studies in humans are supported by evidence from animal models. Drug development and repurposing should benefit from the pleiotropic approach. We believe that future studies should take into account shared genetics between the bone and related traits.
M. A. Christou; E. E. Ntzani; D. Karasik. Genetic Pleiotropy of Bone-Related Phenotypes: Insights from Osteoporosis. Current Osteoporosis Reports 2020, 18, 606 -619.
AMA StyleM. A. Christou, E. E. Ntzani, D. Karasik. Genetic Pleiotropy of Bone-Related Phenotypes: Insights from Osteoporosis. Current Osteoporosis Reports. 2020; 18 (5):606-619.
Chicago/Turabian StyleM. A. Christou; E. E. Ntzani; D. Karasik. 2020. "Genetic Pleiotropy of Bone-Related Phenotypes: Insights from Osteoporosis." Current Osteoporosis Reports 18, no. 5: 606-619.
The development of high‐throughput genotyping technologies and large biobank collections, complemented with rapid methodological advances in statistical genetics, has enabled hypothesis‐free genome‐wide association studies (GWAS), which have identified hundreds of genetic variants across many loci associated with musculoskeletal conditions. Similarly, basic scientists have valuable molecular cellular and animal data based on musculoskeletal disease that would be enhanced by being able to determine the human translation of their findings. By further synthesizing these large scale human genomic musculoskeletal datasets with complementary evidence from model organisms, new and existing genetic loci can be statistically fine‐mapped to plausibly causal variants, candidate genes and biological pathways. Genes and pathways identified using this approach can be further prioritized as drug targets including side‐effect profiling and the potential for new indications. To bring together these big data, and to realize the vision of creating a knowledge portal , the International Federation of Musculoskeletal Research Societies (IFMRS) established a working group to collaborate with scientists from the Broad Institute to create the Musculoskeletal Knowledge Portal (MSK‐KP) that would consolidate ‐omics datasets from humans, cellular experiments, and model organisms into a central repository that can be accessed by researchers. The vision of the MSK‐KP is to enable better understanding of the biological mechanisms underlying musculoskeletal disease and apply this knowledge to identify and develop new disease interventions. This article is protected by copyright. All rights reserved.
Douglas P Kiel; John P. Kemp; Fernando Rivadeneira Md; Jennifer J. Westendorf; David Karasik; Emma L Duncan; Yuuki Imai; Ralph Müller; Jason Flannick; Lynda Bonewald; Noël Burtt. The Musculoskeletal Knowledge Portal: Making Omics Data Useful to the Broader Scientific Community. Journal of Bone and Mineral Research 2020, 35, 1626 -1633.
AMA StyleDouglas P Kiel, John P. Kemp, Fernando Rivadeneira Md, Jennifer J. Westendorf, David Karasik, Emma L Duncan, Yuuki Imai, Ralph Müller, Jason Flannick, Lynda Bonewald, Noël Burtt. The Musculoskeletal Knowledge Portal: Making Omics Data Useful to the Broader Scientific Community. Journal of Bone and Mineral Research. 2020; 35 (9):1626-1633.
Chicago/Turabian StyleDouglas P Kiel; John P. Kemp; Fernando Rivadeneira Md; Jennifer J. Westendorf; David Karasik; Emma L Duncan; Yuuki Imai; Ralph Müller; Jason Flannick; Lynda Bonewald; Noël Burtt. 2020. "The Musculoskeletal Knowledge Portal: Making Omics Data Useful to the Broader Scientific Community." Journal of Bone and Mineral Research 35, no. 9: 1626-1633.
Long non-coding RNAs (lncRNAs) are the master regulators of numerous biological processes. Hypoxia causes oxidative stress with severe and detrimental effects on brain function and acts as a critical initiating factor in the pathogenesis of Alzheimer’s disease (AD). However, no data are available on the regulatory roles of lncRNAs under hypoxia in the zebrafish brain. From the RNA-Seq in the forebrain (Fb), midbrain (Mb), and hindbrain (Hb) regions of hypoxic and normoxic zebrafish, we identified 8114, 7775, and 7816 novel lncRNA transcripts in the Fb, Mb, and Hb regions, respectively. In the hypoxic fish 357, 553, and 786 novel lncRNA genes were differentially expressed in the Fb, Mb, and Hb regions, respectively. Co-expression network analysis identified a series of lncRNA-mRNA pairs in all the regions, which were enriched for AD. In conclusion, functional annotation of lncRNAs induced by hypoxia provided knowledge on potential regulators for genes participating in AD pathogenesis.
