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Osteoporosis: HELP
Articles by David Karasik
Based on 25 articles published since 2008

Between 2008 and 2019, D. Karasik wrote the following 25 articles about Osteoporosis.
+ Citations + Abstracts
1 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.

2 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.

3 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.

4 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.

5 Review Osteoporosis: an evolutionary perspective. 2008

Karasik, David. ·Institute for Aging Research, Hebrew SeniorLife and Harvard Medical School, 1200 Centre Street, Boston, MA 02131, USA. karasik@hrca.harvard.edu ·Hum Genet · Pubmed #18781328.

ABSTRACT: Increased life expectancy has led to an overall aging of the population and greater numbers of elderly people. Therefore, the number of people with osteoporosis has increased substantially, accompanied with an epidemic of hip fractures. Osteoporosis is an age-related systemic condition that naturally occurs, among mammals, only in humans. Osteoporosis is known to be highly heritable. However, assuming a genetic determinant for this post-reproductive disease to be transmitted from one generation to the next is counter-intuitive, based on the principles of human evolution, I will attempt to provide an explanation of the phenomenon from the point of view of evolution, selection, and changed environment in humans, which contributed to human longevity, while on other hand, contribute to diseases of civilization, including osteoporosis. There is a need to delve into evolution of human species in search for adaptive patterns to a specific environment that humans are operating in the last couple of millennia, to clarify whether "good" and "bad" genes exist, and how to find and correct them. The answer to the above questions will help us to identify causes of the current epidemic of osteoporosis and to pin-point a tailored treatment.

6 Review Contribution of gender-specific genetic factors to osteoporosis risk. 2008

Karasik, D / Ferrari, S L. ·Hebrew SeniorLife/IFAR and Harvard Medical School, Boston, MA 02131, USA. karasik@hrca.harvard.edu ·Ann Hum Genet · Pubmed #18485052.

ABSTRACT: Common diseases result from the complex relationship between genetic and environmental factors. The aim of this review is to provide perspective for a conceptual framework aimed at studying the interplay of gender-specific genetic and environmental factors in the etiology of complex disease, using osteoporosis as an example. In recent years, gender differences in the heritability of the osteoporosis-related phenotypes have been reported and sex-specific quantitative-trait loci were discovered by linkage studies in humans and mice. Results of numerous allelic association studies also differed by gender. In most cases, it was not clear whether or not this phenomenon should be attributed to the effect of sex-chromosomes, sex hormones, or other intrinsic or extrinsic differences between the genders, such as the level of bioavailable estrogen and of physical activity. We conclude that there is need to consider gender-specific genetic and environmental factors in the planning of future association studies on the etiology of osteoporosis and other complex diseases prevalent in the general population.

7 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 / Anonymous11331162 / 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

8 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.

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 / Anonymous8980728 / Anonymous8990728 / Anonymous9000728 / Anonymous9010728 / Anonymous9020728 / 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.

21 Article Hip geometry variation is associated with bone mineralization pathway gene variants: The Framingham Study. 2010

Cheung, Ching-Lung / Livshits, Gregory / Zhou, Yanhua / Meigs, James B / McAteer, Jarred B / Florez, Jose C / Cupples, L Adrienne / Demissie, Serkalem / Kiel, Douglas P / Karasik, David. ·Hebrew SeniorLife Institute for Aging Research, Harvard Medical School, Boston, MA, USA. ·J Bone Miner Res · Pubmed #19888898.

