Article | Published:

New loci associated with kidney function and chronic kidney disease

Nature Genetics volume 42, pages 376384 (2010) | Download Citation

Abstract

Chronic kidney disease (CKD) is a significant public health problem, and recent genetic studies have identified common CKD susceptibility variants. The CKDGen consortium performed a meta-analysis of genome-wide association data in 67,093 individuals of European ancestry from 20 predominantly population-based studies in order to identify new susceptibility loci for reduced renal function as estimated by serum creatinine (eGFRcrea), serum cystatin c (eGFRcys) and CKD (eGFRcrea < 60 ml/min/1.73 m2; n = 5,807 individuals with CKD (cases)). Follow-up of the 23 new genome-wide–significant loci (P < 5 × 10−8) in 22,982 replication samples identified 13 new loci affecting renal function and CKD (in or near LASS2, GCKR, ALMS1, TFDP2, DAB2, SLC34A1, VEGFA, PRKAG2, PIP5K1B, ATXN2, DACH1, UBE2Q2 and SLC7A9) and 7 loci suspected to affect creatinine production and secretion (CPS1, SLC22A2, TMEM60, WDR37, SLC6A13, WDR72 and BCAS3). These results further our understanding of the biologic mechanisms of kidney function by identifying loci that potentially influence nephrogenesis, podocyte function, angiogenesis, solute transport and metabolic functions of the kidney.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

References

  1. 1.

    et al. Prevalence of chronic kidney disease in the United States. J. Am. Med. Assoc. 298, 2038–2047 (2007).

  2. 2.

    & Chronic kidney disease: the global challenge. Lancet 365, 331–340 (2005).

  3. 3.

    , , , & Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization. N. Engl. J. Med. 351, 1296–1305 (2004).

  4. 4.

    , , , & Cost of medical care for chronic kidney disease and comorbidity among enrollees in a large HMO population. J. Am. Soc. Nephrol. 15, 1300–1306 (2004).

  5. 5.

    et al. Chronic kidney disease as a global public health problem: approaches and initiatives-a position statement from Kidney Disease Improving Global Outcomes. Kidney Int. 72, 247–259 (2007).

  6. 6.

    et al. Predictors of new-onset kidney disease in a community-based population. J. Am. Med. Assoc. 291, 844–850 (2004).

  7. 7.

    & Trends in diabetes, high cholesterol, and hypertension in chronic kidney disease among U.S. adults: 1988–1994 to 1999–2004. Diabetes Care 31, 1337–1342 (2008).

  8. 8.

    , , & Familial clustering of chronic kidney disease. Semin. Dial. 20, 229–236 (2007).

  9. 9.

    et al. Genomewide linkage analysis to serum creatinine, GFR, and creatinine clearance in a community-based population: the Framingham Heart Study. J. Am. Soc. Nephrol. 15, 2457–2461 (2004).

  10. 10.

    et al. Multiple loci associated with indices of renal function and chronic kidney disease. Nat. Genet. 41, 712–717 (2009).

  11. 11.

    et al. Mapping the genetic architecture of gene expression in human liver. PLoS Biol. 6, e107 (2008).

  12. 12.

    et al. Discovery of expression QTLs using large-scale transcriptional profiling in human lymphocytes. Nat. Genet. 39, 1208–1216 (2007).

  13. 13.

    et al. A genome-wide association study of global gene expression. Nat. Genet. 39, 1202–1207 (2007).

  14. 14.

    et al. PAR3β, a novel homologue of the cell polarity protein PAR3, localizes to tight junctions. Biochem. Biophys. Res. Commun. 299, 641–646 (2002).

  15. 15.

    & Caspase in renal development. Nephrol. Dial. Transplant. 17Suppl 9, 8–10 (2002).

  16. 16.

    Genomewide association studies–illuminating biologic pathways. N. Engl. J. Med. 360, 1699–1701 (2009).

  17. 17.

    & An open access database of genome-wide association results. BMC Med. Genet. 10, 6 (2009).

  18. 18.

    et al. Potential etiologic and functional implications of genome-wide association loci for human diseases and traits. Proc. Natl. Acad. Sci. USA 106, 9362–9367 (2009).

  19. 19.

    & An incredible decade for the primary cilium: a look at a once-forgotten organelle. Am. J. Physiol. Renal Physiol. 289, F1159–F1169 (2005).

  20. 20.

    , & Common disorders are quantitative traits. Nat. Rev. Genet. 10, 872–878 (2009).

  21. 21.

    , & Genome-wide association scans for secondary traits using case-control samples. Genet. Epidemiol. 33, 717–728 (2009).

  22. 22.