Bodhisattwa Banerjee; Debaprasad Koner; David Karasik; Nirmalendu Saha. Genome-wide identification of novel long non-coding RNAs and their possible roles in hypoxic zebrafish brain. 2020, 1 .
AMA StyleBodhisattwa Banerjee, Debaprasad Koner, David Karasik, Nirmalendu Saha. Genome-wide identification of novel long non-coding RNAs and their possible roles in hypoxic zebrafish brain. . 2020; ():1.
Chicago/Turabian StyleBodhisattwa Banerjee; Debaprasad Koner; David Karasik; Nirmalendu Saha. 2020. "Genome-wide identification of novel long non-coding RNAs and their possible roles in hypoxic zebrafish brain." , no. : 1.
Low muscle strength is an important heritable indicator of poor health linked to morbidity and mortality in older people. In a genome-wide association study meta-analysis of 256,523 Europeans aged 60 years and over from 22 cohorts we identified 15 loci associated with muscle weakness (European Working Group on Sarcopenia in Older People definition: n=48,596 cases, 18.9% of total), including 12 loci not implicated in previous analyses of continuous measures of grip strength. Loci include genes reportedly involved in autoimmune disease (HLA-DQA1 p=4*10-17), arthritis (GDF5 p=4*10-13), cell cycle control and cancer protection, regulation of transcription, and others involved in the development and maintenance of the musculoskeletal system. Using Mendelian randomization we report possible overlapping causal pathways, including diabetes susceptibility, hematological parameters, and the immune system. We conclude that muscle weakness in older adults has distinct mechanisms from continuous strength, including several pathways considered to be hallmarks of ageing.
Garan Jones; Katerina Trajanoska; Adam J Santanasto; Najada Stringa; Chia-Ling Kuo; Janice L Atkins; Joshua R Lewis; Thuyvy Duong; Shengjun Hong; Mary L Biggs; Jian'an Luan; Chloe Sarnowski; Kathryn L Lunetta; Toshiko Tanaka; Mary K Wojczynski; Ryan Cvejkus; Maria Nethander; Sahar Ghasemi; Jingyun Yang; M. Carola Zillikens; Stefan Walter; Kamil Sicinski; Erika Kague; Cheryl L Ackert-Bicknell; Dan E Arking; B Gwen Windham; Eric Boerwinkle; Megan L Grove; Misa Graff; Dominik Spira; Ilja DeMuth; Nathalie Van Der Velde; Lisette C P G M De Groot; Bruce M Psaty; Michelle C Odden; Alison E Fohner; Claudia Langenberg; Nicholas J Wareham; Stefania Bandinelli; Natasja M Van Schoor; Martijn Huisman; Qihua Tan; Joseph Zmuda; Dan Mellstrom; Magnus Karlsson; David A Bennett; Aron S Buchman; Philip L De Jager; Andre G Uitterlinden; Uwe Volker; Thomas Kocher; Alexander Teumer; Leocadio Rodriguez-Manas; Francisco J Garcia Garcia; Jose A Carnicero; Pamela Herd; Lars Bertram; Claes Ohlsson; Joanne M Murabito; George A Kuchel; Luigi Ferrucci; David Melzer; David Karasik; Fernando Rivadeneira; Douglas P Kiel; Luke C Pilling. Genome-wide meta-analysis of muscle weakness identifies 15 susceptibility loci in older men and women. 2020, 1 .
AMA StyleGaran Jones, Katerina Trajanoska, Adam J Santanasto, Najada Stringa, Chia-Ling Kuo, Janice L Atkins, Joshua R Lewis, Thuyvy Duong, Shengjun Hong, Mary L Biggs, Jian'an Luan, Chloe Sarnowski, Kathryn L Lunetta, Toshiko Tanaka, Mary K Wojczynski, Ryan Cvejkus, Maria Nethander, Sahar Ghasemi, Jingyun Yang, M. Carola Zillikens, Stefan Walter, Kamil Sicinski, Erika Kague, Cheryl L Ackert-Bicknell, Dan E Arking, B Gwen Windham, Eric Boerwinkle, Megan L Grove, Misa Graff, Dominik Spira, Ilja DeMuth, Nathalie Van Der Velde, Lisette C P G M De Groot, Bruce M Psaty, Michelle C Odden, Alison E Fohner, Claudia Langenberg, Nicholas J Wareham, Stefania Bandinelli, Natasja M Van Schoor, Martijn Huisman, Qihua Tan, Joseph Zmuda, Dan Mellstrom, Magnus Karlsson, David A Bennett, Aron S Buchman, Philip L De Jager, Andre G Uitterlinden, Uwe Volker, Thomas Kocher, Alexander Teumer, Leocadio Rodriguez-Manas, Francisco J Garcia Garcia, Jose A Carnicero, Pamela Herd, Lars Bertram, Claes Ohlsson, Joanne M Murabito, George A Kuchel, Luigi Ferrucci, David Melzer, David Karasik, Fernando Rivadeneira, Douglas P Kiel, Luke C Pilling. Genome-wide meta-analysis of muscle weakness identifies 15 susceptibility loci in older men and women. . 2020; ():1.
