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Life-Course Genome-wide Association Study Meta-analysis of Total Body BMD and Assessment of Age-Specific Effects.
Medina-Gomez, Carolina; Kemp, John P; Trajanoska, Katerina; Luan, Jian'an; Chesi, Alessandra; Ahluwalia, Tarunveer S; Mook-Kanamori, Dennis O; Ham, Annelies; Hartwig, Fernando P; Evans, Daniel S; Joro, Raimo; Nedeljkovic, Ivana; Zheng, Hou-Feng; Zhu, Kun; Atalay, Mustafa; Liu, Ching-Ti; Nethander, Maria; Broer, Linda; Porleifsson, Gudmar; Mullin, Benjamin H; Handelman, Samuel K; Nalls, Mike A; Jessen, Leon E; Heppe, Denise H M; Richards, J Brent; Wang, Carol; Chawes, Bo; Schraut, Katharina E; Amin, Najaf; Wareham, Nick; Karasik, David; Van der Velde, Nathalie; Ikram, M Arfan; Zemel, Babette S; Zhou, Yanhua; Carlsson, Christian J; Liu, Yongmei; McGuigan, Fiona E; Boer, Cindy G; Bønnelykke, Klaus; Ralston, Stuart H; Robbins, John A; Walsh, John P; Zillikens, M Carola; Langenberg, Claudia; Li-Gao, Ruifang; Williams, Frances M K; Harris, Tamara B; Akesson, Kristina; Jackson, Rebecca D.
Afiliação
  • Medina-Gomez C; Department of Internal Medicine, Erasmus MC, 3000 CA Rotterdam, the Netherlands; The Generation R Study Group, Erasmus MC, 3000 CA Rotterdam, the Netherlands; Department of Epidemiology, Erasmus MC, 3000 CA Rotterdam, the Netherlands.
  • Kemp JP; University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, QLD 4102, Australia; MRC Integrative Epidemiology Unit, University of Bristol, Bristol BS8 2BN, UK.
  • Trajanoska K; Department of Internal Medicine, Erasmus MC, 3000 CA Rotterdam, the Netherlands; Department of Epidemiology, Erasmus MC, 3000 CA Rotterdam, the Netherlands.
  • Luan J; MRC Epidemiology Unit, University of Cambridge, Cambridge CB2 0QQ, UK.
  • Chesi A; Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
  • Ahluwalia TS; COPSAC, Copenhagen Prospective Studies on Asthma in Childhood, Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen 2820, Denmark; Steno Diabetes Center, Copenhagen 2820, Denmark.
  • Mook-Kanamori DO; Department of Clinical Epidemiology, Leiden University Medical Centre, 2333 ZA Leiden, the Netherlands; Department of Public Health and Primary Care, Leiden University Medical Centre, 2333 ZA Leiden, the Netherlands.
  • Ham A; Department of Internal Medicine, Erasmus MC, 3000 CA Rotterdam, the Netherlands.
  • Hartwig FP; Postgraduate Program in Epidemiology, Federal University of Pelotas, 96020220 Pelotas, Brazil.
  • Evans DS; California Pacific Medical Center Research Institute, San Francisco, CA 94107, USA.
  • Joro R; Institute of Biomedicine, Physiology, University of Eastern Finland, Kuopio 70211, Finland.
  • Nedeljkovic I; Department of Epidemiology, Erasmus MC, 3000 CA Rotterdam, the Netherlands.
  • Zheng HF; Departments of Medicine, Human Genetics, Epidemiology and Biostatistics, McGill University, Montreal, QC H3A 1A2, Canada; Department of Medicine, Lady Davis Institute for Medical Research, Jewish General Hospital, McGill University, Montreal, QC H3T 1E2, Canada; Institute of Basic Medical Sciences,
  • Zhu K; Department of Endocrinology and Diabetes, Sir Charles Gairdner Hospital, Nedlands, WA 6009, Australia; School of Medicine and Pharmacology, University of Western Australia, Crawley, WA 6009, Australia.
  • Atalay M; Institute of Biomedicine, Physiology, University of Eastern Finland, Kuopio 70211, Finland.
  • Liu CT; Department of Biostatistics, Boston University School of Public Health, Boston, MA 02131, USA.
  • Nethander M; Bioinformatics Core Facility, Sahlgrenska Academy, University of Gothenburg, 41390 Gothenburg, Sweden.
  • Broer L; Department of Internal Medicine, Erasmus MC, 3000 CA Rotterdam, the Netherlands.
  • Porleifsson G; deCODE Genetics/Amgen, Reykjavik 101, Iceland.
  • Mullin BH; Department of Endocrinology and Diabetes, Sir Charles Gairdner Hospital, Nedlands, WA 6009, Australia; School of Medicine and Pharmacology, University of Western Australia, Crawley, WA 6009, Australia.
  • Handelman SK; Department of Obstetrics and Gynecology, Wayne State University, Detroit, MI 48201, USA.
  • Nalls MA; Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD 20892, USA; Data Tecnica International, Glen Echo, MD 20812, USA.
  • Jessen LE; COPSAC, Copenhagen Prospective Studies on Asthma in Childhood, Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen 2820, Denmark.
  • Heppe DHM; The Generation R Study Group, Erasmus MC, 3000 CA Rotterdam, the Netherlands; Department of Epidemiology, Erasmus MC, 3000 CA Rotterdam, the Netherlands.
  • Richards JB; Departments of Medicine, Human Genetics, Epidemiology and Biostatistics, McGill University, Montreal, QC H3A 1A2, Canada; Department of Medicine, Lady Davis Institute for Medical Research, Jewish General Hospital, McGill University, Montreal, QC H3T 1E2, Canada.