    & Cystinuria. Semin. Nephrol. 28, 181–191 (2008).

  23. 23.

    et al. Renal crystal deposits and histopathology in patients with cystine stones. Kidney Int. 69, 2227–2235 (2006).

  24. 24.

    et al. Slc7a9-deficient mice develop cystinuria non-I and cystine urolithiasis. Hum. Mol. Genet. 12, 2097–2108 (2003).

  25. 25.

    et al. Nephrolithiasis and osteoporosis associated with hypophosphatemia caused by mutations in the type 2a sodium-phosphate cotransporter. N. Engl. J. Med. 347, 983–991 (2002).

  26. 26.

    et al. Expression cloning of human and rat renal cortex Na/Pi cotransport. Proc. Natl. Acad. Sci. USA 90, 5979–5983 (1993).

  27. 27.

    et al. Spectrum of ALMS1 variants and evaluation of genotype-phenotype correlations in Alstrom syndrome. Hum. Mutat. 28, 1114–1123 (2007).

  28. 28.

    et al. Alstrom syndrome (OMIM 203800): a case report and literature review. Orphanet J. Rare Dis. 2, 49 (2007).

  29. 29.

    et al. A role for Alstrom syndrome protein, alms1, in kidney ciliogenesis and cellular quiescence. PLoS Genet. 3, e8 (2007).

  30. 30.

    et al. N-acetyltransferase 8, a positional candidate for blood pressure and renal regulation: resequencing, association and in silico study. BMC Med. Genet. 9, 25 (2008).

  31. 31.

    et al. Mutually dependent localization of megalin and Dab2 in the renal proximal tubule. Am. J. Physiol. Renal Physiol. 289, F569–F576 (2005).

  32. 32.

    et al. Megalin and nonmuscle myosin heavy chain IIA interact with the adaptor protein Disabled-2 in proximal tubule cells. Kidney Int. 75, 1308–1315 (2009).

  33. 33.

    et al. MYH9 is associated with nondiabetic end-stage renal disease in African Americans. Nat. Genet. 40, 1185–1192 (2008).

  34. 34.

    et al. MYH9 is a major-effect risk gene for focal segmental glomerulosclerosis. Nat. Genet. 40, 1175–1184 (2008).

  35. 35.

    , & Role of the VEGF–a signaling pathway in the glomerulus: evidence for crosstalk between components of the glomerular filtration barrier. Nephron Physiol. 106, 32–37 (2007).

  36. 36.

    et al. Vascular endothelial growth factor induces branching morphogenesis/tubulogenesis in renal epithelial cells in a neuropilin-dependent fashion. Mol. Cell. Biol. 25, 7441–7448 (2005).

  37. 37.

    Molecular physiology of mammalian glucokinase. Cell. Mol. Life Sci. 66, 27–42 (2009).

  38. 38.

    et al. Intraflagellar transport protein 172 is essential for primary cilia formation and plays a vital role in patterning the mammalian brain. Dev. Biol. 325, 24–32 (2009).

  39. 39.

    et al. Mutations in the gamma(2) subunit of AMP-activated protein kinase cause familial hypertrophic cardiomyopathy: evidence for the central role of energy compromise in disease pathogenesis. Hum. Mol. Genet. 10, 1215–1220 (2001).

  40. 40.

    et al. Constitutively active AMP kinase mutations cause glycogen storage disease mimicking hypertrophic cardiomyopathy. J. Clin. Invest. 109, 357–362 (2002).

  41. 41.

    et al. Fatal congenital heart glycogenosis caused by a recurrent activating R531Q mutation in the gamma 2-subunit of AMP-activated protein kinase (PRKAG2), not by phosphorylase kinase deficiency. Am. J. Hum. Genet. 76, 1034–1049 (2005).

  42. 42.

    Glycogen storage diseases: new perspectives. World J. Gastroenterol. 13, 2541–2553 (2007).

  43. 43.

    et al. DACH: genomic characterization, evaluation as a candidate for postaxial polydactyly type A2, and developmental expression pattern of the mouse homologue. Genomics 77, 18–26 (2001).

  44. 44.

    , , & Mouse Dach1 and Dach2 are redundantly required for Mullerian duct development. Genesis 46, 205–213 (2008).

  45. 45.

    , , & Molecular interaction and synergistic activation of a promoter by Six, Eya, and Dach proteins mediated through CREB binding protein. Mol. Cell. Biol. 22, 6759–6766 (2002).

  46. 46.

    et al. A human homologue of the Drosophila eyes absent gene underlies branchio-oto-renal (BOR) syndrome and identifies a novel gene family. Nat. Genet. 15, 157–164 (1997).