Chicago/Turabian StyleGaran Jones; Katerina Trajanoska; Adam J Santanasto; Najada Stringa; Chia-Ling Kuo; Janice L Atkins; Joshua R Lewis; Thuyvy Duong; Shengjun Hong; Mary L Biggs; Jian'an Luan; Chloe Sarnowski; Kathryn L Lunetta; Toshiko Tanaka; Mary K Wojczynski; Ryan Cvejkus; Maria Nethander; Sahar Ghasemi; Jingyun Yang; M. Carola Zillikens; Stefan Walter; Kamil Sicinski; Erika Kague; Cheryl L Ackert-Bicknell; Dan E Arking; B Gwen Windham; Eric Boerwinkle; Megan L Grove; Misa Graff; Dominik Spira; Ilja DeMuth; Nathalie Van Der Velde; Lisette C P G M De Groot; Bruce M Psaty; Michelle C Odden; Alison E Fohner; Claudia Langenberg; Nicholas J Wareham; Stefania Bandinelli; Natasja M Van Schoor; Martijn Huisman; Qihua Tan; Joseph Zmuda; Dan Mellstrom; Magnus Karlsson; David A Bennett; Aron S Buchman; Philip L De Jager; Andre G Uitterlinden; Uwe Volker; Thomas Kocher; Alexander Teumer; Leocadio Rodriguez-Manas; Francisco J Garcia Garcia; Jose A Carnicero; Pamela Herd; Lars Bertram; Claes Ohlsson; Joanne M Murabito; George A Kuchel; Luigi Ferrucci; David Melzer; David Karasik; Fernando Rivadeneira; Douglas P Kiel; Luke C Pilling. 2020. "Genome-wide meta-analysis of muscle weakness identifies 15 susceptibility loci in older men and women." , no. : 1.
Peer teaching helps prepare medical students and house officers for their future roles as health-care professionals. Two collaborative approaches are notable, reciprocal peer eaching (RPT) and near-peer teaching (NPT), wherein students alternate roles as teacher and learner or where students or house staff learn to facilitate training of younger colleagues. Both educational platforms draw on a similar knowledge base and shared generational experiences between students. Both teaching protocols include promotion of another student’s active learning through direct interactions and reinforcement of one’s own learning through instructing others. Examples of the use of these techniques in both preclinical and clinical medical education are presented as well as a near-peer teaching program in the framework of preclinical medical education course in human anatomy. Since teaching is an important skill for future postgraduate education, clinical practice, and academic engagement, education for this role should be introduced early and practiced throughout medical training.
David Karasik; Nomy Dickman. Students as Near-Peer and Peer-Teachers. Active Education for Future Doctors 2020, 123 -134.
AMA StyleDavid Karasik, Nomy Dickman. Students as Near-Peer and Peer-Teachers. Active Education for Future Doctors. 2020; ():123-134.
Chicago/Turabian StyleDavid Karasik; Nomy Dickman. 2020. "Students as Near-Peer and Peer-Teachers." Active Education for Future Doctors , no. : 123-134.
