Meta-Analysis of Genome-Wide Association Studies Identifies Six New Loci for Serum Calcium Concentrations
Calcium is vital to the normal functioning of multiple organ systems and its serum concentration is tightly regulated. Apart from CASR, the genes associated with serum calcium are largely unknown. We conducted a genome-wide association meta-analysis of 39,400 individuals from 17 population-based coh...
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| Vydáno v: | PLoS genetics Ročník 9; číslo 9; s. e1003796 |
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| Hlavní autoři: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
| Médium: | Journal Article |
| Jazyk: | angličtina |
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United States
Public Library of Science
01.09.2013
Public Library of Science (PLoS) |
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| ISSN: | 1553-7404, 1553-7390, 1553-7404 |
| On-line přístup: | Získat plný text |
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| Abstract | Calcium is vital to the normal functioning of multiple organ systems and its serum concentration is tightly regulated. Apart from CASR, the genes associated with serum calcium are largely unknown. We conducted a genome-wide association meta-analysis of 39,400 individuals from 17 population-based cohorts and investigated the 14 most strongly associated loci in ≤ 21,679 additional individuals. Seven loci (six new regions) in association with serum calcium were identified and replicated. Rs1570669 near CYP24A1 (P = 9.1E-12), rs10491003 upstream of GATA3 (P = 4.8E-09) and rs7481584 in CARS (P = 1.2E-10) implicate regions involved in Mendelian calcemic disorders: Rs1550532 in DGKD (P = 8.2E-11), also associated with bone density, and rs7336933 near DGKH/KIAA0564 (P = 9.1E-10) are near genes that encode distinct isoforms of diacylglycerol kinase. Rs780094 is in GCKR. We characterized the expression of these genes in gut, kidney, and bone, and demonstrate modulation of gene expression in bone in response to dietary calcium in mice. Our results shed new light on the genetics of calcium homeostasis. |
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| AbstractList | Calcium is vital to the normal functioning of multiple organ systems and its serum concentration is tightly regulated. Apart from CASR, the genes associated with serum calcium are largely unknown. We conducted a genome-wide association meta-analysis of 39,400 individuals from 17 population-based cohorts and investigated the 14 most strongly associated loci in ≤21,679 additional individuals. Seven loci (six new regions) in association with serum calcium were identified and replicated. Rs1570669 near CYP24A1 (P = 9.1E-12), rs10491003 upstream of GATA3 (P = 4.8E-09) and rs7481584 in CARS (P = 1.2E-10) implicate regions involved in Mendelian calcemic disorders: Rs1550532 in DGKD (P = 8.2E-11), also associated with bone density, and rs7336933 near DGKH/KIAA0564 (P = 9.1E-10) are near genes that encode distinct isoforms of diacylglycerol kinase. Rs780094 is in GCKR. We characterized the expression of these genes in gut, kidney, and bone, and demonstrate modulation of gene expression in bone in response to dietary calcium in mice. Our results shed new light on the genetics of calcium homeostasis. Calcium is vital to many biological processes and its serum concentration is tightly regulated. Family studies have shown that serum calcium is under strong genetic control. Apart from CASR, the genes associated with serum calcium are largely unknown. We conducted a genome-wide association meta-analysis of 39,400 individuals from 17 population-based cohorts and investigated the 14 most strongly associated loci in ≤21,679 additional individuals. We identified seven loci (six new regions) as being robustly associated with serum calcium. Three loci implicate regions involved in rare monogenic diseases including disturbances of serum calcium levels. Several of the newly identified loci harbor genes linked to the hormonal control of serum calcium. In mice experiments, we characterized the expression of these genes in gut, kidney, and bone, and explored the influence of dietary calcium intake on the expression of these genes in these organs. Our results shed new light on the genetics of calcium homeostasis and suggest a role for dietary calcium intake in bone-specific gene expression. Calcium is vital to the normal functioning of multiple organ systems and its serum concentration is tightly regulated. Apart from CASR, the genes associated with