  47. 47.

    et al. Genome-wide association study identifies eight loci associated with blood pressure. Nat. Genet. 41, 666–676 (2009).

  48. 48.

    et al. Newly identified genetic risk variants for celiac disease related to the immune response. Nat. Genet. 40, 395–402 (2008).

  49. 49.

    et al. Robust associations of four new chromosome regions from genome-wide analyses of type 1 diabetes. Nat. Genet. 39, 857–864 (2007).

  50. 50.

    et al. Sequence variants affecting eosinophil numbers associate with asthma and myocardial infarction. Nat. Genet. 41, 342–347 (2009).

  51. 51.

    et al. Calibration and random variation of the serum creatinine assay as critical elements of using equations to estimate glomerular filtration rate. Am. J. Kidney Dis. 39, 920–929 (2002).

  52. 52.

    et al. A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Modification of Diet in Renal Disease Study Group. Ann. Intern. Med. 130, 461–470 (1999).

  53. 53.

    et al. Estimating GFR using serum cystatin C alone and in combination with serum creatinine: a pooled analysis of 3,418 individuals with CKD. Am. J. Kidney Dis. 51, 395–406 (2008).

  54. 54.

    National Kidney Foundation. K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Am. J. Kidney Dis. 39, S1–S266 (2002).

  55. 55.

    & Genomic control for association studies. Biometrics 55, 997–1004 (1999).

  56. 56.

    R Development Core Team. R: a language and environment for statistical computing (The R Project for Statistical Computing, 2009). 〈〉.

  57. 57.

    Sample size requirements for association studies of gene-gene interaction. Am. J. Epidemiol. 155, 478–484 (2002).

  58. 58.

    et al. SNAP: a web-based tool for identification and annotation of proxy SNPs using HapMap. Bioinformatics 24, 2938–2939 (2008).

  59. 59.

    & Statistical significance for genomewide studies. Proc. Natl. Acad. Sci. USA 100, 9440–9445 (2003).

  60. 60.

    et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am. J. Hum. Genet. 81, 559–575 (2007).

  61. 61.

    , , & GenABEL: an R library for genome-wide association analysis. Bioinformatics 23, 1294–1296 (2007).

  62. 62.

    , , & Merlin–rapid analysis of dense genetic maps using sparse gene flow trees. Nat. Genet. 30, 97–101 (2002).

  63. 63.

    , & The power of genomic control. Am. J. Hum. Genet. 66, 1933–1944 (2000).

Download references

Acknowledgements

We thank all participants and the study staff of the Age, Gene/Environment Susceptibility Reykjavik Study (AGES); the Amish Study; the Atherosclerosis Risk in Communities Study (ARIC); the Austrian Stroke Prevention study (ASPS); the Baltimore Longitudinal Study of Aging (BLSA); the Cardiovascular Health Study (CHS); the Erasmus Rucphen Family (ERF) study; the Family Heart Study (FamHS); the Framingham Heart Study (FHS); the Genetic Epidemiology Network of Atherosclerosis (GENOA); the Gutenberg Heart Study; the Health, Aging and Body Composition (HABC) study; the Health Professionals Follow-Up Study (HPFS); the Kooperative Gesundheitsforschung in der Region Augsburg (KORA); the Korcula Study; the Micros Study; the Nurses' Health Study (NHS); the Northern Swedish Population Health Study (NSPHS); the Orkney Complex Disease Study (Orcades); the PopGen Study; the Rotterdam Study (RS); the Swiss Cohort Study on Air Pollution and Lung Diseases in Adults (SAPALDIA); the Salzburg Atherosclerosis Prevention program in subjects at High Individual Risk (SAPHIR); the Study of Health in Pomerania (SHIP); the Sorbs Study; the Split Study; the Vis Study; and the Women's Genome Health Study (WGHS), as well as the Cohorts for Heart and Aging Research in Genome Epidemiology (CHARGE) Consortium, for their invaluable contributions. A detailed list of acknowledgments and funding sources can be found in the Supplementary Note.

Author information

Author notes

    • Anna Köttgen
    • , Cristian Pattaro
    • , Carsten A Böger
    •  & Christian Fuchsberger

    These authors contributed equally to this work.

    • Daniel I Chasman
    • , W H Kao
    • , Iris M Heid
    •  & Caroline S Fox

    These authors jointly directed this work.

Affiliations

  1. Department of Epidemiology, Johns Hopkins University, Baltimore, Maryland, USA.

    • Anna Köttgen
    • , Man Li
    • , Josef Coresh
    •  & W H Kao
  2. Renal Division, University Hospital of Freiburg, Freiburg, Germany.

