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Genomewide meta-analysis identifies loci associated with IGF-I and IGFBP-3 levels with impact on age-related traits.

About this Publication
Title
Genomewide meta-analysis identifies loci associated with IGF-I and IGFBP-3 levels with impact on age-related traits.
Pubmed ID
27329260 (View this publication on the PubMed website)
Digital Object Identifier
Publication
Aging Cell. 2016 Oct; Volume 15 (Issue 5): Pages 811-24
Authors
Teumer A, Qi Q, Nethander M, Aschard H, Bandinelli S, Beekman M, Berndt SI, Bidlingmaier M, Broer L, CHARGE Longevity Working Group, Cappola A, Ceda GP, Chanock S, Chen MH, Chen TC, Chen YD, Chung J, Del Greco Miglianico F, Eriksson J, Ferrucci L, ...show more Friedrich N, Gnewuch C, Goodarzi MO, Grarup N, Guo T, Hammer E, Hayes RB, Hicks AA, Hofman A, Houwing-Duistermaat JJ, Hu F, Hunter DJ, Husemoen LL, Isaacs A, Jacobs KB, Janssen JA, Jansson JO, Jehmlich N, Johnson S, Juul A, Karlsson M, Kilpelainen TO, Kovacs P, Kraft P, Li C, Linneberg A, Liu Y, Loos RJ, Body Composition Genetics Consortium, Lorentzon M, Lu Y, Maggio M, Magi R, Meigs J, Mellström D, Nauck M, Newman AB, Pollak MN, Pramstaller PP, Prokopenko I, Psaty BM, Reincke M, Rimm EB, Rotter JI, Saint Pierre A, Schurmann C, Seshadri S, Sjögren K, Slagboom PE, Strickler HD, Stumvoll M, Suh Y, Sun Q, Zhang C, Svensson J, Tanaka T, Tare A, Tönjes A, Uh HW, van Duijn CM, van Heemst D, Vandenput L, Vasan RS, Völker U, Willems SM, Ohlsson C, Wallaschofski H, Kaplan RC
Affiliations
  • Institute for Community Medicine, University Medicine Greifswald, 17475, Greifswald, Germany.
  • Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY, 10461, USA.
  • Bioinformatics Core Facility, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, 40530, Sweden.
  • Program in Genetic Epidemiology and Statistical Genetics, Department of Epidemiology, Harvard School of Public Health, Boston, MA, 02115, USA.
  • Geriatric Unit, Azienda Sanitaria di Firenze (ASF), Florence, Italy.
  • Molecular Epidemiology, Leiden University Medical Center, Leiden, 2300 RC, The Netherlands.
  • Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, 20892, USA.
  • Medizinische Klinik und Poliklinik IV, Klinikum der Universitaet Muenchen, 80336, Munich, Germany.
  • Department of Epidemiology, Subdivision Genetic Epidemiology, Erasmus Medical Center, Postbus 2040, 3000 CA, Rotterdam, The Netherlands.
  • Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania School of Medicine, Philadelphia, PA, 19104, USA.
...show more
  • Section of Geriatrics, Department of Clinical and Experimental Medicine, University of Parma, Parma, Italy.
  • Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, 17475, Greifswald, Germany.
  • Framingham Heart Study, Framingham, MA, 01702, USA.
  • Section of Endocrinology, Diabetes & Nutrition, Boston University School of Medicine, Boston, MA, 02118, USA.
  • Institute for Translational Genomics and Population Sciences, Los Angeles BioMedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA, 90502, USA.
  • Department of Genetics, Albert Einstein College of Medicine, Bronx, NY, 10461, USA.
  • Center for Biomedicine, European Academy Bozen/Bolzano (EURAC), Bolzano, 39100, Italy.
  • Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, 41345, Gothenburg, Sweden.
  • Translational Gerontology Branch, National Institute on Aging, Baltimore, MD, 21225, USA.
  • Institute of Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, 17475, Greifswald, Germany.
  • Institute for Clinical Chemistry and Laboratory Medicine, Regensburg University Medical Center, D-93053, Regensburg, Germany.
  • Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA.
  • The Novo Nordisk Foundation Center for Basic Metabolic Research, Section of Metabolic Genetics, Faculty of Health and Medical Sciences, University of Copenhagen, 2100, Copenhagen, Denmark.
  • Division of Epidemiology, Department of Population Health, New York University School of Medicine, New York, NY, 10016, USA.
  • Department of Epidemiology, Erasmus University Medical Center, Rotterdam, 3000 CA, The Netherlands.
  • Leiden University Medical Center, Medical Statistics and Bioinformatics, Leiden, 2300 RC, The Netherlands.
  • Department of Nutrition, Harvard School of Public Health, Boston, MA, 02115, USA.
  • Research Centre for Prevention and Health, Capital Region of Denmark, Copenhagen, DK-2600, Denmark.
  • Genetic Epidemiology Unit, Department of Epidemiology, Erasmus University Medical Center, Rotterdam, 3000 CA, The Netherland.
  • Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, 3000 CA, The Netherlands.
  • Department of Physiology, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, 41345, Gothenburg, Sweden.
  • Department of Growth and Reproduction, Rigshospitalet, University of Copenhagen, Copenhagen, DK-2100, Denmark.
  • Clinical and Molecular Osteoporosis Research Unit, Department of Clinical Sciences, Lund University, 20502, Malmö, Sweden.
  • IFB Adiposity Diseases, University of Leipzig, 04103, Leipzig, Germany.
  • Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, 02115, USA.
  • Division of Public Health Sciences, Department of Epidemiology and Prevention, Wake Forest School of Medicine, Winston-Salem, NC, 27157, USA.
  • The Genetics of Obesity and Related Metabolic Traits Program, The Charles Bronfman Institute for Personalized Medicine, The Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
  • Estonian Genome Center, University of Tartu, Tartu, Estonia.
  • General Medicine Division, Department of Medicine, Massachusetts General Hospital, Boston, MA, 02114, USA.
  • Department of Epidemiology, School of Public Health, University of Pittsburgh, Pittsburgh, PA, 15261, USA.
  • Departments of Experimental Medicine and Oncology, McGill University, Montréal, Québec, Canada, H3A 0G4.
  • Department of Genomics of Common Disease, School of Public Health, Imperial College London, London, W12ONN, UK.
  • Departments of Epidemiology, Medicine and Health Services, University of Washington, Seattle, WA, 98101, USA.
  • INSERM U1078, Brest, France.
  • The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
  • Epidemiology Branch, Division of Epidemiology, Statistics and Prevention Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, 6100 Executive Blvd, Rockville, MD, 20852, USA.
  • Medical Department, University of Leipzig, 04103, Leipzig, Germany.
  • Gerontology and Geriatrics, Leiden University Medical Center, Leiden, 2300 RC, The Netherlands.
  • Boston University and National Heart, Lung & Blood Institute's Framingham Heart Study, Framingham, MA, 01702, USA.
Abstract