serum calcium are largely unknown. We conducted a genome-wide association meta-analysis of 39,400 individuals from 17 population-based cohorts and investigated the 14 most strongly associated loci in ≤ 21,679 additional individuals. Seven loci (six new regions) in association with serum calcium were identified and replicated. Rs1570669 near CYP24A1 (P = 9.1E-12), rs10491003 upstream of GATA3 (P = 4.8E-09) and rs7481584 in CARS (P = 1.2E-10) implicate regions involved in Mendelian calcemic disorders: Rs1550532 in DGKD (P = 8.2E-11), also associated with bone density, and rs7336933 near DGKH/KIAA0564 (P = 9.1E-10) are near genes that encode distinct isoforms of diacylglycerol kinase. Rs780094 is in GCKR. We characterized the expression of these genes in gut, kidney, and bone, and demonstrate modulation of gene expression in bone in response to dietary calcium in mice. Our results shed new light on the genetics of calcium homeostasis. Calcium is vital to the normal functioning of multiple organ systems and its serum concentration is tightly regulated. Apart from CASR, the genes associated with serum calcium are largely unknown. We conducted a genome-wide association meta-analysis of 39,400 individuals from 17 population-based cohorts and investigated the 14 most strongly associated loci in <= 21,679 additional individuals. Seven loci (six new regions) in association with serum calcium were identified and replicated. Rs1570669 near CYP24A1 (P = 9.1E-12), rs10491003 upstream of GATA3 (P = 4.8E-09) and rs7481584 in CARS (P = 1.2E-10) implicate regions involved in Mendelian calcemic disorders: Rs1550532 in DGKD (P = 8.2E-11), also associated with bone density, and rs7336933 near DGKH/KIAA0564 (P = 9.1E-10) are near genes that encode distinct isoforms of diacylglycerol kinase. Rs780094 is in GCKR. We characterized the expression of these genes in gut, kidney, and bone, and demonstrate modulation of gene expression in bone in response to dietary calcium in mice. Our results shed new light on the genetics of calcium homeostasis. Calcium is vital to the normal functioning of multiple organ systems and its serum concentration is tightly regulated. Apart from CASR, the genes associated with serum calcium are largely unknown. We conducted a genome-wide association meta-analysis of 39,400 individuals from 17 population-based cohorts and investigated the 14 most strongly associated loci in ≤21,679 additional individuals. Seven loci (six new regions) in association with serum calcium were identified and replicated. Rs1570669 near CYP24A1 (P = 9.1E-12), rs10491003 upstream of GATA3 (P = 4.8E-09) and rs7481584 in CARS (P = 1.2E-10) implicate regions involved in Mendelian calcemic disorders: Rs1550532 in DGKD (P = 8.2E-11), also associated with bone density, and rs7336933 near DGKH/KIAA0564 (P = 9.1E-10) are near genes that encode distinct isoforms of diacylglycerol kinase. Rs780094 is in GCKR. We characterized the expression of these genes in gut, kidney, and bone, and demonstrate modulation of gene expression in bone in response to dietary calcium in mice. Our results shed new light on the genetics of calcium homeostasis. Calcium is vital to the normal functioning of multiple organ systems and its serum concentration is tightly regulated. Apart from CASR, the genes associated with serum calcium are largely unknown. We conducted a genome-wide association meta-analysis of 39,400 individuals from 17 population-based cohorts and investigated the 14 most strongly associated loci in ≤ 21,679 additional individuals. Seven loci (six new regions) in association with serum calcium were identified and replicated. Rs1570669 near CYP24A1 (P = 9.1E-12), rs10491003 upstream of GATA3 (P = 4.8E-09) and rs7481584 in CARS (P = 1.2E-10) implicate regions involved in Mendelian calcemic disorders: Rs1550532 in DGKD (P = 8.2E-11), also associated with bone density, and rs7336933 near DGKH/KIAA0564 (P = 9.1E-10) are near genes that encode distinct isoforms of diacylglycerol kinase. Rs780094 is in GCKR. We characterized the expression of these genes in gut, kidney, and bone, and demonstrate modulation of gene expression in bone in response to dietary calcium in mice. Our results shed new light on the genetics of calcium homeostasis.Calcium is vital to the normal functioning of multiple organ systems and its serum concentration is tightly regulated. Apart from CASR, the genes associated with serum calcium are largely unknown. We conducted a genome-wide association meta-analysis of 39,400 individuals from 17 population-based cohorts and