    • Anna Köttgen
  3. Institute of Genetic Medicine, European Academy Bozen/Bolzano (EURAC), Bolzano, Italy.

    • Cristian Pattaro
    • , Christian Fuchsberger
    • , Cosetta Minelli
    •  & Peter P Pramstaller
  4. Affiliated Institute of the University of Lübeck, Germany, Viale Druso, Bolzano, Italy.

    • Cristian Pattaro
    • , Christian Fuchsberger
    • , Cosetta Minelli
    •  & Peter P Pramstaller
  5. Department of Internal Medicine II, University Medical Center Regensburg, Regensburg, Germany.

    • Carsten A Böger
    •  & Matthias Olden
  6. Department of Epidemiology and Preventive Medicine, University Medical Center Regensburg, Regensburg, Germany.

    • Matthias Olden
    •  & Iris M Heid
  7. Cardiovascular Health Research Unit, University of Washington, Seattle, Washington, USA.

    • Nicole L Glazer
  8. Department of Medicine, University of Washington, Seattle, Washington, USA.

    • Nicole L Glazer
    •  & David Siscovick
  9. University of Maryland Medical School, Baltimore, Maryland, USA.

    • Afshin Parsa
    • , Jeffrey R O'Connell
    • , Braxton D Mitchell
    •  & Alan R Shuldiner
  10. Division of Statistical Genomics, Washington University School of Medicine, St. Louis, Missouri, USA.

    • Xiaoyi Gao
    • , Shamika Ketkar
    • , Mary Feitosa
    • , Michael Province
    •  & Ingrid Borecki
  11. Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts, USA.

    • Qiong Yang
  12. Icelandic Heart Association, Kopavogur, Iceland.

    • Albert V Smith
    • , Thor Aspelund
    • , Gudny Eiriksdottir
    •  & Vilmundur Gudnason
  13. University of Iceland, Reykjavik, Iceland.

    • Albert V Smith
    • , Thor Aspelund
    •  & Vilmundur Gudnason
  14. Department of Neurogeriatrics, Austrian Stroke Prevention Study, Institute of Molecular Biology and Biochemistry and University Clinic of Neurology, Medical University Graz, Graz, Austria.

    • Helena Schmidt
  15. Clinical Research Branch, National Institute on Aging, Baltimore, Maryland, USA.

    • Toshiko Tanaka
  16. Medstar Research Institute, Baltimore, Maryland, USA.

    • Toshiko Tanaka
  17. Department of Epidemiology, Erasmus MC, Rotterdam, The Netherlands.

    • Aaron Isaacs
    • , Abbas Dehghan
    • , Ben A Oostra
    • , Yurii S Aulchenko
    • , Janine F Felix
    • , Fernando Rivadeneira
    • , Andre G Uitterlinden
    • , Albert Hofman
    • , Cornelia M van Duijn
    •  & Jacqueline C Witteman
  18. The National Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, Massachusetts, USA.

    • Shih-Jen Hwang
    • , Andrew D Johnson
    •  & Caroline S Fox
  19. Center for Population Studies, Framingham, Massachusetts, USA.

    • Shih-Jen Hwang
    • , Andrew D Johnson
    •  & Caroline S Fox
  20. Netherlands Genomics Initiative (NGI)-sponsored Netherlands Consortium for Healthy Aging (NCHA), Leiden, The Netherlands.

    • Abbas Dehghan
    • , M Carola Zillikens
    • , Yurii S Aulchenko
    • , Janine F Felix
    • , Fernando Rivadeneira
    • , Andre G Uitterlinden
    • , Albert Hofman
    • , Cornelia M van Duijn
    •  & Jacqueline C Witteman
  21. Interfaculty Institute for Genetics and Functional Genomics, Ernst-Moritz-Arndt University Greifswald, Greifswald, Germany.

    • Alexander Teumer
    •  & Uwe Völker
  22. Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada.

    • Guillaume Paré
  23. Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, Minnesota, USA.

    • Elizabeth J Atkinson
    •  & Mariza de Andrade
  24. Department of Medicine II, University Medical Center Mainz, Mainz, Germany.

    • Tanja Zeller
    • , Philipp S Wild
    • , Renate B Schnabel
    • , Sandra Wilde
    • , Thomas F Munzel
    •  & Stefan Blankenberg
  25. Department of Biostatistical Sciences, Wake Forest University, Division of Public Health Sciences, Winston-Salem, North Carolina, USA.

    • Kurt Lohman
  26. Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts, USA.

    • Marilyn C Cornelis
    •  & Frank B Hu
  27. Swiss Tropical and Public Health Institute, Basel, Switzerland.

    • Nicole M Probst-Hensch
    •  & Medea Imboden
  28. University of Basel, Basel, Switzerland.

