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Osteoporosis: HELP
Articles by David Karasik
Based on 20 articles published since 2010
(Why 20 articles?)
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Between 2010 and 2020, D. Karasik wrote the following 20 articles about Osteoporosis.
 
+ Citations + Abstracts
1 Review Genetics of Bone and Muscle Interactions in Humans. 2019

Trajanoska, Katerina / Rivadeneira, Fernando / Kiel, Douglas P / Karasik, David. ·Department of Internal Medicine, Erasmus MC, University Medical Center Rotterdam, Rotterdam, Netherlands. · Department of Internal Medicine, Erasmus MC, University Medical Center Rotterdam, Rotterdam, Netherlands. f.rivadeneira@erasmusmc.nl. · Hebrew SeniorLife, Institute for Aging Research, Boston, MA, USA. · Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA. · Broad Institute of Harvard and Massachusetts Institute of Technology, Boston, MA, USA. · Hebrew SeniorLife, Institute for Aging Research, Boston, MA, USA. karasik@hsl.harvard.edu. · Azrieli Faculty of Medicine, Bar-Ilan University, Safed, Israel. karasik@hsl.harvard.edu. ·Curr Osteoporos Rep · Pubmed #30820831.

ABSTRACT: PURPOSE OF REVIEW: To summarize the evidence from recent studies on the shared genetics between bone and muscle in humans. RECENT FINDINGS: 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.

2 Review The genetics of bone mass and susceptibility to bone diseases. 2016

Karasik, David / Rivadeneira, Fernando / Johnson, Mark L. ·Institute for Aging Research, Hebrew SeniorLife, 1200 Centre Street, Boston, Massachusetts 02131, USA. · Faculty of Medicine in the Galilee, Bar-Ilan University, 8 Henrietta Szold Street, Safed 13010, Israel. · Departments of Internal Medicine and Epidemiology, Erasmus Medical Centre, Rotterdams-Gravendijkwal 230, 3015 CE, Netherlands. · Department of Oral and Craniofacial Sciences, University of Missouri-Kansas City School of Dentistry, 650 East 25th Street, Kansas City, Missouri 64108, USA. ·Nat Rev Rheumatol · Pubmed #27052486.

ABSTRACT: Osteoporosis is characterized by low bone mass and an increased risk of fracture. Genetic factors, environmental factors and gene-environment interactions all contribute to a person's lifetime risk of developing an osteoporotic fracture. This Review summarizes key advances in understanding of the genetics of bone traits and their role in osteoporosis. Candidate-gene approaches dominated this field 20 years ago, but clinical and preclinical genetic studies published in the past 5 years generally utilize more-sophisticated and better-powered genome-wide association studies (GWAS). High-throughput DNA sequencing, large genomic databases and improved methods of data analysis have greatly accelerated the gene-discovery process. Linkage analyses of single-gene traits that segregate in families with extreme phenotypes have led to the elucidation of critical pathways controlling bone mass. For example, components of the Wnt-β-catenin signalling pathway have been validated (in both GWAS and functional studies) as contributing to various bone phenotypes. These notable advances in gene discovery suggest that the next decade will witness cataloguing of the hundreds of genes that influence bone mass and osteoporosis, which in turn will provide a roadmap for the development of new drugs that target diseases of low bone mass, including osteoporosis.

3 Review Impact of the environment on the skeleton: is it modulated by genetic factors? 2013

Ackert-Bicknell, Cheryl L / Karasik, David. ·The Jackson Laboratory, 600 Main St, Bar Harbor, ME, 04609, USA, cheryl.ackertb@jax.org. ·Curr Osteoporos Rep · Pubmed #23846556.

ABSTRACT: The etiology of skeletal disease is driven by genetic and environmental factors. Genome-wide association studies (GWAS) of osteoporotic phenotypes have identified novel candidate genes, but have only uncovered a small proportion of the trait variance explained. This "missing heritability" is caused by several factors, including the failure to consider gene-by-environmental (G*E) interactions. Some G*E interactions have been investigated, but new approaches to integrate environmental data into genomic studies are needed. Advances in genotyping and meta-analysis techniques now allow combining genotype data from multiple studies, but the measurement of key environmental factors in large human cohorts still lags behind, as do the statistical tools needed to incorporate these measures in genome-wide association meta-studies. This review focuses on discussing ways to enhance G*E interaction studies in humans and how the use of rodent models can inform genetic studies. Understanding G*E interactions will provide opportunities to effectively target intervention strategies for individualized therapy.

4 Review Associations of APOE gene polymorphisms with bone mineral density and fracture risk: a meta-analysis. 2011

Peter, I / Crosier, M D / Yoshida, M / Booth, S L / Cupples, L A / Dawson-Hughes, B / Karasik, D / Kiel, D P / Ordovas, J M / Trikalinos, T A. ·Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine, New York 10029, USA. inga.peter@mssm.edu ·Osteoporos Int · Pubmed #20533025.

ABSTRACT: INTRODUCTION: APOE has been studied for its potential role in osteoporosis risk. It is hypothesized that genetic variation at APOE locus, known as E2, E3, and E4, may modulate BMD through its effects on lipoproteins and vitamin K transport. The purpose of this study was to determine the association of the APOE-E4 gene polymorphism with bone-related phenotypes. METHODS: We conducted a meta-analysis that combined newly analyzed individual data from two community-based cohorts, the Framingham Offspring Study (N = 1,495) and the vitamin K clinical trial (N = 377), with 15 other eligible published reports. Bone phenotypes included BMD measurements of the hip (total hip and trochanteric and femoral neck sites) and lumbar spine (from the L2 to L4 vertebrae) and prevalence or incidence of vertebral, hip, and other fractures. RESULTS: In sex-pooled analyses, APOE4 carriers had a 0.018 g/cm(2) lower weighted mean trochanteric BMD than non carriers (p = 0.0002) with no evidence for between-study heterogeneity. A significant association was also detected with lumbar spine BMD (p = 0.006); however, inter-study heterogeneity was observed. Associations with lumbar spine and trochanteric BMD were observed predominantly in women and became less significant in meta-regression (p = 0.055 and 0.01, respectively). There were no consistent associations of APOE4 genotype with BMD at other skeletal sites or with fracture risk. CONCLUSIONS: Based on these findings, there is insufficient evidence to support a strong and consistent association of the APOE genotype with BMD and fracture incidence.

5 Review Evidence for pleiotropic factors in genetics of the musculoskeletal system. 2010

Karasik, David / Kiel, Douglas P. ·Institute for Aging Research, Hebrew SeniorLife, 1200 Centre Street, Boston, MA 02131, USA. karasik@hrca.harvard.edu ·Bone · Pubmed #20149904.

ABSTRACT: There are both theoretical and empirical underpinnings that provide evidence that the musculoskeletal system develops, functions, and ages as a whole. Thus, the risk of osteoporotic fracture can be viewed as a function of loading conditions and the ability of the bone to withstand the load. Both bone loss (osteoporosis) and muscle wasting (sarcopenia) are the two sides of the same coin, an involution of the musculoskeletal system. Skeletal loads are dominated by muscle action; both bone and muscle share environmental, endocrine and paracrine influences. Muscle also has an endocrine function by producing bioactive molecules, which can contribute to homeostatic regulation of both bone and muscle. It also becomes clear that bone and muscle share genetic determinants; therefore the consideration of pleiotropy is an important aspect in the study of the genetics of osteoporosis and sarcopenia. The aim of this review is to provide an additional evidence for existence of the tight genetic co-regulation of muscles and bones, starting early in development and still evident in aging. Recently, important papers were published, including those dealing with the cellular mechanisms and anatomic substrate of bone mechanosensitivity. Further evidence has emerged suggesting that the relationship between skeletal muscle and bone parameters extends beyond the general paradigm of bone responses to mechanical loading. We provide insights into several pathways and single genes, which apparently have a biologically plausible pleiotropic effect on both bones and muscles; the list is continuing to grow. Understanding the crosstalk between muscles and bones will translate into a conceptual framework aimed at studying the pleiotropic genetic relationships in the etiology of complex musculoskeletal disease. We believe that further progress in understanding the common genetic etiology of osteoporosis and sarcopenia will provide valuable insight into important biological underpinnings for both musculoskeletal conditions. This may translate into new approaches to reduce the burden of both conditions, which are prevalent in the elderly population.