ABSTRACT: Mineralization of bone matrix is an important process in bone formation; thus defects in mineralization have been implicated in bone mineral density (BMD) and bone structure alterations. Three central regulators of phosphate balance, ALPL, ANKH, and ENPP1, are central in the matrix mineralization process; therefore, the genes encoding them are considered important candidates genes for BMD and bone geometry. To test for an association between these three candidate genes and BMD and bone geometry traits, 124 informative singlenucleotide polymorphisms (SNPs) were selected and genotyped in 1513 unrelated subjects from the Framingham offspring cohort. Initial results showed that SNP rs1974201 in the gene ENPP1 was a susceptibility variant associated with several hip geometric indices, with the strongest p value of 3.8 × 10(7) being observed for femoral neck width. A few modest associations were observed between SNPs in or near ALPL and several bone traits, but no association was observed with ANKH. The association signals observed for SNPs around rs1974201 were attenuated after conditional analysis on rs1974201. Transcription factor binding-site prediction revealed that the HOXA7 binding site was present in the reference sequence with the major allele, whereas this potential binding site is lost in the sequence with the minor allele of rs1974201. In conclusion, we found evidence for association of bone geometry variation with an SNP in ENPP1, a gene in the mineralization pathway. The alteration of a binding site of the deregulator of extracellular matrix HOXA7 warrants further investigation.

22 Article Collaborative meta-analysis: associations of 150 candidate genes with osteoporosis and osteoporotic fracture. 2009

Richards, J Brent / Kavvoura, Fotini K / Rivadeneira, Fernando / Styrkársdóttir, Unnur / Estrada, Karol / Halldórsson, Bjarni V / Hsu, Yi-Hsiang / Zillikens, M Carola / Wilson, Scott G / Mullin, Benjamin H / Amin, Najaf / Aulchenko, Yurii S / Cupples, L Adrienne / Deloukas, Panagiotis / Demissie, Serkalem / Hofman, Albert / Kong, Augustine / Karasik, David / van Meurs, Joyce B / Oostra, Ben A / Pols, Huibert A P / Sigurdsson, Gunnar / Thorsteinsdottir, Unnur / Soranzo, Nicole / Williams, Frances M K / Zhou, Yanhua / Ralston, Stuart H / Thorleifsson, Gudmar / van Duijn, Cornelia M / Kiel, Douglas P / Stefansson, Kari / Uitterlinden, André G / Ioannidis, John P A / Spector, Tim D / Anonymous860641. ·McGill University, Montreal, Quebec, Canada. ·Ann Intern Med · Pubmed #19841454.

ABSTRACT: BACKGROUND: Osteoporosis is a highly heritable trait. Many candidate genes have been proposed as being involved in regulating bone mineral density (BMD). Few of these findings have been replicated in independent studies. OBJECTIVE: To assess the relationship between BMD and fracture and all common single-nucleotide polymorphisms (SNPs) in previously proposed osteoporosis candidate genes. DESIGN: Large-scale meta-analysis of genome-wide association data. SETTING: 5 international, multicenter, population-based studies. PARTICIPANTS: Data on BMD were obtained from 19 195 participants (14 277 women) from 5 populations of European origin. Data on fracture were obtained from a prospective cohort (n = 5974) from the Netherlands. MEASUREMENTS: Systematic literature review using the Human Genome Epidemiology Navigator identified autosomal genes previously evaluated for association with osteoporosis. We explored the common SNPs arising from the haplotype map of the human genome (HapMap) across all these genes. BMD at the femoral neck and lumbar spine was measured by dual-energy x-ray absorptiometry. Fractures were defined as clinically apparent, site-specific, validated nonvertebral and vertebral low-energy fractures. RESULTS: 150 candidate genes were identified and 36 016 SNPs in these loci were assessed. SNPs from 9 gene loci (ESR1, LRP4, ITGA1, LRP5, SOST, SPP1, TNFRSF11A, TNFRSF11B, and TNFSF11) were associated with BMD at either site. For most genes, no SNP was statistically significant. For statistically significant SNPs (n = 241), effect sizes ranged from 0.04 to 0.18 SD per allele. SNPs from the LRP5, SOST, SPP1, and TNFRSF11A loci were significantly associated with fracture risk; odds ratios ranged from 1.13 to 1.43 per allele. These effects on fracture were partially independent of BMD at SPP1 and SOST. LIMITATION: Only common polymorphisms in linkage disequilibrium with SNPs in HapMap could be assessed, and previously reported associations for SNPs in some candidate genes could not be excluded. CONCLUSION: In this large-scale collaborative genome-wide meta-analysis, 9 of 150 candidate genes were associated with regulation of BMD, 4 of which also significantly affected risk for fracture. However, most candidate genes had no consistent association with BMD.