    • Nicole M Probst-Hensch
    •  & Medea Imboden
  29. Division of Genetic Epidemiology, Innsbruck Medical University, Innsbruck, Austria.

    • Florian Kronenberg
    • , Anita Brandstätter
    •  & Barbara Kollerits
  30. Department of Medicine, University of Leipzig, Leipzig, Germany.

    • Anke Tönjes
    • , Michael Stumvoll
    •  & Peter Kovacs
  31. Medical Research Council Human Genetics Unit, Institute of Genetics and Molecular Medicine, Western General Hospital, Edinburgh, Scotland, UK.

    • Caroline Hayward
    • , Alan F Wright
    • , Susan Campbell
    • , Veronique Vitart
    •  & Nick Hastie
  32. Laboratory of Epidemiology, Demography and Biometry, National Institute on Aging, Bethesda, Maryland, USA.

    • Lenore J Launer
    •  & Tamara B Harris
  33. Miami Institute for Human Genomics, Miami, Florida, USA.

    • Evadnie Rampersaud
  34. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

    • Dan E Arking
  35. Human Genetics Center, University of Texas Health Science Center, Houston, Texas, USA.

    • Eric Boerwinkle
  36. Department of Epidemiology and Biostatistics, Department of Forensic Molecular Biology, Rotterdam, The Netherlands.

    • Maksim Struchalin
  37. Department of Neurogeriatrics, Austrian Stroke Prevention Study, University Clinic of Neurology, Medical University Graz, Graz, Austria.

    • Margherita Cavalieri
    •  & Reinhold Schmidt
  38. Laboratory of Neurogenetics, National Institute on Aging, Bethesda, Maryland, USA.

    • Andrew Singleton
  39. Clinical Research Branch, National Institute on Aging, Baltimore, Maryland, USA.

    • Francesco Giallauria
    • , Jeffrey Metter
    •  & Luigi Ferrucci
  40. Kidney Research Institute and Division of Nephrology, University of Washington, Seattle, Washington, USA.

    • Ian H de Boer
  41. Medical Genetics Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.

    • Talin Haritunians
  42. Department of Biostatistics, University of Washington, Seattle, Washington, USA.

    • Thomas Lumley
  43. Department of Epidemiology, University of Washington, Seattle, Washington, USA.

    • David Siscovick
  44. Department of Medicine, Cardiovascular Health Research Unit, University of Washington and Group Health Research Institute, Seattle, Washington, USA.

    • Bruce M Psaty
  45. Department of Epidemiology, University of Washington and Group Health Research Institute, Seattle, Washington, USA.

    • Bruce M Psaty
  46. Department of Health Services, University of Washington, Seattle, Washington, USA.

    • Bruce M Psaty
  47. Department of Internal Medicine, Erasmus University, Rotterdam, The Netherlands.

    • M Carola Zillikens
    • , Fernando Rivadeneira
    •  & Andre G Uitterlinden
  48. Department of Internal Medicine,Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota, USA.

    • Stephen T Turner
  49. Institute for Medical Biometry and Statistics, University at Lübeck, Lübeck University Hospital Schleswig-Holstein, Campus Lübeck, Germany.

    • Arne Schillert
    •  & Andreas Ziegler
  50. Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.

    • Tennille S Leak
  51. Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.

    • Thomas Illig
    • , Norman Klopp
    • , Christa Meisinger
    • , H-Erich Wichmann
    •  & Iris M Heid
  52. Institute of Medical Informatics, Biometry and Epidemiology, Ludwig-Maximilians-Universität, Munich, Germany.

    • H-Erich Wichmann
  53. Klinikum Grosshadern, Munich, Germany.

    • H-Erich Wichmann
  54. Zentrum für Innere Medizin, Klinik für Innere Medizin II–Kardiologie, Universitätsklinikum Ulm, Ulm, Germany.

    • Wolfgang Koenig
  55. Centre for Population Health Sciences, University of Edinburgh Medical School, Edinburgh, Scotland, UK.

    • Lina Zgaga
    • , Sarah H Wild
    • , Harry Campbell
    • , Igor Rudan
    •  & James F Wilson
  56. Croatian Centre for Global Health, University of Split Medical School, Split, Croatia.

    • Tatijana Zemunik
    • , Mladen Boban
    •  & Wei Wang
  57. Andrija Stampar School of Public Health, Medical School, University of Zagreb, Zagreb, Croatia.

    • Ivana Kolcic
    •  & Ozren Polasek
  58. Department of Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden.

    • Åsa Johansson
    • , Wilmar Igl
    • , Ghazal Zaboli
    •  & Ulf Gyllensten
  59. Institute of Clinical Molecular Biology, Christian-Albrechts-University, Kiel, Germany.