6 Article An atlas of genetic influences on osteoporosis in humans and mice. 2019

Morris, John A / Kemp, John P / Youlten, Scott E / Laurent, Laetitia / Logan, John G / Chai, Ryan C / Vulpescu, Nicholas A / Forgetta, Vincenzo / Kleinman, Aaron / Mohanty, Sindhu T / Sergio, C Marcelo / Quinn, Julian / Nguyen-Yamamoto, Loan / Luco, Aimee-Lee / Vijay, Jinchu / Simon, Marie-Michelle / Pramatarova, Albena / Medina-Gomez, Carolina / Trajanoska, Katerina / Ghirardello, Elena J / Butterfield, Natalie C / Curry, Katharine F / Leitch, Victoria D / Sparkes, Penny C / Adoum, Anne-Tounsia / Mannan, Naila S / Komla-Ebri, Davide S K / Pollard, Andrea S / Dewhurst, Hannah F / Hassall, Thomas A D / Beltejar, Michael-John G / Anonymous2961133 / Adams, Douglas J / Vaillancourt, Suzanne M / Kaptoge, Stephen / Baldock, Paul / Cooper, Cyrus / Reeve, Jonathan / Ntzani, Evangelia E / Evangelou, Evangelos / Ohlsson, Claes / Karasik, David / Rivadeneira, Fernando / Kiel, Douglas P / Tobias, Jonathan H / Gregson, Celia L / Harvey, Nicholas C / Grundberg, Elin / Goltzman, David / Adams, David J / Lelliott, Christopher J / Hinds, David A / Ackert-Bicknell, Cheryl L / Hsu, Yi-Hsiang / Maurano, Matthew T / Croucher, Peter I / Williams, Graham R / Bassett, J H Duncan / Evans, David M / Richards, J Brent. ·Department of Human Genetics, McGill University, Montréal, Québec, Canada. · Lady Davis Institute, Jewish General Hospital, McGill University, Montréal, Québec, Canada. · University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, Queensland, Australia. · MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK. · Garvan Institute of Medical Research, Sydney, New South Wales, Australia. · Molecular Endocrinology Laboratory, Department of Medicine, Imperial College London, London, UK. · Institute for Systems Genetics, New York University Langone Medical Center, New York, NY, USA. · Department of Research, 23andMe, Inc., Mountain View, CA, USA. · Research Institute of the McGill University Health Centre, Montréal, Québec, Canada. · McGill University and Genome Quebec Innovation Centre, Montréal, Québec, Canada. · Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands. · Department of Biomedical Genetics, University of Rochester, Rochester, NY, USA. · Department of Orthopedics, University of Colorado Anschutz Medical Campus, Aurora, CO, USA. · Department of Medicine, McGill University, Montréal, Québec, Canada. · Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK. · MRC Lifecourse Epidemiology Unit, University of Southampton, Southampton, UK. · NIHR Southampton Biomedical Research Centre, University of Southampton and University Hospital Southampton NHS Foundation Trust, Southampton, UK. · NIHR Oxford Biomedical Research Centre, University of Oxford, Oxford, UK. · Department of Hygiene and Epidemiology, University of Ioannina Medical School, Ioannina, Greece. · Center for Evidence Synthesis in Health, Department of Health Services, Policy and Practice, School of Public Health, Brown University, Providence, RI, USA. · Department of Epidemiology and Biostatistics, Imperial College London, London, UK. · Department of Internal Medicine and Clinical Nutrition, University of Gothenburg, Gothenburg, Sweden. · Institute for Aging Research, Hebrew SeniorLife, Boston, MA, USA. · Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA. · Department of Medicine, Harvard Medical School, Boston, MA, USA. · Broad Institute of Harvard and Massachusetts Institute of Technology, Boston, MA, USA. · Musculoskeletal Research Unit, Department of Translational Health Sciences, University of Bristol, Bristol, UK. · Children's Mercy Hospitals and Clinics, Kansas City, MO, USA. · Wellcome Trust Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, UK. · Center for Musculoskeletal Research, Department of Orthopaedics, University of Rochester, Rochester, NY, USA. · University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, Queensland, Australia. d.evans1@uq.edu.au. · MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK. d.evans1@uq.edu.au. · Department of Human Genetics, McGill University, Montréal, Québec, Canada. brent.richards@mcgill.ca. · Lady Davis Institute, Jewish General Hospital, McGill University, Montréal, Québec, Canada. brent.richards@mcgill.ca. · Department of Medicine, McGill University, Montréal, Québec, Canada. brent.richards@mcgill.ca. · Department of Epidemiology, Biostatistics & Occupational Health, McGill University, Montréal, Québec, Canada. brent.richards@mcgill.ca. · Department of Twin Research and Genetic Epidemiology, King's College London, London, UK. brent.richards@mcgill.ca. ·Nat Genet · Pubmed #30598549.

ABSTRACT: Osteoporosis is a common aging-related disease diagnosed primarily using bone mineral density (BMD). We assessed genetic determinants of BMD as estimated by heel quantitative ultrasound in 426,824 individuals, identifying 518 genome-wide significant loci (301 novel), explaining 20% of its variance. We identified 13 bone fracture loci, all associated with estimated BMD (eBMD), in ~1.2 million individuals. We then identified target genes enriched for genes known to influence bone density and strength (maximum odds ratio (OR) = 58, P = 1 × 10

7 Article Novel therapeutic intervention for osteoporosis prepared with strontium hydroxyapatite and zoledronic acid: In vitro and pharmacodynamic evaluation. 2017

Khajuria, Deepak Kumar / Vasireddi, Ramakrishna / Trebbin, Martin / Karasik, David / Razdan, Rema. ·The Musculoskeletal Genetics Laboratory, Faculty of Medicine in the Galilee, Bar-Ilan University, Safed, Israel; Department of Pharmacology, Al-Ameen College of Pharmacy, Bangalore, India. Electronic address: deepak_kumarkhajuria@yahoo.co.in. · Hamburg Center for Ultrafast Imaging, University of Hamburg, Hamburg, Germany. · The Musculoskeletal Genetics Laboratory, Faculty of Medicine in the Galilee, Bar-Ilan University, Safed, Israel. · Department of Pharmacology, Al-Ameen College of Pharmacy, Bangalore, India. ·Mater Sci Eng C Mater Biol Appl · Pubmed #27987763.