Immobilization, such as prolonged bed rest, is a risk factor for bone loss in humans. Motivated by the emerging utility of zebrafish (Danio rerio) as an animal of choice for the study of musculoskeletal disease, here we report a model of restricted‐mobility‐induced osteopenia in adult zebrafish. Aquatic tanks with small cubical compartments to restrict the movement and locomotion of single fish were designed and fabricated for this study. Adult zebrafish were divided into two groups, i.e. normal control (CONT) and restricted mobility group (RMG) (18 fish/group). Six fish from each group were euthanized on day 14, 21, and 35 of the movement restriction. By using microcomputed tomography (micro‐CT), we assessed bone volume/tissue volume (BV/TV) and bone density in the whole skeleton of the fish. Further, we assessed skeletal shape in the vertebrae (radius, length, volume, neural and haemal AAAs, neural and haemal arch angle and thickness of the intervertebral space), single vertebra bone volume and bone density. Movement restriction significantly decreased vertebral skeletal parameters such as radius, length, volume, arch aperture areas and angles as well as the thickness of the intervertebral space in RMG. Further, restricted mobility significantly (p < 0.001) decreased BV/TV and bone density as compared to CONT group, starting as early as 14 days. By analysing zebrafish from CONT and RMG, we show that micro‐CT imaging is a sensitive method to quantify distinct skeletal properties in zebrafish. We further defined the micro‐CT parameters which can be used to examine the effects of restricted mobility on the skeleton of the fish. Our findings propose a rapid and effective osteopenia “stabulation” model, which could be used widely for osteoporosis drug screening. Significance Statement Bone loss and fragility are regarded as a public health problem and necessitate new treatments and prevention strategies. Zebrafish serves as a reliable model‐organism system, faithfully resembling the phenotype of osteopenia. We propose a rapid and effective zebrafish model, which could be used widely for osteoporosis drug screening, as well as studying etiology of immobilization‐related musculoskeletal conditions.
Deepak Kumar Khajuria; David Karasik. Novel model of restricted mobility induced osteopenia in zebrafish. Journal of Fish Biology 2020, 98, 1031 -1038.
AMA StyleDeepak Kumar Khajuria, David Karasik. Novel model of restricted mobility induced osteopenia in zebrafish. Journal of Fish Biology. 2020; 98 (4):1031-1038.
Chicago/Turabian StyleDeepak Kumar Khajuria; David Karasik. 2020. "Novel model of restricted mobility induced osteopenia in zebrafish." Journal of Fish Biology 98, no. 4: 1031-1038.
Sarcopenia – the accelerated age-related loss of muscle mass and function – is an under-diagnosed condition, and is central to deteriorating mobility, disability and frailty in older age. There is a lack of treatment options for older adults at risk of sarcopenia. Although sarcopenia's pathogenesis is multifactorial, its major phenotypes – muscle mass and muscle strength – are highly heritable. Several genome-wide association studies of muscle-related traits were published recently, providing dozens of candidate genes, many with unknown function. Therefore, animal models are required not only to identify causal mechanisms, but also to clarify the underlying biology and translate this knowledge into new interventions. Over the past several decades, small teleost fishes had emerged as powerful systems for modeling the genetics of human diseases. Owing to their amenability to rapid genetic intervention and the large number of conserved genetic and physiological features, small teleosts – such as zebrafish, medaka and killifish – have become indispensable for skeletal muscle genomic studies. The goal of this Review is to summarize evidence supporting the utility of small fish models for accelerating our understanding of human skeletal muscle in health and disease. We do this by providing a basic foundation of the (zebra)fish skeletal muscle morphology and physiology, and evidence of muscle-related gene homology. We also outline challenges in interpreting zebrafish mutant phenotypes and in translating them to human disease. Finally, we conclude with recommendations on future directions to leverage the large body of tools developed in small fish for the needs of genomic exploration in sarcopenia.
Alon Daya; Rajashekar Donaka; David Karasik. Zebrafish models of sarcopenia. Disease Models & Mechanisms 2020, 13, dmm042689 .
AMA StyleAlon Daya, Rajashekar Donaka, David Karasik. Zebrafish models of sarcopenia. Disease Models & Mechanisms. 2020; 13 (3):dmm042689.
Chicago/Turabian StyleAlon Daya; Rajashekar Donaka; David Karasik. 2020. "Zebrafish models of sarcopenia." Disease Models & Mechanisms 13, no. 3: dmm042689.
Cardiometabolic traits pose a major global public health burden. Large-scale genome-wide association studies (GWAS) have identified multiple loci accounting for up to 30% of the genetic variance in complex traits such as cardiometabolic traits. However, the contribution of parent-of-origin effects (POEs) to complex traits has been largely ignored in GWAS. Family-based studies enable the assessment of POEs in genetic association analyses. We investigated POEs on a range of complex traits in 3 family-based studies. The discovery phase was carried out in large pedigrees from the Kibbutzim Family Study (n = 901 individuals) and in 872 parent–offspring trios from the Jerusalem Perinatal Study. Focusing on imprinted genomic regions, we examined parent-specific associations with 12 complex traits (i.e., body-size, blood pressure, lipids), mostly cardiometabolic risk traits. Forty five of the 11,967 SNPs initially found to have POE were evaluated for replication (p value < 1 × 10−4) in Framingham Heart Study families (max n = 8000 individuals). Three common variants yielded evidence of POE in the meta-analysis. Two variants, located on chr6 in the HLA region, showed a paternal effect on height (rs1042136: βpaternal = −0.023, p value = 1.5 × 10−8 and rs1431403: βpaternal = −0.011, p value = 5.4 × 10−6). The corresponding maternally-derived effects were statistically nonsignificant. The variant rs9332053, located on chr13 in RCBTB2 gene, demonstrated a maternal effect on hip circumference (βmaternal = −4.24, p value = 9.6 × 10−6; βpaternal = 1.29, p value = 0.23). These findings provide evidence for the utility of incorporating POEs into association studies of cardiometabolic traits, especially anthropometric traits. The study highlights the benefits of using family-based data for deciphering the genetic architecture of complex traits.