    • David Ellinghaus
    • , Stefan Schreiber
    •  & Andre Franke
  60. Department of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London, UK.

    • Dorothea Nitsch
  61. First Department of Internal Medicine, Paracelsus Medical University, Salzburg, Austria.

    • Lyudmyla Kedenko
    •  & Bernhard Paulweber
  62. Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.

    • Reedik Mägi
    •  & Inga Prokopenko
  63. Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, UK.

    • Reedik Mägi
    •  & Inga Prokopenko
  64. Institute of Anatomy and Cell Biology, Ernst-Moritz-Arndt University Greifswald, Greifswald, Germany.

    • Karlhans Endlich
  65. Institute for Community Medicine, Ernst-Moritz-Arndt University Greifswald, Greifswald, Germany.

    • Henry Völzke
  66. Institute of Pharmacology, Ernst-Moritz-Arndt University Greifswald, Greifswald, Germany.

    • Heyo K Kroemer
  67. Institute of Clinical Chemistry and Laboratory Medicine, Ernst-Moritz-Arndt University Greifswald, Greifswald, Germany.

    • Matthias Nauck
  68. Amgen, Cambridge, Massachusetts, USA.

    • Sunita Badola
    •  & Alexander N Parker
  69. Brigham and Women's Hospital, Boston, Massachusetts, USA.

    • Paul M Ridker
    •  & Daniel I Chasman
  70. Department of Epidemiology, University of Michigan School of Public Health, Ann Arbor, Michigan, USA.

    • Sharon L R Kardia
  71. Department of Epidemiology and Prevention, Wake Forest University, Division of Public Health Sciences, Winston-Salem, North Carolina, USA.

    • Yongmei Liu
  72. Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.

    • Gary C Curhan
  73. University Hospitals of Geneva, Geneva, Switzerland.

    • Thierry Rochat
  74. School of Public Health and Family Medicine, Capital Medical University, Beijing, China.

    • Wei Wang
  75. Welch Center for Prevention, Epidemiology and Clinical Research, Johns Hopkins University, Baltimore, Maryland, USA.

    • Josef Coresh
    •  & W H Kao
  76. General Internal Medicine, University of California, San Francisco, San Francisco, California, USA.

    • Michael G Shlipak
  77. Department of Medicine V, Mannheim University Hospital, University of Heidelberg, Mannheim, Germany.

    • Bernhard K Krämer
  78. Institute of Physiology, Ernst-Moritz-Arndt University Greifswald, Greifswald, Germany.

    • Rainer Rettig
  79. Brigham and Women's Hospital Department of Endocrinology and Harvard Medical School, Boston, Massachusetts, USA.