ABSTRACT: Osteoporosis therapeutics has been monopolized mainly by bisphosphonates, which are potent anti-osteoporotic drugs, while they do not promote bone formation or replenish the already resorbed bone. Although strontium substituted hydroxyapatite (SrHA) has been proclaimed to improve bone properties in an osteoporotic animal model, there is no published data on direct delivery of SrHA nanoparticles by bisphosphonate-like zoledronic acid (ZOL) to the bone. Therefore, this study was designed to investigate the potential of using SrHA/ZOL nanoparticle-based drug formulation in an ovariectomized rat model of postmenopausal osteoporosis. SrHA and SrHA/ZOL nanoparticles were prepared and characterized by field-emission scanning electron microscopy (FESEM), X-ray diffraction (XRD) and Fourier transform infrared spectroscopy (FTIR). Twelve weeks after ovariectomy, rats were treated with either single intravenous dose of SrHA/ZOL (100, 50 or 25μg/kg); ZOL (100μg/kg); or SrHA (100μg/kg). Saline-treated OVX and SHAM-OVX groups served as controls. The energy-dispersive X-ray (EDX) microanalysis of bone specimen obtained from SrHA/ZOL groups yielded range between 64.3±6.7 to 66.9±6.8 of calcium weight (wt) % and 1.64±0.6 to 1.74±0.8 of calcium/phosphorus (Ca/P) ratio which was significantly higher when compared with 39.7±9.3 calcium and 1.30±0.2 Ca/P ratio for OVX group. Moreover, the strontium wt% in SrHA/ZOL group (between 3.1±0.5 and 6.8±0.4) was significantly higher than SrHA group (1.8±0.9). These results confirmed targeted delivery of SrHA nanoparticles by ZOL to the bone. Therapy with SrHA/ZOL showed significant improvements in trabecular bone microarchitecture and mechanical strength as compared to ZOL or SrHA (p<0.05). Moreover, treatment with SrHA/ZOL significantly precluded an increase in serum bone-specific alkaline phosphatase and tartrate-resistant acid phosphatase than either ZOL or SrHA (p<0.05). These results strongly implicate that SrHA/ZOL nanoparticle-based drug formulation showed better efficacy at a much lower dose of ZOL. SrHA/ZOL drug formulation has a therapeutic advantage over ZOL or SrHA monotherapy for experimental osteoporosis.

8 Article Novel Genetic Variants Associated With Increased Vertebral Volumetric BMD, Reduced Vertebral Fracture Risk, and Increased Expression of SLC1A3 and EPHB2. 2016

Nielson, Carrie M / Liu, Ching-Ti / Smith, Albert V / Ackert-Bicknell, Cheryl L / Reppe, Sjur / Jakobsdottir, Johanna / Wassel, Christina / Register, Thomas C / Oei, Ling / Alonso, Nerea / Oei, Edwin H / Parimi, Neeta / Samelson, Elizabeth J / Nalls, Mike A / Zmuda, Joseph / Lang, Thomas / Bouxsein, Mary / Latourelle, Jeanne / Claussnitzer, Melina / Siggeirsdottir, Kristin / Srikanth, Priya / Lorentzen, Erik / Vandenput, Liesbeth / Langefeld, Carl / Raffield, Laura / Terry, Greg / Cox, Amanda J / Allison, Matthew A / Criqui, Michael H / Bowden, Don / Ikram, M Arfan / Mellström, Dan / Karlsson, Magnus K / Carr, John / Budoff, Matthew / Phillips, Caroline / Cupples, L Adrienne / Chou, Wen-Chi / Myers, Richard H / Ralston, Stuart H / Gautvik, Kaare M / Cawthon, Peggy M / Cummings, Steven / Karasik, David / Rivadeneira, Fernando / Gudnason, Vilmundur / Orwoll, Eric S / Harris, Tamara B / Ohlsson, Claes / Kiel, Douglas P / Hsu, Yi-Hsiang. ·School of Public Health, Oregon Health & Science University, Portland, OR, USA. · Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA. · Icelandic Heart Association, Kópavogur, Iceland. · Faculty of Medicine, University of Iceland, Reykjavík, Iceland. · Department of Orthopaedics and Rehabilitation, University of Rochester, Rochester, NY, USA. · Department of Medical Biochemistry, Oslo University Hospital, Ullevål, Oslo, Norway. · Lovisenberg Diakonale Hospital, Oslo, Norway. · Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway. · Department of Pathology and Laboratory Medicine, University of Vermont College of Medicine, Burlington, VT, USA. · Department of Pathology, Wake Forest School of Medicine, Winston-Salem, NC, USA. · Internal Medicine, Erasmus MC, Rotterdam, The Netherlands. · Netherlands Genomics Initiative (NGI)-sponsored Netherlands Consortium for Healthy Aging (NCHA), Leiden, The Netherlands. · Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, Scotland, UK. · Radiology & Nuclear Medicine, Erasmus MC, Rotterdam, The Netherlands. · California Pacific Medical Center Research Institute, San Francisco, CA, USA. · Institute for Aging Research, Hebrew SeniorLife, Harvard Medical School, Boston, MA, USA. · National Institute on Aging (NIA), National Institutes of Health, Bethesda, MD, USA. · Department of Epidemiology, University of Pittsburgh Graduate School of Public Health, Pittsburgh, PA, USA. · Department of Radiology, University of California, San Francisco (UCSF) School of Medicine, San Francisco, CA, USA. · Center for Advanced Orthopedic Studies, Beth Israel Deaconess Medical Center, Harvard University Medical School, Boston, MA, USA. · Department of Neurology, Boston University, Boston, MA, USA. · Department of Medicine, Beth Israel Deaconess Medical Center, Harvard University Medical School, Boston, MA, USA. · Broad Institute of MIT and Harvard, Cambridge, MA, USA. · Technical University Munich, Munich, Germany. · Imaging, Icelandic Heart Association, Kópavogur, Iceland. · Department of Bioinformatics, Gothenburg University, Gothenburg, Sweden. · Centre for Bone and Arthritis Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden. · Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, NC, USA. · Center for Human Genomics, Wake Forest School of Medicine, Winston-Salem, NC, USA. · Center for Diabetes Research, Wake Forest School of Medicine, Winston-Salem, NC, USA. · Department of Radiology & Radiological Sciences, Vanderbilt University Medical Center, Vanderbilt University, Nashville, TN, USA. · Center for Diabetes Research, Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, NC, USA. · Department of Family Medicine and Public Health, University of California, San Diego (UCSD), La Jolla, CA, USA. · Internal Medicine/Endocrinology, Wake Forest School of Medicine, Winston-Salem, NC, USA. · Center for Genomics and Personalized Medicine Research, Wake Forest School of Medicine, Winston-Salem, NC, USA. · Department of Epidemiology, Erasmus MC, Rotterdam, The Netherlands. · Department of Orthopaedics and Clinical Sciences, Malmö University Hospital, Lund University, Malmö, Sweden. · Los Angeles Biomedical Research Institute, Torrance, CA, USA. · Rheumatic Diseases Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, Scotland, UK. · Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA, USA. · Faculty of Medicine in the Galilee, Bar-Ilan University, Safed, Israel. · Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands. · Division of Endocrinology, Oregon Health & Science University, Portland, OR, USA. · Molecular and Integrative Physiological Sciences, Harvard School of Public Health, Boston, MA, USA. ·J Bone Miner Res · Pubmed #27476799.