Einat Granot-Hershkovitz; Peitao Wu; David Karasik; Inga Peter; Gina M. Peloso; Daniel Levy; Ramachandran S. Vasan; L. Adrienne Cupples; Ching-Ti Liu; James B. Meigs; David S. Siscovick; Josée Dupuis; Yechiel Friedlander; Hagit Hochner. Searching for parent-of-origin effects on cardiometabolic traits in imprinted genomic regions. European Journal of Human Genetics 2020, 28, 646 -655.
AMA StyleEinat Granot-Hershkovitz, Peitao Wu, David Karasik, Inga Peter, Gina M. Peloso, Daniel Levy, Ramachandran S. Vasan, L. Adrienne Cupples, Ching-Ti Liu, James B. Meigs, David S. Siscovick, Josée Dupuis, Yechiel Friedlander, Hagit Hochner. Searching for parent-of-origin effects on cardiometabolic traits in imprinted genomic regions. European Journal of Human Genetics. 2020; 28 (5):646-655.
Chicago/Turabian StyleEinat Granot-Hershkovitz; Peitao Wu; David Karasik; Inga Peter; Gina M. Peloso; Daniel Levy; Ramachandran S. Vasan; L. Adrienne Cupples; Ching-Ti Liu; James B. Meigs; David S. Siscovick; Josée Dupuis; Yechiel Friedlander; Hagit Hochner. 2020. "Searching for parent-of-origin effects on cardiometabolic traits in imprinted genomic regions." European Journal of Human Genetics 28, no. 5: 646-655.
Maarouf Baghdadi; David Karasik; Joris Deelen. Genetic Control of Aging. Encyclopedia of Gerontology and Population Aging 2019, 1 -8.
AMA StyleMaarouf Baghdadi, David Karasik, Joris Deelen. Genetic Control of Aging. Encyclopedia of Gerontology and Population Aging. 2019; ():1-8.
Chicago/Turabian StyleMaarouf Baghdadi; David Karasik; Joris Deelen. 2019. "Genetic Control of Aging." Encyclopedia of Gerontology and Population Aging , no. : 1-8.
Human longevity is heritable, but genome-wide association (GWA) studies have had limited success. Here, we perform two meta-analyses of GWA studies of a rigorous longevity phenotype definition including 11,262/3484 cases surviving at or beyond the age corresponding to the 90th/99th survival percentile, respectively, and 25,483 controls whose age at death or at last contact was at or below the age corresponding to the 60th survival percentile. Consistent with previous reports, rs429358 (apolipoprotein E (ApoE) ε4) is associated with lower odds of surviving to the 90th and 99th percentile age, while rs7412 (ApoE ε2) shows the opposite. Moreover, rs7676745, located near GPR78, associates with lower odds of surviving to the 90th percentile age. Gene-level association analysis reveals a role for tissue-specific expression of multiple genes in longevity. Finally, genetic correlation of the longevity GWA results with that of several disease-related phenotypes points to a shared genetic architecture between health and longevity.