    • Caroline S Fox

Authors

  1. Search for Anna Köttgen in:

  2. Search for Cristian Pattaro in:

  3. Search for Carsten A Böger in:

  4. Search for Christian Fuchsberger in:

  5. Search for Matthias Olden in:

  6. Search for Nicole L Glazer in:

  7. Search for Afshin Parsa in:

  8. Search for Xiaoyi Gao in:

  9. Search for Qiong Yang in:

  10. Search for Albert V Smith in:

  11. Search for Jeffrey R O'Connell in:

  12. Search for Man Li in:

  13. Search for Helena Schmidt in:

  14. Search for Toshiko Tanaka in:

  15. Search for Aaron Isaacs in:

  16. Search for Shamika Ketkar in:

  17. Search for Shih-Jen Hwang in:

  18. Search for Andrew D Johnson in:

  19. Search for Abbas Dehghan in:

  20. Search for Alexander Teumer in:

  21. Search for Guillaume Paré in:

  22. Search for Elizabeth J Atkinson in:

  23. Search for Tanja Zeller in:

  24. Search for Kurt Lohman in:

  25. Search for Marilyn C Cornelis in:

  26. Search for Nicole M Probst-Hensch in:

  27. Search for Florian Kronenberg in:

  28. Search for Anke Tönjes in:

  29. Search for Caroline Hayward in:

  30. Search for Thor Aspelund in:

  31. Search for Gudny Eiriksdottir in:

  32. Search for Lenore J Launer in:

  33. Search for Tamara B Harris in:

  34. Search for Evadnie Rampersaud in:

  35. Search for Braxton D Mitchell in:

  36. Search for Dan E Arking in:

  37. Search for Eric Boerwinkle in:

  38. Search for Maksim Struchalin in:

  39. Search for Margherita Cavalieri in:

  40. Search for Andrew Singleton in:

  41. Search for Francesco Giallauria in:

  42. Search for Jeffrey Metter in:

  43. Search for Ian H de Boer in:

  44. Search for Talin Haritunians in:

  45. Search for Thomas Lumley in:

  46. Search for David Siscovick in:

  47. Search for Bruce M Psaty in:

  48. Search for M Carola Zillikens in:

  49. Search for Ben A Oostra in:

  50. Search for Mary Feitosa in:

  51. Search for Michael Province in:

  52. Search for Mariza de Andrade in:

  53. Search for Stephen T Turner in:

  54. Search for Arne Schillert in:

  55. Search for Andreas Ziegler in:

  56. Search for Philipp S Wild in:

  57. Search for Renate B Schnabel in:

  58. Search for Sandra Wilde in:

  59. Search for Thomas F Munzel in:

  60. Search for Tennille S Leak in:

  61. Search for Thomas Illig in:

  62. Search for Norman Klopp in:

  63. Search for Christa Meisinger in:

  64. Search for H-Erich Wichmann in:

  65. Search for Wolfgang Koenig in:

  66. Search for Lina Zgaga in:

  67. Search for Tatijana Zemunik in:

  68. Search for Ivana Kolcic in:

  69. Search for Cosetta Minelli in:

  70. Search for Frank B Hu in:

  71. Search for Åsa Johansson in:

  72. Search for Wilmar Igl in:

  73. Search for Ghazal Zaboli in:

  74. Search for Sarah H Wild in:

  75. Search for Alan F Wright in:

  76. Search for Harry Campbell in:

  77. Search for David Ellinghaus in:

  78. Search for Stefan Schreiber in:

  79. Search for Yurii S Aulchenko in:

  80. Search for Janine F Felix in:

  81. Search for Fernando Rivadeneira in:

  82. Search for Andre G Uitterlinden in:

  83. Search for Albert Hofman in:

  84. Search for Medea Imboden in:

  85. Search for Dorothea Nitsch in:

  86. Search for Anita Brandstätter in:

  87. Search for Barbara Kollerits in:

  88. Search for Lyudmyla Kedenko in:

  89. Search for Reedik Mägi in:

  90. Search for Michael Stumvoll in:

  91. Search for Peter Kovacs in:

  92. Search for Mladen Boban in:

  93. Search for Susan Campbell in:

  94. Search for Karlhans Endlich in:

  95. Search for Henry Völzke in:

  96. Search for Heyo K Kroemer in:

  97. Search for Matthias Nauck in:

  98. Search for Uwe Völker in:

  99. Search for Ozren Polasek in:

  100. Search for Veronique Vitart in:

  101. Search for Sunita Badola in:

  102. Search for Alexander N Parker in:

  103. Search for Paul M Ridker in:

  104. Search for Sharon L R Kardia in:

  105. Search for Stefan Blankenberg in:

  106. Search for Yongmei Liu in:

  107. Search for Gary C Curhan in:

  108. Search for Andre Franke in:

  109. Search for Thierry Rochat in:

  110. Search for Bernhard Paulweber in:

  111. Search for Inga Prokopenko in:

  112. Search for Wei Wang in:

  113. Search for Vilmundur Gudnason in:

  114. Search for Alan R Shuldiner in:

  115. Search for Josef Coresh in:

  116. Search for Reinhold Schmidt in:

  117. Search for Luigi Ferrucci in:

  118. Search for Michael G Shlipak in:

  119. Search for Cornelia M van Duijn in:

  120. Search for Ingrid Borecki in:

  121. Search for Bernhard K Krämer in:

  122. Search for Igor Rudan in:

  123. Search for Ulf Gyllensten in:

  124. Search for James F Wilson in:

  125. Search for Jacqueline C Witteman in:

  126. Search for Peter P Pramstaller in:

  127. Search for Rainer Rettig in:

  128. Search for Nick Hastie in:

  129. Search for Daniel I Chasman in:

  130. Search for W H Kao in:

  131. Search for Iris M Heid in:

  132. Search for Caroline S Fox in:

Contributions

Writing group: A.K., C.P., C.A.B., C.F., N.L.G., A.P., X.G., W.H.K., I.M.H., C.S.F.

Study design: L.J.L., T.B.H., V.G., A.P., E.B., J.C., A.K., L.F., J.M., N.L.G., T.L., D.S., B.M.P., M.G.S., B.A.O., C.M.v.D., I.B., M.P., C.S.F., Q.Y., S.K., M.d.A., E.J.A., Y.L., C.A.B., I.M.H., T.I., H.-E.W., N.K., C.M., I.R., P.P.P., F.B.H., G.C.C., U.G., J.F.W., S.H.W., A.F.W., H.C., A.H., N.M.P.-H., M.I., D.N., T.R., B.P., R.R., K.E., H.V., P.K., A.T., M.B., W.W., O.P., N.H., C.H., V.V., D.I.C., G.P., A.N.P., P.M.R., S.B., T.F.M.