investigated the 14 most strongly associated loci in ≤ 21,679 additional individuals. Seven loci (six new regions) in association with serum calcium were identified and replicated. Rs1570669 near CYP24A1 (P = 9.1E-12), rs10491003 upstream of GATA3 (P = 4.8E-09) and rs7481584 in CARS (P = 1.2E-10) implicate regions involved in Mendelian calcemic disorders: Rs1550532 in DGKD (P = 8.2E-11), also associated with bone density, and rs7336933 near DGKH/KIAA0564 (P = 9.1E-10) are near genes that encode distinct isoforms of diacylglycerol kinase. Rs780094 is in GCKR. We characterized the expression of these genes in gut, kidney, and bone, and demonstrate modulation of gene expression in bone in response to dietary calcium in mice. Our results shed new light on the genetics of calcium homeostasis. |
| Audience | Academic |
| Author | Siscovick, David S. Psaty, Bruce M. Gudnason, Vilmundur Guessous, Idris Lohman, Kurt Yang, Qiong d'Adamo, Adamo Pio Pirastu, Mario Nakamura, Yusuke Zemunik, Tatijana Singleton, Andrew B. Liu, Yongmei Ernst, Florian D. Rudan, Igor Eiriksdottir, Gudny Gasparini, Paolo Boehm, Bernhard O. Matsuda, Koichi Robino, Antonietta Uitterlinden, Andre G. Vollenweider, Peter Munroe, Patricia B. Zuber, Annie Mercier Girotto, Giorgia Theler, Jean-Marc Brockhaus, A. Catharina Navarro, Pau Hayward, Caroline Ruggiero, Daniela Estrada, Karol Campbell, Harry Boerwinckle, Eric Davies, Gail Henry, Hughes Dehghan, Abbas Lind, Lars Köttgen, Anna Sorice, Rossella Gieger, Christian Ferrucci, Luigi Kapur, Karen Spector, Tim D. Hannemann, Anke Ding, Jingzhong Meisinger, Christa Franco, Oscar H. Ulivi, Sheila Wright, Alan F. Smith, Albert V. Portas, Laura Chambers, John C. Lopez, Lorna M. Polasek, Ozren Morris, Andrew P. Starr, John M. Schurmann, Claudia März, Winfried Rivadeneira, Fernando Völker, Uwe Brown, Edward M. Tanaka, Toshiko Kolcic, Ivana Murgia, Federico Arking, Dan |
| AuthorAffiliation | 24 Cardiology Group, ClinPhenomics GmbH&Co KG, Frankfurt-Sachsenhausen, Germany 54 Ulm University Medical Centre, Department of Internal Medicine I, Ulm University, Ulm, Germany 67 Institute of Medical Sciences, Uppsala University Hospital, Uppsala, Sweden 1 National Heart, Lung, and Blood Institute's Framingham Heart Study and Center for Population Studies, Framingham, Massachusetts, United States of America 2 Renal Division, Massachusetts General Hospital, Boston, Massachusetts, United States of America 20 Clinical Research Branch, National Institute on Aging, Baltimore, Maryland, United States of America 43 Department of Medicine, Internal Medicine, Lausanne University Hospital, Lausanne, Switzerland 3 Department of Biostatistics, Boston University, Boston, Massachusetts, United States of America 48 Department of Human Genetics, Wellcome Trust Sanger Institute, Hinxton, Cambridge, United Kingdom 7 Unit of Population Epidemiology, Division of Primary Care Medicine, Department of Community Med |
| AuthorAffiliation_xml | – name: 58 Centre for Population Health Sciences, The University of Edinburgh Medical School, Edinburgh, Scotland, United Kingdom – name: 70 Faculty of Medicine, National Heart & Lung Institute, Cardiovascular Science, Hammersmith Hospital, Hammersmith Campus, Imperial College London, London, United Kingdom – name: 26 BHF Glasgow Cardiovascular Research Centre, Division of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, Scotland – name: 36 University of Texas Health Science Center at Houston, Houston, Texas, United States of America – name: 5 Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland – name: 8 Geriatric Unit, Azienda Sanitaria Firenze (ASF), Florence, Italy – name: 16 Catheter Lab, Cardiology, Ealing Hospital, Southall, Middlesex, United Kingdom – name: 38 Cambridge Institute of Medical Research, University of Cambridge, Cambridge, United Kingdom – name: 67 Institute of Medical Sciences, Uppsala University Hospital, Uppsala, Sweden – name: 24 Cardiology Group, ClinPhenomics GmbH&Co KG, Frankfurt-Sachsenhausen, Germany – name: 54 Ulm University Medical Centre, Department of Internal Medicine I, Ulm University, Ulm, Germany – name: 56 Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, Georgia, United States of America – name: 14 King's College London, St. Thomas' Hospital Campus, London, United Kingdom – name: 25 Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, University of Tokyo, Tokyo, Japan – name: 50 Institute of Human Genetics, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany – name: 53 Epidemiology and Biostatistics, Imperial College London, Norfolk