ABSTRACT: Genome-wide association studies (GWASs) have revealed numerous loci for areal bone mineral density (aBMD). We completed the first GWAS meta-analysis (n = 15,275) of lumbar spine volumetric BMD (vBMD) measured by quantitative computed tomography (QCT), allowing for examination of the trabecular bone compartment. SNPs that were significantly associated with vBMD were also examined in two GWAS meta-analyses to determine associations with morphometric vertebral fracture (n = 21,701) and clinical vertebral fracture (n = 5893). Expression quantitative trait locus (eQTL) analyses of iliac crest biopsies were performed in 84 postmenopausal women, and murine osteoblast expression of genes implicated by eQTL or by proximity to vBMD-associated SNPs was examined. We identified significant vBMD associations with five loci, including: 1p36.12, containing WNT4 and ZBTB40; 8q24, containing TNFRSF11B; and 13q14, containing AKAP11 and TNFSF11. Two loci (5p13 and 1p36.12) also contained associations with radiographic and clinical vertebral fracture, respectively. In 5p13, rs2468531 (minor allele frequency [MAF] = 3%) was associated with higher vBMD (β = 0.22, p = 1.9 × 10

9 Article METTL21C is a potential pleiotropic gene for osteoporosis and sarcopenia acting through the modulation of the NF-κB signaling pathway. 2014

Huang, Jian / Hsu, Yi-Hsiang / Mo, Chenglin / Abreu, Eduardo / Kiel, Douglas P / Bonewald, Lynda F / Brotto, Maxrco / Karasik, David. ·Muscle Biology Research Group, Schools of Nursing & Health Studies, University of Missouri Kansas City, 2464 Charlotte Street, Kansas City, MO. · Institute for Aging Research, Hebrew SeniorLife, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA. · Harvard Medical School, Boston, MA, USA. · Department of Oral and Craniofacial Sciences, School of Dentistry, University of Missouri, Kansas City, MO, USA. ·J Bone Miner Res · Pubmed #24677265.

ABSTRACT: Sarcopenia and osteoporosis are important public health problems that occur concurrently. A bivariate genome-wide association study (GWAS) identified METTL21c as a suggestive pleiotropic gene for both bone and muscle. The METTL21 family of proteins methylates chaperones involved in the etiology of both myopathy and inclusion body myositis with Paget's disease. To validate these GWAS results, Mettl21c mRNA expression was reduced with siRNA in a mouse myogenic C2C12 cell line and the mouse osteocyte-like cell line MLO-Y4. At day 3, as C2C12 myoblasts start to differentiate into myotubes, a significant reduction in the number of myocytes aligning/organizing for fusion was observed in the siRNA-treated cells. At day 5, both fewer and smaller myotubes were observed in the siRNA-treated cells as confirmed by histomorphometric analyses and immunostaining with myosin heavy chain (MHC) antibody, which only stains myocytes/myotubes but not myoblasts. Intracellular calcium (Ca(2+)) measurements of the siRNA-treated myotubes showed a decrease in maximal amplitude peak response to caffeine, suggesting that less Ca(2+) is available for release due to the partial silencing of Mettl21c, correlating with impaired myogenesis. In siRNA-treated MLO-Y4 cells, 48 hours after treatment with dexamethasone there was a significant increase in cell death, suggesting a role of Mettl21c in osteocyte survival. To investigate the molecular signaling machinery induced by the partial silencing of Mettl21c, we used a real-time PCR gene array to monitor the activity of 10 signaling pathways. We discovered that Mettl21c knockdown modulated only the NF-κB signaling pathway (ie, Birc3, Ccl5, and Tnf). These results suggest that Mettl21c might exert its bone-muscle pleiotropic function via the regulation of the NF-κB signaling pathway, which is critical for bone and muscle homeostasis. These studies also provide rationale for cellular and molecular validation of GWAS, and warrant additional in vitro and in vivo studies to advance our understanding of role of METTL21C in musculoskeletal biology.

10 Article Genetic determinants of heel bone properties: genome-wide association meta-analysis and replication in the GEFOS/GENOMOS consortium. 2014

Moayyeri, Alireza / Hsu, Yi-Hsiang / Karasik, David / Estrada, Karol / Xiao, Su-Mei / Nielson, Carrie / Srikanth, Priya / Giroux, Sylvie / Wilson, Scott G / Zheng, Hou-Feng / Smith, Albert V / Pye, Stephen R / Leo, Paul J / Teumer, Alexander / Hwang, Joo-Yeon / Ohlsson, Claes / McGuigan, Fiona / Minster, Ryan L / Hayward, Caroline / Olmos, José M / Lyytikäinen, Leo-Pekka / Lewis, Joshua R / Swart, Karin M A / Masi, Laura / Oldmeadow, Chris / Holliday, Elizabeth G / Cheng, Sulin / van Schoor, Natasja M / Harvey, Nicholas C / Kruk, Marcin / del Greco M, Fabiola / Igl, Wilmar / Trummer, Olivia / Grigoriou, Efi / Luben, Robert / Liu, Ching-Ti / Zhou, Yanhua / Oei, Ling / Medina-Gomez, Carolina / Zmuda, Joseph / Tranah, Greg / Brown, Suzanne J / Williams, Frances M / Soranzo, Nicole / Jakobsdottir, Johanna / Siggeirsdottir, Kristin / Holliday, Kate L / Hannemann, Anke / Go, Min Jin / Garcia, Melissa / Polasek, Ozren / Laaksonen, Marika / Zhu, Kun / Enneman, Anke W / McEvoy, Mark / Peel, Roseanne / Sham, Pak Chung / Jaworski, Maciej / Johansson, Åsa / Hicks, Andrew A / Pludowski, Pawel / Scott, Rodney / Dhonukshe-Rutten, Rosalie A M / van der Velde, Nathalie / Kähönen, Mika / Viikari, Jorma S / Sievänen, Harri / Raitakari, Olli T / González-Macías, Jesús / Hernández, Jose L / Mellström, Dan / Ljunggren, Osten / Cho, Yoon Shin / Völker, Uwe / Nauck, Matthias / Homuth, Georg / Völzke, Henry / Haring, Robin / Brown, Matthew A / McCloskey, Eugene / Nicholson, Geoffrey C / Eastell, Richard / Eisman, John A / Jones, Graeme / Reid, Ian R / Dennison, Elaine M / Wark, John / Boonen, Steven / Vanderschueren, Dirk / Wu, Frederick C W / Aspelund, Thor / Richards, J Brent / Bauer, Doug / Hofman, Albert / Khaw, Kay-Tee / Dedoussis, George / Obermayer-Pietsch, Barbara / Gyllensten, Ulf / Pramstaller, Peter P / Lorenc, Roman S / Cooper, Cyrus / Kung, Annie Wai Chee / Lips, Paul / Alen, Markku / Attia, John / Brandi, Maria Luisa / de Groot, Lisette C P G M / Lehtimäki, Terho / Riancho, José A / Campbell, Harry / Liu, Yongmei / Harris, Tamara B / Akesson, Kristina / Karlsson, Magnus / Lee, Jong-Young / Wallaschofski, Henri / Duncan, Emma L / O'Neill, Terence W / Gudnason, Vilmundur / Spector, Timothy D / Rousseau, François / Orwoll, Eric / Cummings, Steven R / Wareham, Nick J / Rivadeneira, Fernando / Uitterlinden, Andre G / Prince, Richard L / Kiel, Douglas P / Reeve, Jonathan / Kaptoge, Stephen K. ·Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK. ·Hum Mol Genet · Pubmed #24430505.