Study management: G.E., L.J.L., T.B.H., V.G., A.P., B.D.M., A.R.S., E.B., J.C., W.H.K., J.M., D.S., B.M.P., M.G.S., A.I., M.C.Z., B.A.O., C.M.v.D., I.B., M.P., C.S.F., S.K., M.d.A., C.A.B., I.M.H., M.O., B.K., W.K., T.I., H.-E.W., C.M., I.R., L.Z., T.Z., C.P., C.F., P.P.P., M.C.C., F.B.H., G.C.C., A.J., G.Z., U.G., J.F.W., S.H.W., A.G.U., F.R., N.M.P.-H., M.I., T.R., B.K.K., L.K., B.P., F.K., R.R., K.E., H.V., M.S., A.T., M.B., O.P., N.H., C.H., V.V., D.I.C., G.P., S.B., A.N.P., P.M.R.

Subject recruitment: G.E., T.B.H., V.G., B.D.M., A.R.S., J.C., L.F., B.M.P., B.A.O., C.M.v.D., C.S.F., S.T.T., T.I., H.-E.W., I.R., L.Z., T.Z., I.K., P.P.P., A.J., J.F.W., S.H.W., S.S., A.D., J.C.W., N.M.P.-H., M.I., D.N., T.R., B.P., R.R., H.V., A.T., M.B., O.P., C.H., S.B., T.Z., R.S.

Interpretation of results: T.B.H., A.P., E.B., J.C., W.H.K., A.K., L.F., T.T., F.G., N.L.G., T.L., T.H., B.M.P., A.I., M.C.Z., B.A.O., C.M.v.D., I.B., M.P., X.G., C.S.F., Q.Y., S.-J.H., S.K., S.T.T., M.d.A., E.J.A., Y.L., T.S.L., C.A.B., I.M.H., M.O., B.K., W.K., I.R., T.Z., I.K., C.P., C.F., C.M., P.P.P., G.C.C., A.D.J., W.I., G.Z., U.G., J.F.W., S.H.W., A.D., Y.S.A., M.I., B.K., L.K., B.P., F.K., R.R., K.E., A.T., H.V., H.K.K., M.N., U.V., M.B., O.P., N.H., C.H., V.V., D.I.C., G.P., P.M.R.

Critical review of manuscript: All authors.

Statistical methods and analysis: A.V.S., T.A., V.G., J.R.O., E.R., A.K., M.L., R.S., H.S., T.T., N.L.G., T.L., B.M.P., A.I., X.G., M.F., C.S.F., Q.Y., S.J.H., S.K., M.d.A., E.J.A., K.L., Y.L., C.A.B., I.M.H., M.O., N.K., C.P., C.F., C.M., M.C.C., A.J., W.I., D.E., A.F., A.D., F.R., Y.S.A., N.M.P.-H., B.K., F.K., A.T., U.V., R.M., I.P., C.H., V.V., D.I.C., G.P., A.Z., A.B., S.W., J.F.F., D.E.A.

Genotyping: E.B., R.S., H.S., L.F., T.H., A.I., B.A.O., C.M.v.D., M.d.A., Y.L., T.I., H.-E.W., C.M., J.F.W., H.C., A.F., A.G.U., F.R., M.I., F.K., H.K.K., M.N., U.V., M.S., S.C., C.H., S.B., A.N.P., A.B., N.K.

Bioinformatics: A.V.S., T.A., J.R.O., M.S., M.C., T.T., A.I., B.A.O., C.M.v.D., Q.Y., A.D.J., E.J.A., Y.L., C.A.B., I.M.H., M.O., C.P., C.F., M.C.C., A.J., W.I., D.E., A.D., F.R., Y.S.A., F.K., A.T., H.K.K., U.V., D.I.C., G.P., D.E.A.

Competing interests

C.A.B. has received lecture fees from Novartis Deutschland GmbH, Fresenius Medical Care Deutschland GmbH and Sandoz Pharmaceuticals GmbH. S.B. and A.N.P. are employees of Amgen.

Corresponding authors

Correspondence to Daniel I Chasman or W H Kao or Iris M Heid or Caroline S Fox.

Supplementary information

PDF files

  1. 1.

    Supplementary Text and Figures

    Supplementary Note, Supplementary Tables 1–7 and Supplementary Figures 1 and 2

About this article

Publication history

Received

Accepted

Published

DOI

https://doi.org/10.1038/ng.568

Further reading