Joris Deelen; Daniel S. Evans; Dan E. Arking; Niccolò Tesi; Marianne Nygaard; Xiaomin Liu; Mary K. Wojczynski; Mary L. Biggs; Ashley van der Spek; Gil Atzmon; Erin B. Ware; Chloé Sarnowski; Albert V. Smith; Ilkka Seppälä; Heather J. Cordell; Janina Dose; Najaf Amin; Alice M. Arnold; Kristin L. Ayers; Nir Barzilai; Elizabeth J. Becker; Marian Beekman; Hélène Blanché; Kaare Christensen; Lene Christiansen; Joanna C. Collerton; Sarah Cubaynes; Steven R. Cummings; Karen Davies; Birgit Debrabant; Jean-François Deleuze; Rachel Duncan; Jessica D. Faul; Claudio Franceschi; Pilar Galan; Vilmundur Gudnason; Tamara B. Harris; Martijn Huisman; Mikko A. Hurme; Carol Jagger; Iris Jansen; Marja Jylhä; Mika Kähönen; David Karasik; Sharon L. R. Kardia; Andrew Kingston; Thomas B. L. Kirkwood; Lenore J. Launer; Terho Lehtimäki; Wolfgang Lieb; Leo-Pekka Lyytikäinen; Carmen Martin-Ruiz; Junxia Min; Almut Nebel; Anne B. Newman; Chao Nie; Ellen A. Nohr; Eric S. Orwoll; Thomas T. Perls; Michael A. Province; Bruce M. Psaty; Olli T. Raitakari; Marcel J. T. Reinders; Jean-Marie Robine; Jerome I. Rotter; Paola Sebastiani; Jennifer Smith; Thorkild I. A. Sørensen; Kent D. Taylor; André G. Uitterlinden; Wiesje van der Flier; Sven J. van der Lee; Cornelia M. van Duijn; Diana van Heemst; James W. Vaupel; David Weir; Kenny Ye; Yi Zeng; Wanlin Zheng; Henne Holstege; Douglas P. Kiel; Kathryn L. Lunetta; P. Eline Slagboom; Joanne M. Murabito. A meta-analysis of genome-wide association studies identifies multiple longevity genes. Nature Communications 2019, 10, 1 -14.
AMA StyleJoris Deelen, Daniel S. Evans, Dan E. Arking, Niccolò Tesi, Marianne Nygaard, Xiaomin Liu, Mary K. Wojczynski, Mary L. Biggs, Ashley van der Spek, Gil Atzmon, Erin B. Ware, Chloé Sarnowski, Albert V. Smith, Ilkka Seppälä, Heather J. Cordell, Janina Dose, Najaf Amin, Alice M. Arnold, Kristin L. Ayers, Nir Barzilai, Elizabeth J. Becker, Marian Beekman, Hélène Blanché, Kaare Christensen, Lene Christiansen, Joanna C. Collerton, Sarah Cubaynes, Steven R. Cummings, Karen Davies, Birgit Debrabant, Jean-François Deleuze, Rachel Duncan, Jessica D. Faul, Claudio Franceschi, Pilar Galan, Vilmundur Gudnason, Tamara B. Harris, Martijn Huisman, Mikko A. Hurme, Carol Jagger, Iris Jansen, Marja Jylhä, Mika Kähönen, David Karasik, Sharon L. R. Kardia, Andrew Kingston, Thomas B. L. Kirkwood, Lenore J. Launer, Terho Lehtimäki, Wolfgang Lieb, Leo-Pekka Lyytikäinen, Carmen Martin-Ruiz, Junxia Min, Almut Nebel, Anne B. Newman, Chao Nie, Ellen A. Nohr, Eric S. Orwoll, Thomas T. Perls, Michael A. Province, Bruce M. Psaty, Olli T. Raitakari, Marcel J. T. Reinders, Jean-Marie Robine, Jerome I. Rotter, Paola Sebastiani, Jennifer Smith, Thorkild I. A. Sørensen, Kent D. Taylor, André G. Uitterlinden, Wiesje van der Flier, Sven J. van der Lee, Cornelia M. van Duijn, Diana van Heemst, James W. Vaupel, David Weir, Kenny Ye, Yi Zeng, Wanlin Zheng, Henne Holstege, Douglas P. Kiel, Kathryn L. Lunetta, P. Eline Slagboom, Joanne M. Murabito. A meta-analysis of genome-wide association studies identifies multiple longevity genes. Nature Communications. 2019; 10 (1):1-14.