ABSTRACT: Quantitative ultrasound of the heel captures heel bone properties that independently predict fracture risk and, with bone mineral density (BMD) assessed by X-ray (DXA), may be convenient alternatives for evaluating osteoporosis and fracture risk. We performed a meta-analysis of genome-wide association (GWA) studies to assess the genetic determinants of heel broadband ultrasound attenuation (BUA; n = 14 260), velocity of sound (VOS; n = 15 514) and BMD (n = 4566) in 13 discovery cohorts. Independent replication involved seven cohorts with GWA data (in silico n = 11 452) and new genotyping in 15 cohorts (de novo n = 24 902). In combined random effects, meta-analysis of the discovery and replication cohorts, nine single nucleotide polymorphisms (SNPs) had genome-wide significant (P < 5 × 10(-8)) associations with heel bone properties. Alongside SNPs within or near previously identified osteoporosis susceptibility genes including ESR1 (6q25.1: rs4869739, rs3020331, rs2982552), SPTBN1 (2p16.2: rs11898505), RSPO3 (6q22.33: rs7741021), WNT16 (7q31.31: rs2908007), DKK1 (10q21.1: rs7902708) and GPATCH1 (19q13.11: rs10416265), we identified a new locus on chromosome 11q14.2 (rs597319 close to TMEM135, a gene recently linked to osteoblastogenesis and longevity) significantly associated with both BUA and VOS (P < 8.23 × 10(-14)). In meta-analyses involving 25 cohorts with up to 14 985 fracture cases, six of 10 SNPs associated with heel bone properties at P < 5 × 10(-6) also had the expected direction of association with any fracture (P < 0.05), including three SNPs with P < 0.005: 6q22.33 (rs7741021), 7q31.31 (rs2908007) and 10q21.1 (rs7902708). In conclusion, this GWA study reveals the effect of several genes common to central DXA-derived BMD and heel ultrasound/DXA measures and points to a new genetic locus with potential implications for better understanding of osteoporosis pathophysiology.

11 Article A genome-wide copy number association study of osteoporotic fractures points to the 6p25.1 locus. 2014

Oei, Ling / Hsu, Yi-Hsiang / Styrkarsdottir, Unnur / Eussen, Bert H / de Klein, Annelies / Peters, Marjolein J / Halldorsson, Bjarni / Liu, Ching-Ti / Alonso, Nerea / Kaptoge, Stephen K / Thorleifsson, Gudmar / Hallmans, Göran / Hocking, Lynne J / Husted, Lise Bjerre / Jameson, Karen A / Kruk, Marcin / Lewis, Joshua R / Patel, Millan S / Scollen, Serena / Svensson, Olle / Trompet, Stella / van Schoor, Natasja M / Zhu, Kun / Buckley, Brendan M / Cooper, Cyrus / Ford, Ian / Goltzman, David / González-Macías, Jesús / Langdahl, Bente Lomholt / Leslie, William D / Lips, Paul / Lorenc, Roman S / Olmos, José M / Pettersson-Kymmer, Ulrika / Reid, David M / Riancho, José A / Slagboom, P Eline / Garcia-Ibarbia, Carmen / Ingvarsson, Thorvaldur / Johannsdottir, Hrefna / Luben, Robert / Medina-Gómez, Carolina / Arp, Pascal / Nandakumar, Kannabiran / Palsson, Stefan Th / Sigurdsson, Gunnar / van Meurs, Joyce B J / Zhou, Yanhua / Hofman, Albert / Jukema, J Wouter / Pols, Huibert A P / Prince, Richard L / Cupples, L Adrienne / Marshall, Christian R / Pinto, Dalila / Sato, Daisuke / Scherer, Stephen W / Reeve, Jonathan / Thorsteinsdottir, Unnur / Karasik, David / Richards, J Brent / Stefansson, Kari / Uitterlinden, André G / Ralston, Stuart H / Ioannidis, John P A / Kiel, Douglas P / Rivadeneira, Fernando / Estrada, Karol. ·Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands. ·J Med Genet · Pubmed #24343915.

ABSTRACT: BACKGROUND: Osteoporosis is a systemic skeletal disease characterised by reduced bone mineral density and increased susceptibility to fracture; these traits are highly heritable. Both common and rare copy number variants (CNVs) potentially affect the function of genes and may influence disease risk. AIM: To identify CNVs associated with osteoporotic bone fracture risk. METHOD: We performed a genome-wide CNV association study in 5178 individuals from a prospective cohort in the Netherlands, including 809 osteoporotic fracture cases, and performed in silico lookups and de novo genotyping to replicate in several independent studies. RESULTS: A rare (population prevalence 0.14%, 95% CI 0.03% to 0.24%) 210 kb deletion located on chromosome 6p25.1 was associated with the risk of fracture (OR 32.58, 95% CI 3.95 to 1488.89; p = 8.69 × 10(-5)). We performed an in silico meta-analysis in four studies with CNV microarray data and the association with fracture risk was replicated (OR 3.11, 95% CI 1.01 to 8.22; p = 0.02). The prevalence of this deletion showed geographic diversity, being absent in additional samples from Australia, Canada, Poland, Iceland, Denmark, and Sweden, but present in the Netherlands (0.34%), Spain (0.33%), USA (0.23%), England (0.15%), Scotland (0.10%), and Ireland (0.06%), with insufficient evidence for association with fracture risk. CONCLUSIONS: These results suggest that deletions in the 6p25.1 locus may predispose to higher risk of fracture in a subset of populations of European origin; larger and geographically restricted studies will be needed to confirm this regional association. This is a first step towards the evaluation of the role of rare CNVs in osteoporosis.

12 Article Impact of common variation in bone-related genes on type 2 diabetes and related traits. 2012

Billings, Liana K / Hsu, Yi-Hsiang / Ackerman, Rachel J / Dupuis, Josée / Voight, Benjamin F / Rasmussen-Torvik, Laura J / Hercberg, Serge / Lathrop, Mark / Barnes, Daniel / Langenberg, Claudia / Hui, Jennie / Fu, Mao / Bouatia-Naji, Nabila / Lecoeur, Cecile / An, Ping / Magnusson, Patrik K / Surakka, Ida / Ripatti, Samuli / Christiansen, Lene / Dalgård, Christine / Folkersen, Lasse / Grundberg, Elin / Anonymous9330728 / Anonymous9340728 / Anonymous9350728 / Anonymous9360728 / Anonymous9370728 / Eriksson, Per / Kaprio, Jaakko / Ohm Kyvik, Kirsten / Pedersen, Nancy L / Borecki, Ingrid B / Province, Michael A / Balkau, Beverley / Froguel, Philippe / Shuldiner, Alan R / Palmer, Lyle J / Wareham, Nick / Meneton, Pierre / Johnson, Toby / Pankow, James S / Karasik, David / Meigs, James B / Kiel, Douglas P / Florez, Jose C. ·Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, USA. ·Diabetes · Pubmed #22698912.

ABSTRACT: Exploring genetic pleiotropy can provide clues to a mechanism underlying the observed epidemiological association between type 2 diabetes and heightened fracture risk. We examined genetic variants associated with bone mineral density (BMD) for association with type 2 diabetes and glycemic traits in large well-phenotyped and -genotyped consortia. We undertook follow-up analysis in ∼19,000 individuals and assessed gene expression. We queried single nucleotide polymorphisms (SNPs) associated with BMD at levels of genome-wide significance, variants in linkage disequilibrium (r(2) > 0.5), and BMD candidate genes. SNP rs6867040, at the ITGA1 locus, was associated with a 0.0166 mmol/L (0.004) increase in fasting glucose per C allele in the combined analysis. Genetic variants in the ITGA1 locus were associated with its expression in the liver but not in adipose tissue. ITGA1 variants appeared among the top loci associated with type 2 diabetes, fasting insulin, β-cell function by homeostasis model assessment, and 2-h post-oral glucose tolerance test glucose and insulin levels. ITGA1 has demonstrated genetic pleiotropy in prior studies, and its suggested role in liver fibrosis, insulin secretion, and bone healing lends credence to its contribution to both osteoporosis and type 2 diabetes. These findings further underscore the link between skeletal and glucose metabolism and highlight a locus to direct future investigations.