The growth hormone/insulin-like growth factor (IGF) axis can be manipulated in animal models to promote longevity, and IGF-related proteins including IGF-I and IGF-binding protein-3 (IGFBP-3) have also been implicated in risk of human diseases including cardiovascular diseases, diabetes, and cancer. Through genomewide association study of up to 30 884 adults of European ancestry from 21 studies, we confirmed and extended the list of previously identified loci associated with circulating IGF-I and IGFBP-3 concentrations (IGF1, IGFBP3, GCKR, TNS3, GHSR, FOXO3, ASXL2, NUBP2/IGFALS, SORCS2, and CELSR2). Significant sex interactions, which were characterized by different genotype-phenotype associations between men and women, were found only for associations of IGFBP-3 concentrations with SNPs at the loci IGFBP3 and SORCS2. Analyses of SNPs, gene expression, and protein levels suggested that interplay between IGFBP3 and genes within the NUBP2 locus (IGFALS and HAGH) may affect circulating IGF-I and IGFBP-3 concentrations. The IGF-I-decreasing allele of SNP rs934073, which is an eQTL of ASXL2, was associated with lower adiposity and higher likelihood of survival beyond 90 years. The known longevity-associated variant rs2153960 (FOXO3) was observed to be a genomewide significant SNP for IGF-I concentrations. Bioinformatics analysis suggested enrichment of putative regulatory elements among these IGF-I- and IGFBP-3-associated loci, particularly of rs646776 at CELSR2. In conclusion, this study identified several loci associated with circulating IGF-I and IGFBP-3 concentrations and provides clues to the potential role of the IGF axis in mediating effects of known (FOXO3) and novel (ASXL2) longevity-associated loci.

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