Chicago/Turabian StyleJoris Deelen; Daniel S. Evans; Dan E. Arking; Niccolò Tesi; Marianne Nygaard; Xiaomin Liu; Mary K. Wojczynski; Mary L. Biggs; Ashley van der Spek; Gil Atzmon; Erin B. Ware; Chloé Sarnowski; Albert V. Smith; Ilkka Seppälä; Heather J. Cordell; Janina Dose; Najaf Amin; Alice M. Arnold; Kristin L. Ayers; Nir Barzilai; Elizabeth J. Becker; Marian Beekman; Hélène Blanché; Kaare Christensen; Lene Christiansen; Joanna C. Collerton; Sarah Cubaynes; Steven R. Cummings; Karen Davies; Birgit Debrabant; Jean-François Deleuze; Rachel Duncan; Jessica D. Faul; Claudio Franceschi; Pilar Galan; Vilmundur Gudnason; Tamara B. Harris; Martijn Huisman; Mikko A. Hurme; Carol Jagger; Iris Jansen; Marja Jylhä; Mika Kähönen; David Karasik; Sharon L. R. Kardia; Andrew Kingston; Thomas B. L. Kirkwood; Lenore J. Launer; Terho Lehtimäki; Wolfgang Lieb; Leo-Pekka Lyytikäinen; Carmen Martin-Ruiz; Junxia Min; Almut Nebel; Anne B. Newman; Chao Nie; Ellen A. Nohr; Eric S. Orwoll; Thomas T. Perls; Michael A. Province; Bruce M. Psaty; Olli T. Raitakari; Marcel J. T. Reinders; Jean-Marie Robine; Jerome I. Rotter; Paola Sebastiani; Jennifer Smith; Thorkild I. A. Sørensen; Kent D. Taylor; André G. Uitterlinden; Wiesje van der Flier; Sven J. van der Lee; Cornelia M. van Duijn; Diana van Heemst; James W. Vaupel; David Weir; Kenny Ye; Yi Zeng; Wanlin Zheng; Henne Holstege; Douglas P. Kiel; Kathryn L. Lunetta; P. Eline Slagboom; Joanne M. Murabito. 2019. "A meta-analysis of genome-wide association studies identifies multiple longevity genes." Nature Communications 10, no. 1: 1-14.
Hip geometry is an important predictor of fracture. We performed a meta‐analysis of GWAS studies in adults to identify genetic variants that are associated with proximal femur geometry phenotypes. We analyzed four phenotypes: (i) femoral neck length; (ii) neck‐shaft angle; (iii) femoral neck width, and (iv) femoral neck section modulus, estimated from DXA scans using algorithms of hip structure analysis. In the Discovery stage, 10 cohort studies were included in the fixed‐effect meta‐analysis, with up to 18,719 men and women ages 16 to 93 years. Association analyses were performed with ∼2.5 million polymorphisms under an additive model adjusted for age, body mass index, and height. Replication analyses of meta‐GWAS significant loci (at adjusted genomewide significance [GWS], threshold p ≤ 2.6 × 10–8) were performed in seven additional cohorts in silico. We looked up SNPs associated in our analysis, for association with height, bone mineral density (BMD), and fracture. In meta‐analysis (combined Discovery and Replication stages), GWS associations were found at 5p15 (IRX1 and ADAMTS16); 5q35 near FGFR4; at 12p11 (in CCDC91); 11q13 (near LRP5 and PPP6R3 (rs7102273)). Several hip geometry signals overlapped with BMD, including LRP5 (chr. 11). Chr. 11 SNP rs7102273 was associated with any‐type fracture (p = 7.5 × 10–5). We used bone transcriptome data and discovered several significant eQTLs, including rs7102273 and PPP6R3 expression (p = 0.0007), and rs6556301 (intergenic, chr.5 near FGFR4) and PDLIM7 expression (p = 0.005). In conclusion, we found associations between several genes and hip geometry measures that explained 12% to 22% of heritability at different sites. The results provide a defined set of genes related to biological pathways relevant to BMD and etiology of bone fragility. © 2019 American Society for Bone and Mineral Research.
Yi‐Hsiang Hsu; Karol Estrada; Evangelos Evangelou; Cheryl Ackert‐Bicknell; Kristina Akesson; Thomas Beck; Suzanne J Brown; Terence Capellini; Laura Carbone; Jane Cauley; Ching‐Lung Cheung; Steven R Cummings; Stefan Czerwinski; Serkalem Demissie; Michael Econs; Daniel Evans; Charles Farber; Kaare Gautvik; Tamara Harris; Candace Kammerer; John Kemp; Daniel L Koller; Annie Kung; Debbie Lawlor; Miryoung Lee; Mattias Lorentzon; Fiona McGuigan; Carolina Medina‐Gomez; Braxton Mitchell; Anne Newman; Carrie Nielson; Claes Ohlsson; Munro Peacock; Sjur Reppe; J Brent Richards; John Robbins; Gunnar Sigurdsson; Timothy D Spector; Kari Stefansson; Elizabeth Streeten; Unnur Styrkarsdottir; Jonathan Tobias; Katerina Trajanoska; André Uitterlinden; Liesbeth Vandenput; Scott G Wilson; Laura Yerges‐Armstrong; Mariel Young; M Carola Zillikens; Fernando Rivadeneira; Douglas P Kiel; David Karasik. Meta‐Analysis of Genomewide Association Studies Reveals Genetic Variants for Hip Bone Geometry. Journal of Bone and Mineral Research 2019, 34, 1284 -1296.