13 Article Genome-wide meta-analysis identifies 56 bone mineral density loci and reveals 14 loci associated with risk of fracture. 2012

Estrada, Karol / Styrkarsdottir, Unnur / Evangelou, Evangelos / Hsu, Yi-Hsiang / Duncan, Emma L / Ntzani, Evangelia E / Oei, Ling / Albagha, Omar M E / Amin, Najaf / Kemp, John P / Koller, Daniel L / Li, Guo / Liu, Ching-Ti / Minster, Ryan L / Moayyeri, Alireza / Vandenput, Liesbeth / Willner, Dana / Xiao, Su-Mei / Yerges-Armstrong, Laura M / Zheng, Hou-Feng / Alonso, Nerea / Eriksson, Joel / Kammerer, Candace M / Kaptoge, Stephen K / Leo, Paul J / Thorleifsson, Gudmar / Wilson, Scott G / Wilson, James F / Aalto, Ville / Alen, Markku / Aragaki, Aaron K / Aspelund, Thor / Center, Jacqueline R / Dailiana, Zoe / Duggan, David J / Garcia, Melissa / Garcia-Giralt, Natàlia / Giroux, Sylvie / Hallmans, Göran / Hocking, Lynne J / Husted, Lise Bjerre / Jameson, Karen A / Khusainova, Rita / Kim, Ghi Su / Kooperberg, Charles / Koromila, Theodora / Kruk, Marcin / Laaksonen, Marika / Lacroix, Andrea Z / Lee, Seung Hun / Leung, Ping C / Lewis, Joshua R / Masi, Laura / Mencej-Bedrac, Simona / Nguyen, Tuan V / Nogues, Xavier / Patel, Millan S / Prezelj, Janez / Rose, Lynda M / Scollen, Serena / Siggeirsdottir, Kristin / Smith, Albert V / Svensson, Olle / Trompet, Stella / Trummer, Olivia / van Schoor, Natasja M / Woo, Jean / Zhu, Kun / Balcells, Susana / Brandi, Maria Luisa / Buckley, Brendan M / Cheng, Sulin / Christiansen, Claus / Cooper, Cyrus / Dedoussis, George / Ford, Ian / Frost, Morten / Goltzman, David / González-Macías, Jesús / Kähönen, Mika / Karlsson, Magnus / Khusnutdinova, Elza / Koh, Jung-Min / Kollia, Panagoula / Langdahl, Bente Lomholt / Leslie, William D / Lips, Paul / Ljunggren, Östen / Lorenc, Roman S / Marc, Janja / Mellström, Dan / Obermayer-Pietsch, Barbara / Olmos, José M / Pettersson-Kymmer, Ulrika / Reid, David M / Riancho, José A / Ridker, Paul M / Rousseau, François / Slagboom, P Eline / Tang, Nelson L S / Urreizti, Roser / Van Hul, Wim / Viikari, Jorma / Zarrabeitia, María T / Aulchenko, Yurii S / Castano-Betancourt, Martha / Grundberg, Elin / Herrera, Lizbeth / Ingvarsson, Thorvaldur / Johannsdottir, Hrefna / Kwan, Tony / Li, Rui / Luben, Robert / Medina-Gómez, Carolina / Palsson, Stefan Th / Reppe, Sjur / Rotter, Jerome I / Sigurdsson, Gunnar / van Meurs, Joyce B J / Verlaan, Dominique / Williams, Frances M K / Wood, Andrew R / Zhou, Yanhua / Gautvik, Kaare M / Pastinen, Tomi / Raychaudhuri, Soumya / Cauley, Jane A / Chasman, Daniel I / Clark, Graeme R / Cummings, Steven R / Danoy, Patrick / Dennison, Elaine M / Eastell, Richard / Eisman, John A / Gudnason, Vilmundur / Hofman, Albert / Jackson, Rebecca D / Jones, Graeme / Jukema, J Wouter / Khaw, Kay-Tee / Lehtimäki, Terho / Liu, Yongmei / Lorentzon, Mattias / McCloskey, Eugene / Mitchell, Braxton D / Nandakumar, Kannabiran / Nicholson, Geoffrey C / Oostra, Ben A / Peacock, Munro / Pols, Huibert A P / Prince, Richard L / Raitakari, Olli / Reid, Ian R / Robbins, John / Sambrook, Philip N / Sham, Pak Chung / Shuldiner, Alan R / Tylavsky, Frances A / van Duijn, Cornelia M / Wareham, Nick J / Cupples, L Adrienne / Econs, Michael J / Evans, David M / Harris, Tamara B / Kung, Annie Wai Chee / Psaty, Bruce M / Reeve, Jonathan / Spector, Timothy D / Streeten, Elizabeth A / Zillikens, M Carola / Thorsteinsdottir, Unnur / Ohlsson, Claes / Karasik, David / Richards, J Brent / Brown, Matthew A / Stefansson, Kari / Uitterlinden, André G / Ralston, Stuart H / Ioannidis, John P A / Kiel, Douglas P / Rivadeneira, Fernando. ·Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands. ·Nat Genet · Pubmed #22504420.

ABSTRACT: Bone mineral density (BMD) is the most widely used predictor of fracture risk. We performed the largest meta-analysis to date on lumbar spine and femoral neck BMD, including 17 genome-wide association studies and 32,961 individuals of European and east Asian ancestry. We tested the top BMD-associated markers for replication in 50,933 independent subjects and for association with risk of low-trauma fracture in 31,016 individuals with a history of fracture (cases) and 102,444 controls. We identified 56 loci (32 new) associated with BMD at genome-wide significance (P < 5 × 10(-8)). Several of these factors cluster within the RANK-RANKL-OPG, mesenchymal stem cell differentiation, endochondral ossification and Wnt signaling pathways. However, we also discovered loci that were localized to genes not known to have a role in bone biology. Fourteen BMD-associated loci were also associated with fracture risk (P < 5 × 10(-4), Bonferroni corrected), of which six reached P < 5 × 10(-8), including at 18p11.21 (FAM210A), 7q21.3 (SLC25A13), 11q13.2 (LRP5), 4q22.1 (MEPE), 2p16.2 (SPTBN1) and 10q21.1 (DKK1). These findings shed light on the genetic architecture and pathophysiological mechanisms underlying BMD variation and fracture susceptibility.

14 Article A Polymorphism in a gene encoding Perilipin 4 is associated with height but not with bone measures in individuals from the Framingham Osteoporosis Study. 2012

Cusano, Natalie E / Kiel, Douglas P / Demissie, Serkalem / Karasik, David / Adrienne Cupples, L / Corella, Dolores / Gao, Qiong / Richardson, Kris / Yiannakouris, Nikos / Ordovas, Jose M. ·Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA. nc2433@columbia.edu ·Calcif Tissue Int · Pubmed #22210160.