23 Article PPARG by dietary fat interaction influences bone mass in mice and humans. 2008

Ackert-Bicknell, Cheryl L / Demissie, Serkalem / Marín de Evsikova, Caralina / Hsu, Yi-Hsiang / DeMambro, Victoria E / Karasik, David / Cupples, L Adrienne / Ordovas, Jose M / Tucker, Katherine L / Cho, Kelly / Canalis, Ernesto / Paigen, Beverly / Churchill, Gary A / Forejt, Jiri / Beamer, Wesley G / Ferrari, Serge / Bouxsein, Mary L / Kiel, Douglas P / Rosen, Clifford J. ·The Jackson Laboratory, Bar Harbor, Maine 04609, USA. ·J Bone Miner Res · Pubmed #18707223.

ABSTRACT: Adult BMD, an important risk factor for fracture, is the result of genetic and environmental interactions. A quantitative trait locus (QTL) for the phenotype of volumetric BMD (vBMD), named Bmd8, was found on mid-distal chromosome (Chr) 6 in mice. This region is homologous to human Chr 3p25. The B6.C3H-6T (6T) congenic mouse was previously created to study this QTL. Using block haplotyping of the 6T congenic region, expression analysis in the mouse, and examination of nonsynonymous SNPs, peroxisome proliferator activated receptor gamma (Pparg) was determined to be the most likely candidate gene for the Bmd8 QTL of the 630 genes located in the congenic region. Furthermore, in the C3H/HeJ (C3H) strain, which is the donor strain for the 6T congenic, several polymorphisms were found in the Pparg gene. On challenge with a high-fat diet, we found that the 6T mouse has a lower areal BMD (aBMD) and volume fraction of trabecular bone (BV/TV%) of the distal femur compared with B6 mice. Interactions between SNPs in the PPARG gene and dietary fat for the phenotype of BMD were examined in the Framingham Offspring Cohort. This analysis showed that there was a similar interaction of the PPARG gene and diet (fat intake) on aBMD in both men and women. These findings suggest that dietary fat has a significant influence on BMD that is dependent on the alleles present for the PPARG gene.

24 Article Large-scale analysis of association between LRP5 and LRP6 variants and osteoporosis. 2008

van Meurs, Joyce B J / Trikalinos, Thomas A / Ralston, Stuart H / Balcells, Susana / Brandi, Maria Luisa / Brixen, Kim / Kiel, Douglas P / Langdahl, Bente L / Lips, Paul / Ljunggren, Osten / Lorenc, Roman / Obermayer-Pietsch, Barbara / Ohlsson, Claes / Pettersson, Ulrika / Reid, David M / Rousseau, Francois / Scollen, Serena / Van Hul, Wim / Agueda, Lidia / Akesson, Kristina / Benevolenskaya, Lidia I / Ferrari, Serge L / Hallmans, Göran / Hofman, Albert / Husted, Lise Bjerre / Kruk, Marcin / Kaptoge, Stephen / Karasik, David / Karlsson, Magnus K / Lorentzon, Mattias / Masi, Laura / McGuigan, Fiona E A / Mellström, Dan / Mosekilde, Leif / Nogues, Xavier / Pols, Huibert A P / Reeve, Jonathan / Renner, Wilfried / Rivadeneira, Fernando / van Schoor, Natasja M / Weber, Kurt / Ioannidis, John P A / Uitterlinden, André G / Anonymous140595. ·Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands. ·JAMA · Pubmed #18349089.

