Letter | Published:

Common variants at 6q22 and 17q21 are associated with intracranial volume

Nature Genetics volume 44, pages 539544 (2012) | Download Citation

  • An Erratum to this article was published on 29 May 2012
  • A Corrigendum to this article was published on 29 May 2013

This article has been updated

Abstract

During aging, intracranial volume remains unchanged and represents maximally attained brain size, while various interacting biological phenomena lead to brain volume loss. Consequently, intracranial volume and brain volume in late life reflect different genetic influences. Our genome-wide association study (GWAS) in 8,175 community-dwelling elderly persons did not reveal any associations at genome-wide significance (P < 5 × 10−8) for brain volume. In contrast, intracranial volume was significantly associated with two loci: rs4273712 (P = 3.4 × 10−11), a known height-associated locus on chromosome 6q22, and rs9915547 (P = 1.5 × 10−12), localized to the inversion on chromosome 17q21. We replicated the associations of these loci with intracranial volume in a separate sample of 1,752 elderly persons (P = 1.1 × 10−3 for 6q22 and 1.2 × 10−3 for 17q21). Furthermore, we also found suggestive associations of the 17q21 locus with head circumference in 10,768 children (mean age of 14.5 months). Our data identify two loci associated with head size, with the inversion at 17q21 also likely to be involved in attaining maximal brain size.

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Change history

  • 27 April 2012

    In the version of this article initially published online, the percentage of females in the AGES study in Table 1 was left blank. This number should be 59%. The error has been corrected for the PDF and HTML versions of this article.

  • 08 May 2013

    In the version of this article initially published, Thorkild I.A. Sørensen was listed incorrectly as a contributing member of the EGG Consortium. The error has been corrected for the HTML and PDF versions of this article.

References

  1. 1.

    , , & The influence of head growth in fetal life, infancy, and childhood on intelligence at the ages of 4 and 8 years. Pediatrics 118, 1486–1492 (2006).

  2. 2.

    , , , & Critical periods of brain growth and cognitive function in children. Brain 127, 321–329 (2004).

  3. 3.

    et al. Measures of brain morphology and infarction in the framingham heart study: establishing what is normal. Neurobiol. Aging 26, 491–510 (2005).

  4. 4.

    et al. Brain tissue volumes in the general elderly population. The Rotterdam Scan Study. Neurobiol. Aging 29, 882–890 (2008).

  5. 5.

    et al. Evidence for genetic variance in white matter hyperintensity volume in normal elderly male twins. Stroke 29, 1177–1181 (1998).

  6. 6.

    et al. Genetic variation in white matter hyperintensity volume in the Framingham Study. Stroke 35, 1609–1613 (2004).

  7. 7.

    et al. Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. Design of prospective meta-analyses of genome-wide association studies from 5 cohorts. Circ. Cardiovasc. Genet. 2, 73–80 (2009).

  8. 8.

    et al. Genome-wide analysis of genetic loci associated with Alzheimer disease. J. Am. Med. Assoc. 303, 1832–1840 (2010).

  9. 9.

    et al. Genomewide association studies of stroke. N. Engl. J. Med. 360, 1718–1728 (2009).

  10. 10.

    et al. Common variants at 12q15 and 12q24 are associated with infant head circumference. Nat. Genet. published online (15 April 2012); doi:10.1038/ng.2238.

  11. 11.

    et al. Hundreds of variants clustered in genomic loci and biological pathways affect human height. Nature 467, 832–838 (2010).

  12. 12.

    et al. The H1 haplotype of the tau gene (MAPT) is associated with mild cognitive impairment. J. Alzheimers Dis. 19, 909–914 (2010).

  13. 13.

    et al. Evolutionary toggling of the MAPT 17q21.31 inversion region. Nat. Genet. 40, 1076–1083 (2008).

  14. 14.

    et al. Molecular evolution and genetics of the Saitohin gene and tau haplotype in Alzheimer's disease and argyrophilic grain disease. J. Neurochem. 89, 179–188 (2004).

  15. 15.

    et al. Association of polymorphisms in the Tau and Saitohin genes with Parkinson's disease. J. Neurol. Neurosurg. Psychiatry 75, 478–480 (2004).

  16. 16.

    , & Granulin mutations associated with frontotemporal lobar degeneration and related disorders: an update. Hum. Mutat. 29, 1373–1386 (2008).

  17. 17.

    et al. Progranulin locus deletion in frontotemporal dementia. Hum. Mutat. 29, 53–58 (2008).

  18. 18.

    , , , & Corticotropin-releasing hormone receptor–1 in cerebral microvessels changes during development and influences urocortin transport across the blood-brain barrier. Endocrinology 151, 1221–1227 (2010).

  19. 19.

    , & Head circumference, education and risk of dementia: findings from the Nun Study. J. Clin. Exp. Neuropsychol. 25, 671–679 (2003).

  20. 20.

    et al. A new chromosome 17q21.31 microdeletion syndrome associated with a common inversion polymorphism. Nat. Genet. 38, 999–1001 (2006).

  21. 21.

    et al. Clinical and molecular delineation of the 17q21.31 microdeletion syndrome. J. Med. Genet. 45, 710–720 (2008).

  22. 22.

    et al. A common inversion under selection in Europeans. Nat. Genet. 37, 129–137 (2005).

  23. 23.

    et al. The distribution and most recent common ancestor of the 17q21 inversion in humans. Am. J. Hum. Genet. 86, 161–171 (2010).

  24. 24.

    & Evolution of the brain and intelligence. Trends Cogn. Sci. 9, 250–257 (2005).

  25. 25.