ABSTRACT: There is increasing interest in identifying new pathways and candidate genes that confer susceptibility to osteoporosis. There is evidence that adipogenesis and osteogenesis may be related, including a common bone marrow progenitor cell for both adipocytes and osteoblasts. Perilipin 1 (PLIN1) and Perilipin 4 (PLIN4) are members of the PATS family of genes and are involved in lipolysis of intracellular lipid deposits. A previous study reported gender-specific associations between one polymorphism of PLIN1 and bone mineral density (BMD) in a Japanese population. We hypothesized that polymorphisms in PLIN1 and PLIN4 would be associated with bone measures in adult Caucasian participants of the Framingham Osteoporosis Study (FOS). We genotyped 1,206 male and 1,445 female participants of the FOS for four single-nucleotide polymorphism (SNPs) in PLIN1 and seven SNPs in PLIN4 and tested for associations with measures of BMD, bone ultrasound, hip geometry, and height. We found several gender-specific significant associations with the measured traits. The association of PLIN4 SNP rs8887, G>A with height in females trended toward significance after simulation testing (adjusted P = 0.07) and remained significant after simulation testing in the combined-sex model (adjusted P = 0.033). In a large study sample of men and women, we found a significant association between one SNP in PLIN4 and height but not with bone traits, suggesting that PATS family genes are not important in the regulation of bone. Identification of genes that influence human height may lead to a better understanding of the processes involved in growth and development.

15 Article Genome-wide association of an integrated osteoporosis-related phenotype: is there evidence for pleiotropic genes? 2012

Karasik, David / Cheung, Ching Lung / Zhou, Yanhua / Cupples, L Adrienne / Kiel, Douglas P / Demissie, Serkalem. ·Hebrew SeniorLife Institute for Aging Research and Harvard Medical School, Boston, MA 02131, USA. karasik@hsl.harvard.edu ·J Bone Miner Res · Pubmed #22072498.

ABSTRACT: Multiple musculoskeletal traits assessed by various methods at different skeletal sites serve as surrogates for osteoporosis risk. However, it is a challenge to select the most relevant phenotypes for genetic study of fractures. Principal component analyses (PCA) were conducted in participants of the Framingham Osteoporosis Study on 17 measures including bond mineral density (BMD) (hip and spine), heel ultrasound, leg lean mass (LLM), and hip geometric indices, adjusting for covariates (age, height, body mass index [BMI]), in a combined sample of 1180 men and 1758 women, as well as in each sex. Four principal components (PCs) jointly explained ~69% of the total variability of musculoskeletal traits. PC1, explaining ~33% of the total variance, was referred to as the component of "Bone strength," because it included the hip and spine BMD as well as several hip cross-sectional properties. PC2 (20.5% variance) was labeled as "Femoral cross-sectional geometry;" PC3 (~8% variance) captured only ultrasound measures; PC4, explaining ~7% variance, was correlated with LLM and hip geometry. We then evaluated ~2.5 mil SNPs for association with PCs 1, 2, and 4. There were genome-wide significant associations (p < 5 × 10⁻⁸) between PC2 and HTR1E (that codes for one of the serotonin receptors) and PC4 with COL4A2 in women. In the sexes-combined sample, AKAP6 was associated with PC2 (p = 1.40 × 10⁻⁷). A single nucleotide polymorphism (SNP) in HTR1E was also associated with the risk of nonvertebral fractures in women (p = 0.005). Functions of top associated genes were enriched for the skeletal and muscular system development (p < 0.05). In conclusion, multivariate combination provides genetic associations not identified in the analysis of primary phenotypes. Genome-wide screening for the linear combinations of multiple osteoporosis-related phenotypes suggests that there are variants with potentially pleiotropic effects in established and novel pathways to be followed up to provide further evidence of their functions.

16 Article Identification of homogeneous genetic architecture of multiple genetically correlated traits by block clustering of genome-wide associations. 2011

Gupta, Mayetri / Cheung, Ching-Lung / Hsu, Yi-Hsiang / Demissie, Serkalem / Cupples, L Adrienne / Kiel, Douglas P / Karasik, David. ·Department of Biostatistics, Boston University, Boston, MA, USA. ·J Bone Miner Res · Pubmed #21611967.

ABSTRACT: Genome-wide association studies (GWAS) using high-density genotyping platforms offer an unbiased strategy to identify new candidate genes for osteoporosis. It is imperative to be able to clearly distinguish signal from noise by focusing on the best phenotype in a genetic study. We performed GWAS of multiple phenotypes associated with fractures [bone mineral density (BMD), bone quantitative ultrasound (QUS), bone geometry, and muscle mass] with approximately 433,000 single-nucleotide polymorphisms (SNPs) and created a database of resulting associations. We performed analysis of GWAS data from 23 phenotypes by a novel modification of a block clustering algorithm followed by gene-set enrichment analysis. A data matrix of standardized regression coefficients was partitioned along both axes--SNPs and phenotypes. Each partition represents a distinct cluster of SNPs that have similar effects over a particular set of phenotypes. Application of this method to our data shows several SNP-phenotype connections. We found a strong cluster of association coefficients of high magnitude for 10 traits (BMD at several skeletal sites, ultrasound measures, cross-sectional bone area, and section modulus of femoral neck and shaft). These clustered traits were highly genetically correlated. Gene-set enrichment analyses indicated the augmentation of genes that cluster with the 10 osteoporosis-related traits in pathways such as aldosterone signaling in epithelial cells, role of osteoblasts, osteoclasts, and chondrocytes in rheumatoid arthritis, and Parkinson signaling. In addition to several known candidate genes, we also identified PRKCH and SCNN1B as potential candidate genes for multiple bone traits. In conclusion, our mining of GWAS results revealed the similarity of association results between bone strength phenotypes that may be attributed to pleiotropic effects of genes. This knowledge may prove helpful in identifying novel genes and pathways that underlie several correlated phenotypes, as well as in deciphering genetic and phenotypic modularity underlying osteoporosis risk.

17 Article An integration of genome-wide association study and gene expression profiling to prioritize the discovery of novel susceptibility Loci for osteoporosis-related traits. 2010

Hsu, Yi-Hsiang / Zillikens, M Carola / Wilson, Scott G / Farber, Charles R / Demissie, Serkalem / Soranzo, Nicole / Bianchi, Estelle N / Grundberg, Elin / Liang, Liming / Richards, J Brent / Estrada, Karol / Zhou, Yanhua / van Nas, Atila / Moffatt, Miriam F / Zhai, Guangju / Hofman, Albert / van Meurs, Joyce B / Pols, Huibert A P / Price, Roger I / Nilsson, Olle / Pastinen, Tomi / Cupples, L Adrienne / Lusis, Aldons J / Schadt, Eric E / Ferrari, Serge / Uitterlinden, André G / Rivadeneira, Fernando / Spector, Timothy D / Karasik, David / Kiel, Douglas P. ·Hebrew SeniorLife Institute for Aging Research, Harvard Medical School, Boston, Massachusetts, USA. ·PLoS Genet · Pubmed #20548944.

ABSTRACT: Osteoporosis is a complex disorder and commonly leads to fractures in elderly persons. Genome-wide association studies (GWAS) have become an unbiased approach to identify variations in the genome that potentially affect health. However, the genetic variants identified so far only explain a small proportion of the heritability for complex traits. Due to the modest genetic effect size and inadequate power, true association signals may not be revealed based on a stringent genome-wide significance threshold. Here, we take advantage of SNP and transcript arrays and integrate GWAS and expression signature profiling relevant to the skeletal system in cellular and animal models to prioritize the discovery of novel candidate genes for osteoporosis-related traits, including bone mineral density (BMD) at the lumbar spine (LS) and femoral neck (FN), as well as geometric indices of the hip (femoral neck-shaft angle, NSA; femoral neck length, NL; and narrow-neck width, NW). A two-stage meta-analysis of GWAS from 7,633 Caucasian women and 3,657 men, revealed three novel loci associated with osteoporosis-related traits, including chromosome 1p13.2 (RAP1A, p = 3.6x10(-8)), 2q11.2 (TBC1D8), and 18q11.2 (OSBPL1A), and confirmed a previously reported region near TNFRSF11B/OPG gene. We also prioritized 16 suggestive genome-wide significant candidate genes based on their potential involvement in skeletal metabolism. Among them, 3 candidate genes were associated with BMD in women. Notably, 2 out of these 3 genes (GPR177, p = 2.6x10(-13); SOX6, p = 6.4x10(-10)) associated with BMD in women have been successfully replicated in a large-scale meta-analysis of BMD, but none of the non-prioritized candidates (associated with BMD) did. Our results support the concept of our prioritization strategy. In the absence of direct biological support for identified genes, we highlighted the efficiency of subsequent functional characterization using publicly available expression profiling relevant to the skeletal system in cellular or whole animal models to prioritize candidate genes for further functional validation.