AMA StyleYi‐Hsiang Hsu, Karol Estrada, Evangelos Evangelou, Cheryl Ackert‐Bicknell, Kristina Akesson, Thomas Beck, Suzanne J Brown, Terence Capellini, Laura Carbone, Jane Cauley, Ching‐Lung Cheung, Steven R Cummings, Stefan Czerwinski, Serkalem Demissie, Michael Econs, Daniel Evans, Charles Farber, Kaare Gautvik, Tamara Harris, Candace Kammerer, John Kemp, Daniel L Koller, Annie Kung, Debbie Lawlor, Miryoung Lee, Mattias Lorentzon, Fiona McGuigan, Carolina Medina‐Gomez, Braxton Mitchell, Anne Newman, Carrie Nielson, Claes Ohlsson, Munro Peacock, Sjur Reppe, J Brent Richards, John Robbins, Gunnar Sigurdsson, Timothy D Spector, Kari Stefansson, Elizabeth Streeten, Unnur Styrkarsdottir, Jonathan Tobias, Katerina Trajanoska, André Uitterlinden, Liesbeth Vandenput, Scott G Wilson, Laura Yerges‐Armstrong, Mariel Young, M Carola Zillikens, Fernando Rivadeneira, Douglas P Kiel, David Karasik. Meta‐Analysis of Genomewide Association Studies Reveals Genetic Variants for Hip Bone Geometry. Journal of Bone and Mineral Research. 2019; 34 (7):1284-1296.
Chicago/Turabian StyleYi‐Hsiang Hsu; Karol Estrada; Evangelos Evangelou; Cheryl Ackert‐Bicknell; Kristina Akesson; Thomas Beck; Suzanne J Brown; Terence Capellini; Laura Carbone; Jane Cauley; Ching‐Lung Cheung; Steven R Cummings; Stefan Czerwinski; Serkalem Demissie; Michael Econs; Daniel Evans; Charles Farber; Kaare Gautvik; Tamara Harris; Candace Kammerer; John Kemp; Daniel L Koller; Annie Kung; Debbie Lawlor; Miryoung Lee; Mattias Lorentzon; Fiona McGuigan; Carolina Medina‐Gomez; Braxton Mitchell; Anne Newman; Carrie Nielson; Claes Ohlsson; Munro Peacock; Sjur Reppe; J Brent Richards; John Robbins; Gunnar Sigurdsson; Timothy D Spector; Kari Stefansson; Elizabeth Streeten; Unnur Styrkarsdottir; Jonathan Tobias; Katerina Trajanoska; André Uitterlinden; Liesbeth Vandenput; Scott G Wilson; Laura Yerges‐Armstrong; Mariel Young; M Carola Zillikens; Fernando Rivadeneira; Douglas P Kiel; David Karasik. 2019. "Meta‐Analysis of Genomewide Association Studies Reveals Genetic Variants for Hip Bone Geometry." Journal of Bone and Mineral Research 34, no. 7: 1284-1296.
To summarize the evidence from recent studies on the shared genetics between bone and muscle in humans. Genome-wide association studies (GWAS) have successfully identified a multitude of loci influencing the variability of different bone or muscle parameters, with multiple loci overlapping between the traits. In addition, joint analyses of multiple correlated musculoskeletal traits (i.e., multivariate GWAS) have underscored several genes with possible pleiotropic effects on both bone and muscle including MEF2C and SREBF1. Notably, several of the proposed pleiotropic genes have been validated using human cells or animal models. It is clear that the study of pleiotropy may provide novel insights into disease pathophysiology potentially leading to the identification of new treatment strategies that simultaneously prevent or treat both osteoporosis and sarcopenia. However, the role of muscle factors (myokines) that stimulate bone metabolism, as well as osteokines that affect muscles, is in its earliest stage of understanding.
Katerina Trajanoska; Fernando Rivadeneira; Douglas P. Kiel; David Karasik. Genetics of Bone and Muscle Interactions in Humans. Current Osteoporosis Reports 2019, 17, 86 -95.
AMA StyleKaterina Trajanoska, Fernando Rivadeneira, Douglas P. Kiel, David Karasik. Genetics of Bone and Muscle Interactions in Humans. Current Osteoporosis Reports. 2019; 17 (2):86-95.
Chicago/Turabian StyleKaterina Trajanoska; Fernando Rivadeneira; Douglas P. Kiel; David Karasik. 2019. "Genetics of Bone and Muscle Interactions in Humans." Current Osteoporosis Reports 17, no. 2: 86-95.