ABSTRACT: CONTEXT: Mutations in the low-density lipoprotein receptor-related protein 5 (LRP5) gene cause rare syndromes characterized by altered bone mineral density (BMD). More common LRP5 variants may affect osteoporosis risk in the general population. OBJECTIVE: To generate large-scale evidence on whether 2 common variants of LRP5 (Val667Met, Ala1330Val) and 1 variant of LRP6 (Ile1062Val) are associated with BMD and fracture risk. DESIGN AND SETTING: Prospective, multicenter, collaborative study of individual-level data on 37,534 individuals from 18 participating teams in Europe and North America. Data were collected between September 2004 and January 2007; analysis of the collected data was performed between February and May 2007. Bone mineral density was assessed by dual-energy x-ray absorptiometry. Fractures were identified via questionnaire, medical records, or radiographic documentation; incident fracture data were available for some cohorts, ascertained via routine surveillance methods, including radiographic examination for vertebral fractures. MAIN OUTCOME MEASURES: Bone mineral density of the lumbar spine and femoral neck; prevalence of all fractures and vertebral fractures. RESULTS: The Met667 allele of LRP5 was associated with reduced lumbar spine BMD (n = 25,052 [number of participants with available data]; 20-mg/cm2 lower BMD per Met667 allele copy; P = 3.3 x 10(-8)), as was the Val1330 allele (n = 24,812; 14-mg/cm2 lower BMD per Val1330 copy; P = 2.6 x 10(-9)). Similar effects were observed for femoral neck BMD, with a decrease of 11 mg/cm2 (P = 3.8 x 10(-5)) and 8 mg/cm2 (P = 5.0 x 10(-6)) for the Met667 and Val1330 alleles, respectively (n = 25 193). Findings were consistent across studies for both LRP5 alleles. Both alleles were associated with vertebral fractures (odds ratio [OR], 1.26; 95% confidence interval [CI], 1.08-1.47 for Met667 [2001 fractures among 20 488 individuals] and OR, 1.12; 95% CI, 1.01-1.24 for Val1330 [1988 fractures among 20,096 individuals]). Risk of all fractures was also increased with Met667 (OR, 1.14; 95% CI, 1.05-1.24 per allele [7876 fractures among 31,435 individuals)]) and Val1330 (OR, 1.06; 95% CI, 1.01-1.12 per allele [7802 fractures among 31 199 individuals]). Effects were similar when adjustments were made for age, weight, height, menopausal status, and use of hormone therapy. Fracture risks were partly attenuated by adjustment for BMD. Haplotype analysis indicated that Met667 and Val1330 variants both independently affected BMD. The LRP6 Ile1062Val polymorphism was not associated with any osteoporosis phenotype. All aforementioned associations except that between Val1330 and all fractures and vertebral fractures remained significant after multiple-comparison adjustments. CONCLUSIONS: Common LRP5 variants are consistently associated with BMD and fracture risk across different white populations. The magnitude of the effect is modest. LRP5 may be the first gene to reach a genome-wide significance level (a conservative level of significance [herein, unadjusted P < 10(-7)] that accounts for the many possible comparisons in the human genome) for a phenotype related to osteoporosis.

25 Article Genetics of the musculoskeletal system: a pleiotropic approach. 2008

Karasik, David / Kiel, Douglas P. ·Institute for Aging Research, Hebrew SeniorLife, Harvard Medical School, Boston, Massachusetts 02131, USA. karasik@hrca.harvard.edu ·J Bone Miner Res · Pubmed #18269309.

ABSTRACT: The risk of osteoporotic fracture can be viewed as a function of loading conditions and the ability of the bone to withstand the load. Skeletal loads are dominated by muscle action. Recently, it has become clear that bone and muscle share genetic determinants. Involution of the musculoskeletal system manifests as bone loss (osteoporosis) and muscle wasting (sarcopenia). Therefore, the consideration of pleiotropy is an important aspect in the study of the genetics of osteoporosis and sarcopenia. This Perspective will provide the evidence for a shared genetic influence on bone and muscle. We will start with an overview of accumulating evidence that physical exercise produces effects on the adult skeleton, seeking to unravel some of the contradictory findings published thus far. We will provide indications that there are pleiotropic relationships between bone structure/mass and muscle mass/function. Finally, we will offer some insights and practical recommendations as to the value of studying shared genetic factors and will explore possible directions for future research. We consider several related questions that together comprise the general paradigm of bone responses to mechanical loading and the relationship between muscle strength and bone parameters, including the genetic factors that modulate these responses. 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 conditions and may translate into new approaches to reduce the burdens of both conditions through improved diagnosis, prevention, and early targeted treatment.