  • Wang C; School of Women's and Infants' Health, University of Western Australia, Crawley, WA 6009, Australia.
  • Chawes B; COPSAC, Copenhagen Prospective Studies on Asthma in Childhood, Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen 2820, Denmark.
  • Schraut KE; Centre for Global Health Research, Usher Institute for Population Health Sciences and Informatics, University of Edinburgh, Edinburgh EH16 4UX, Scotland; Centre for Cardiovascular Sciences, Queen's Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, Scotland.
  • Amin N; Department of Epidemiology, Erasmus MC, 3000 CA Rotterdam, the Netherlands.
  • Wareham N; MRC Epidemiology Unit, University of Cambridge, Cambridge CB2 0QQ, UK.
  • Karasik D; Hebrew SeniorLife, Institute for Aging Research, Roslindale, MA 02131, USA; Faculty of Medicine in the Galilee, Bar-Ilan University, Safed 1311502, Israel.
  • Van der Velde N; Department of Internal Medicine, Erasmus MC, 3000 CA Rotterdam, the Netherlands; Department of Internal Medicine, Section of Geriatrics, Academic Medical Center, 1105 AZ Amsterdam, the Netherlands.
  • Ikram MA; Department of Epidemiology, Erasmus MC, 3000 CA Rotterdam, the Netherlands.
  • Zemel BS; Division of GI, Hepatology, and Nutrition, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
  • Zhou Y; Department of Biostatistics, Boston University School of Public Health, Boston, MA 02131, USA.
  • Carlsson CJ; COPSAC, Copenhagen Prospective Studies on Asthma in Childhood, Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen 2820, Denmark.
  • Liu Y; Wake Forest School of Medicine, Winston-Salem, NC 27101, USA.
  • McGuigan FE; Lund University, Department of Clinical Sciences Malmö, Clinical and Molecular Osteoporosis Research Unit, 20502 Malmö, Sweden.
  • Boer CG; Department of Internal Medicine, Erasmus MC, 3000 CA Rotterdam, the Netherlands.
  • Bønnelykke K; COPSAC, Copenhagen Prospective Studies on Asthma in Childhood, Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen 2820, Denmark.
  • Ralston SH; Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, Scotland.
  • Robbins JA; Department of Medicine, University of California, Davis, Sacramento, CA 95817, USA.
  • Walsh JP; Department of Endocrinology and Diabetes, Sir Charles Gairdner Hospital, Nedlands, WA 6009, Australia; School of Medicine and Pharmacology, University of Western Australia, Crawley, WA 6009, Australia.
  • Zillikens MC; Department of Internal Medicine, Erasmus MC, 3000 CA Rotterdam, the Netherlands.
  • Langenberg C; MRC Epidemiology Unit, University of Cambridge, Cambridge CB2 0QQ, UK.
  • Li-Gao R; Department of Clinical Epidemiology, Leiden University Medical Centre, 2333 ZA Leiden, the Netherlands.
  • Williams FMK; Department of Twin Research & Genetic Epidemiology, King's College London, London SE1 7EH, UK.
  • Harris TB; Laboratory of Epidemiology and Population Sciences, National Institute on Aging, NIH, Bethesda, MD 20892, USA.
  • Akesson K; Lund University, Department of Clinical Sciences Malmö, Clinical and Molecular Osteoporosis Research Unit, 20502 Malmö, Sweden; Skåne University Hospital, Department of Orthopedics, 21428 Malmö, Sweden.
  • Jackson RD; Division of Endocrinology, Diabetes, and Metabolism, Department of Internal Medicine, The Ohio State University, Columbus, OH 43210, USA.
Am J Hum Genet ; 102(1): 88-102, 2018 01 04.
Article em En | MEDLINE | ID: mdl-29304378
ABSTRACT
Bone mineral density (BMD) assessed by DXA is used to evaluate bone health. In children, total body (TB) measurements are commonly used; in older individuals, BMD at the lumbar spine (LS) and femoral neck (FN) is used to diagnose osteoporosis. To date, genetic variants in more than 60 loci have been identified as associated with BMD. To investigate the genetic determinants of TB-BMD variation along the life course and test for age-specific effects, we performed a meta-analysis of 30 genome-wide association studies (GWASs) of TB-BMD including 66,628 individuals overall and divided across five age strata, each spanning 15 years. We identified variants associated with TB-BMD at 80 loci, of which 36 have not been previously identified; overall, they explain approximately 10% of the TB-BMD variance when combining all age groups and influence the risk of fracture. Pathway and enrichment analysis of the association signals showed clustering within gene sets implicated in the regulation of cell growth and SMAD proteins, overexpressed in the musculoskeletal system, and enriched in enhancer and promoter regions. These findings reveal TB-BMD as a relevant trait for genetic studies of osteoporosis, enabling the identification of variants and pathways influencing different bone compartments. Only variants in ESR1 and close proximity to RANKL showed a clear effect dependency on age. This most likely indicates that the majority of genetic variants identified influence BMD early in life and that their effect can be captured throughout the life course.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Densidade Óssea / Estudo de Associação Genômica Ampla Tipo de estudo: Diagnostic_studies / Prognostic_studies / Risk_factors_studies / Systematic_reviews Limite: Adolescent / Animals / Child / Child, preschool / Humans / Infant / Newborn Idioma: En Ano de publicação: 2018 Tipo de documento: Article
Texto completo
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Densidade Óssea / Estudo de Associação Genômica Ampla Tipo de estudo: Diagnostic_studies / Prognostic_studies / Risk_factors_studies / Systematic_reviews Limite: Adolescent / Animals / Child / Child, preschool / Humans / Infant / Newborn Idioma: En Ano de publicação: 2018 Tipo de documento: Article