Place, London, United Kingdom – name: 73 Service of Nephrology, Lausanne University Hospital, Lausanne, Switzerland – name: 52 Institute of Epidemiology II, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany – name: 65 William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom – name: 49 Molecular Genetics Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, United States of America – name: 6 Institute of Social and Preventive Medicine (IUMSP), Lausanne University Hospital, Lausanne, Switzerland – name: 61 Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany – name: 18 Icelandic Heart Association Research Institute, Kopavogur, Iceland – name: 21 Institute of Population Genetics, CNR-Traversa La Crucca, Reg. Baldinca Li Punti, Sassari, Italy – name: 51 Department of Computer Science and Networking, Wentworth Institute of Technology, Boston, Massachusetts, United States of America – name: 62 Human Genetics, Wellcome Trust Sanger Institute, Hinxton, United Kingdom – name: 7 Unit of Population Epidemiology, Division of Primary Care Medicine, Department of Community Medicine and Primary Care and Emergency Medicine, Geneva University Hospitals, Geneva, Switzerland – name: 45 Department of Pharmacology, Faculty of Medicine, University of Split, Split, Croatia – name: 59 Institute of Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, Ernst-Moritz-Arndt University Greifswald, Greifswald, Germany – name: 33 Wellcome Trust Centre for Human Genetics, Roosevelt Drive, Oxford, United Kingdom – name: 63 Department of Biostatistical Sciences, Division of Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, North Carolina, United States of America – name: 17 Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United Kingdom – name: 31 Department of Internal Medicine II – Cardiology, University of Ulm Medical Centre, Ulm, Germany – name: 19 Cardiovascular Health Research Unit, University of Washington, Seattle, Washington, United States of America – name: 46 Division of Laboratory Medicine, Geneva University Hospitals, Geneva, Switzerland – name: 60 Department of Prosthetic Dentistry, Gerostomatology and Dental Materials, University Medicine Greifswald, Greifswald, Germany – name: 71 Imperial College Healthcare NHS Trust, London, United Kingdom – name: 39 Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands – name: 72 Welch Center for Prevention, Epidemiology and Clinical Research, John Hopkins University, Baltimore, Maryland, United States of America – name: 47 Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, North Carolina, United States of America – name: 37 McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America – name: 23 MRC Human Genetics Unit, MRC IGMM, University of Edinburgh, Edinburgh, United Kingdom – name: 66 Synlab Centre of Laboratory Diagnostics, Heidelberg, Germany – name: 4 Department of Medical Biology, University of Split, School of Medicine, Split, Croatia – name: 27 Institute of Genetics and Biophysics ‘Adriano-Buzzati Traverso’, CNR, Napoli, Italy – name: 2 Renal Division, Massachusetts General Hospital, Boston, Massachusetts, United States of America – name: 22 Centre for Cognitive Ageing and Cognitive Epidemiology, The University of Edinburgh, Edinburgh, United Kingdom – name: 3 Department of Biostatistics, Boston University, Boston, Massachusetts, United States of America – name: 44 Faculty of Medicine, University of Split, Split, Croatia – name: 28 Institute for Maternal and Child Health - IRCCS “Burlo Garofolo”, Trieste, Italy – name: 57 Division of Primary Care Medicine, Department of Community Medicine and Primary Care and Emergency Medicine , Geneva University Hospitals, Geneva, Switzerland – name: 43 Department of Medicine, Internal Medicine, Lausanne University Hospital, Lausanne, Switzerland – name: 40 Departments of Medicine and Epidemiology, University of Washington, Seattle, Washington, United States of America – name: 32 Mannheim Institute of Public Health, Social and Preventive Medicine, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany – name: 41 Group Health Research Institute, Group Health Cooperative, Seattle, Washington, United States of America – name: University of Michigan, United States of America – name: 11 Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, United States of America – name: 10 Renal Division, Freiburg University Hospital, Freiburg, Germany – name: 29 Institute of Genetic Epidemiology, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany – name: 74 Division of Endocrinology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, United