18 Article Genome-wide pleiotropy of osteoporosis-related phenotypes: the Framingham Study. 2010

Karasik, David / Hsu, Yi-Hsiang / Zhou, Yanhua / Cupples, L Adrienne / Kiel, Douglas P / Demissie, Serkalem. ·Hebrew SeniorLife Institute for Aging Research and Harvard Medical School, Boston, MA 02131, USA. karasik@mail.hrca.harvard.edu ·J Bone Miner Res · Pubmed #20200953.

ABSTRACT: Genome-wide association studies offer an unbiased approach to identify new candidate genes for osteoporosis. We examined the Affymetrix 500K + 50K SNP GeneChip marker sets for associations with multiple osteoporosis-related traits at various skeletal sites, including bone mineral density (BMD, hip and spine), heel ultrasound, and hip geometric indices in the Framingham Osteoporosis Study. We evaluated 433,510 single-nucleotide polymorphisms (SNPs) in 2073 women (mean age 65 years), members of two-generational families. Variance components analysis was performed to estimate phenotypic, genetic, and environmental correlations (rho(P), rho(G), and rho(E)) among bone traits. Linear mixed-effects models were used to test associations between SNPs and multivariable-adjusted trait values. We evaluated the proportion of SNPs associated with pairs of the traits at a nominal significance threshold alpha = 0.01. We found substantial correlation between the proportion of associated SNPs and the rho(P) and rho(G) (r = 0.91 and 0.84, respectively) but much lower with rho(E) (r = 0.38). Thus, for example, hip and spine BMD had 6.8% associated SNPs in common, corresponding to rho(P) = 0.55 and rho(G) = 0.66 between them. Fewer SNPs were associated with both BMD and any of the hip geometric traits (eg, femoral neck and shaft width, section moduli, neck shaft angle, and neck length); rho(G) between BMD and geometric traits ranged from -0.24 to +0.40. In conclusion, we examined relationships between osteoporosis-related traits based on genome-wide associations. Most of the similarity between the quantitative bone phenotypes may be attributed to pleiotropic effects of genes. This knowledge may prove helpful in defining the best phenotypes to be used in genetic studies of osteoporosis.

19 Article Association of JAG1 with bone mineral density and osteoporotic fractures: a genome-wide association study and follow-up replication studies. 2010

Kung, Annie W C / Xiao, Su-Mei / Cherny, Stacey / Li, Gloria H Y / Gao, Yi / Tso, Gloria / Lau, Kam S / Luk, Keith D K / Liu, Jian-min / Cui, Bin / Zhang, Min-Jia / Zhang, Zhen-lin / He, Jin-wei / Yue, Hua / Xia, Wia-bo / Luo, Lian-mei / He, Shu-li / Kiel, Douglas P / Karasik, David / Hsu, Yi-Hsiang / Cupples, L Adrienne / Demissie, Serkalem / Styrkarsdottir, Unnur / Halldorsson, Bjarni V / Sigurdsson, Gunnar / Thorsteinsdottir, Unnur / Stefansson, Kari / Richards, J Brent / Zhai, Guangju / Soranzo, Nicole / Valdes, Ana / Spector, Tim D / Sham, Pak C. ·Department of Medicine, Research Centre of Heart, Brain, Hormone & Healthy Aging, Faculty of Medicine, The University of Hong Kong, Hong Kong, China. awckung@hkucc.hku.hk ·Am J Hum Genet · Pubmed #20096396.

ABSTRACT: Bone mineral density (BMD), a diagnostic parameter for osteoporosis and a clinical predictor of fracture, is a polygenic trait with high heritability. To identify genetic variants that influence BMD in different ethnic groups, we performed a genome-wide association study (GWAS) on 800 unrelated Southern Chinese women with extreme BMD and carried out follow-up replication studies in six independent study populations of European descent and Asian populations including 18,098 subjects. In the meta-analysis, rs2273061 of the Jagged1 (JAG1) gene was associated with high BMD (p = 5.27 x 10(-8) for lumbar spine [LS] and p = 4.15 x 10(-5) for femoral neck [FN], n = 18,898). This SNP was further found to be associated with the low risk of osteoporotic fracture (p = 0.009, OR = 0.7, 95% CI 0.57-0.93, n = 1881). Region-wide and haplotype analysis showed that the strongest association evidence was from the linkage disequilibrium block 5, which included rs2273061 of the JAG1 gene (p = 8.52 x 10(-9) for LS and 3.47 x 10(-5) at FN). To assess the function of identified variants, an electrophoretic mobility shift assay demonstrated the binding of c-Myc to the "G" but not "A" allele of rs2273061. A mRNA expression study in both human bone-derived cells and peripheral blood mononuclear cells confirmed association of the high BMD-related allele G of rs2273061 with higher JAG1 expression. Our results identify the JAG1 gene as a candidate for BMD regulation in different ethnic groups, and it is a potential key factor for fracture pathogenesis.

20 Article Refined QTLs of osteoporosis-related traits by linkage analysis with genome-wide SNPs: Framingham SHARe. 2010

Karasik, David / Dupuis, Josée / Cho, Kelly / Cupples, L Adrienne / Zhou, Yanhua / Kiel, Douglas P / Demissie, Serkalem. ·Hebrew SeniorLife Institute for Aging Research and Harvard Medical School, Boston, MA 02131, USA. karasik@hrca.harvard.edu ·Bone · Pubmed #20064633.

ABSTRACT: Genome-wide association studies (GWAS) using high-density array of single-nucleotide polymorphisms (SNPs) offer an unbiased strategy to identify new candidate genes for osteoporosis. We used a subset of autosomal SNPs from the Affymetrix 500K+50K SNP GeneChip marker set to examine genetic linkage with multiple highly heritable osteoporosis-related traits, including BMD of the hip and spine, heel ultrasound (attenuation and speed of sound), and geometric indices of the hip, in two generations from the Framingham Osteoporosis Study. Variance component linkage analysis was performed using normalized residuals (adjusted for age, height, BMI, and estrogen status in women). Multipoint linkage analyses produced LOD scores > or =3.0 for BMD on chromosomes (chr.) 9 and 11 and for ultrasound speed of sound on chr. 5. Hip geometric traits were linked with higher LOD scores, such as with shaft width on chr. 4 (LOD=3.9) and chr. 16 (LOD=3.8) and with shaft section modulus on chr. 22 (LOD=4.0). LOD score > or =5.0 was obtained for femoral neck width on chr. 7. In conclusion, with an SNP-based linkage approach, we identified several novel potential QTLs and confirmed previously identified chromosomal regions linked to bone mass and geometry. Subsequent focus on the spectrum of genetic polymorphisms in these refined regions may contribute to finding variants predisposing to osteoporosis.