States of America – name: 13 Swiss Institute of Bioinformatics, Lausanne, Switzerland – name: 42 Departments of Medicine, Epidemiology and Health Services, University of Washington, Seattle, Washington, United States of America – name: 20 Clinical Research Branch, National Institute on Aging, Baltimore, Maryland, United States of America – name: 48 Department of Human Genetics, Wellcome Trust Sanger Institute, Hinxton, Cambridge, United Kingdom – name: 35 Laboratory of Epidemiology, Demography and Biometry, National Institute on Aging, Bethesda, Maryland, United States of America – name: 15 Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands – name: 9 Department of Pharmacology and Toxicology, University of Lausanne, Lausanne, Switzerland – name: 55 LKC School of Medicine, Imperial College London and Nanyang Technological University, Singapore, Singapore – name: 30 Department of Medicine I, University Hospital Grosshadern, Ludwig-Maximilians University Munich, Munich, Germany – name: 69 Department of Medicine, Division of Nephrology, University of Washington, Seattle, Washington, United States of America – name: 68 Department of Epidemiology and Prevention, Division of Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, North Carolina, United States of America – name: 12 Interfaculty Institute for Genetics and Functional Genomics, Ernst-Moritz-Arndt-University Greifswald, Greifswald, Germany – name: 1 National Heart, Lung, and Blood Institute's Framingham Heart Study and Center for Population Studies, Framingham, Massachusetts, United States of America – name: 34 University of Iceland, Reykjavik, Iceland – name: 64 Clinical Chemistry Laboratory, Lausanne University Hospital, Lausanne, Switzerland |
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| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/24068962$$D View this record in MEDLINE/PubMed https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-210256$$DView record from Swedish Publication Index (Uppsala universitet) |
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| Copyright | COPYRIGHT 2013 Public Library of Science 2013 2013 Public Library of Science. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited: Citation: O'Seaghdha CM, Wu H, Yang Q, Kapur K, Guessous I, et al. (2013) Meta-Analysis of Genome-Wide Association Studies Identifies Six New Loci for Serum Calcium Concentrations. PLoS Genet 9(9): e1003796. doi:10.1371/journal.pgen.1003796 |
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| Notes | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Writing group. The authors have declared that no competing interests exist. Conceived and designed the experiments: CMOS HWu QY KK WHLK HWa OB CSF MBoc. Performed the experiments: CMOS HWu QY KK IG AMZ AK CSt ZK TH GE LJL VG DEA LF DSS BMP OHF AHo AGU JCMW IJD JMS MP EMB PV SBe CH VV SBa IR OP JW HC JSK JCC AHa CSc MN RB UV PBM MJB JMT JMG TDS WH APM LL WM BOB BRW CG CM WHLK HWa OB CSF MBoc. Analyzed the data: CMOS HWu QY KK IG AMZ AK AT ZK YL TH JD KL AVS GE LJL VG TT GL AD FR LML LP FM JH AMac SBe CH VV JFW WZ AHo AGU FR KE SP MM FDE AMah WH APM MEK ACB CG WHLK HWa OB CSF MBoc. Contributed reagents/materials/analysis tools: IG YL VG EB DH AS DSS BMP AGU FR IJD JMS MP PV GD VV CH JSK JCC PBM MM SYS APM MEK TM WHLK HWa CSF MBoc. Wrote the paper: CMOS IG AK HWa OB CSF MBoc. Revising and reviewing the manuscript for important intellectual content: CMOS HWu QY KK IG AMZ AK CSto AT ZK MM AD WZ GE GL TT LP LML CH KL KM SP DF RS SU ACB MEK AMah FDE VG LJL AMac EB DEA CT YN MJB JMG JMT DSS BMP SBe PV VV AFW TZ MBob IK PN EMB KE JD TBH SBa DH ABS GG DR APA AR TM CM GD JMS JCC BOB BRW JH FM SHW HC APM OHF AHo AGU FR UV AHa RB WH SYS PL HH CSc PBM PG NP MC CG WM LL TDS AVS IR JFW OP IJD MP LF YL BK JSK JCMW MN WHLK HWa OB CSF MBoc. |
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| SubjectTerms | Animals Bone and Bones - metabolism Bone density Bone Density - genetics Calcium Calcium - blood Calcium, Dietary Experiments Gene expression Gene Expression Regulation Genetic aspects Genome-wide association studies Genome-Wide Association Study Genomes Homeostasis Homeostasis - genetics Humans Kidney - metabolism Kinases Meta-analysis Mice Ontology Physiological aspects Polymorphism, Single Nucleotide Population White People - genetics |
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| Title | Meta-Analysis of Genome-Wide Association Studies Identifies Six New Loci for Serum Calcium Concentrations |
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