    & The thrombospondin type 1 repeat (TSR) superfamily: diverse proteins with related roles in neuronal development. Dev. Dyn. 218, 280–299 (2000).

  26. 26.

    , , , & The novel cytosolic RING finger protein dactylidin is up-regulated in brains of patients with Alzheimer's disease. Eur. J. Neurosci. 21, 1289–1298 (2005).

  27. 27.

    et al. Nat. Genet. 38, 904–909 (2006).

Download references

Acknowledgements

Aging Gene-Environment Susceptibility–Reykjavik Study (AGES-RS): Research was funded by the US National Institute on Aging (NIA) (N01-AG-12100), with contributions from the US National Eye Institute (NEI), National Institute on Deafness and Other Communication Disorders (NIDCD) and the NHLBI, the NIA Intramural Research Program, Hjartavernd (the Icelandic Heart Association), and the Althingi (the Icelandic Parliament).

Atherosclerosis Risk in Communities Study (ARIC): The authors thank the staff and participants of the ARIC study for their important contributions. Research is carried out as a collaborative study supported by the US NHLBI (N01-HC-55015, N01-HC-55016, N01-HC-55018, N01-HC-55019, N01-HC-55020, N01-HC-55021, N01-HC-55022, R01-HL087641 and R01-HL093029), the National Human Genome Research Institute (U01-HG004402) and the NIH (HHSN268200625226C). Infrastructure was partly supported by a component of the NIH and NIH Roadmap for Medical Research (UL1RR025005).

Austrian Stroke Prevention Study (ASPS): The authors thank the staff and participants of the ASPS for their valuable contributions. We thank B. Reinhart for her long-term administrative commitment and I.J. Semmler for technical assistance in creating the DNA bank. The research reported here was funded by the Austrian Science Fond (FWF) (P20545-P05 and P13180). The Medical University of Graz supports the databank of the ASPS.

Framingham Heart Study (FHS): This study is carried out by the US NHLBI of the NIH and Boston University School of Medicine. This work was supported by the Framingham Heart Study of the NHLBI (N01-HC-25195) and its contract with Affymetrix, Inc, for genotyping services (N02-HL-6-4278). A portion of this research used the Linux Cluster for Genetic Analysis (LinGA-II) funded by the Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine and Boston Medical Center. This study was also supported by grants from the National Institute of Neurological Disorders and Stroke (NS17950), the NHLBI (HL093029) and the NIA (AG08122, AG16495, AG033193, AG033040, AG031287 and P30AG013846).

Rotterdam Study (RS): The authors are grateful to the study participants, the staff from the Rotterdam Study and the participating general practitioners and pharmacists. The authors thank P. Arp, M. Jhamai, M. Verkerk, L. Herrera and M. Peters for their help in creating the GWAS database and K. Estrada and M.V. Struchalin for their support in creation and analysis of imputed data. The generation and management of GWAS genotype data for the Rotterdam Study were supported by the Netherlands Organisation of Scientific Research (NWO) Investments (nr. 175.010.2005.011 and 911-03-012). This study is funded by the Research Institute for Diseases in the Elderly (014-93-015; RIDE2), the Netherlands Genomics Initiative (NGI)- NWO project (nr. 050-060-810). The Rotterdam Study is funded by Erasmus Medical Center and Erasmus University Organization for Health Research and Development (ZonMw), the Research Institute for Diseases in the Elderly (RIDE), the Ministry of Education, Culture and Science, the Ministry for Health, Welfare and Sports, the European Commission (DG XII) and the Municipality of Rotterdam. The Rotterdam Scan Study is supported by the NWO (nrs. 918-46-615, 904-61-096, 904-61-133 and 948-00-010), the Nederlandse Hartstichting (2009B102) and the Internationaal Parkinson Fonds.

EGG Consortium: We gratefully acknowledge the contribution of general practitioners, hospitals, midwives and pharmacies in Rotterdam. Financial support was received from the Academy of Finland (104781, 120315, 1114194 and Center of Excellence in Complex Disease Genetics), University Hospital Oulu, Biocenter, University of Oulu, the US NHLBI (5R01HL087679-02, through the STAMPEED program 1RL1MH083268-01), the ENGAGE project and grant agreement HEALTH-F4-2007-201413, the UK MRC (G0500539 and PrevMetSyn/Salve/MRC) and the Wellcome Trust (GR069224). DNA extraction, sample quality control, biobank upkeep and aliquotting were performed at the National Public Health Institute, Biomedicum Helsinki (Helsinki, Finland) and supported financially by the Academy of Finland and Biocentrum Helsinki. The Generation R Study is conducted by the Erasmus Medical Center in close collaboration with the School of Law and Faculty of Social Sciences of the Erasmus University Rotterdam, the Municipal Health Service Rotterdam area, the Rotterdam Homecare Foundation and the Stichting Trombosedienst & Artsenlaboratorium Rijnmond (STAR). The Generation R Study is made possible by financial support from the Erasmus Medical Center, Rotterdam, the Erasmus University Rotterdam and the Netherlands Organization for Health Research and Development (ZonMw 21000074). V.J. received additional grants from the Netherlands Organization for Health Research and Development (ZonMw 90700303 and 916.10159). Additional support was provided by a grant from the Dutch Kidney Foundation (C08.2251).

The authors would like to thank all participating subjects and families from the Children's Hospital in Philadelphia. The research was financially supported by an Institute Development Award from the Children's Hospital of Philadelphia, a Research Development Award from the Cotswold Foundation and by the US NIH (1R01HD056465-01A1). The authors are grateful to the Raine Foundation, the RAINE Study families and the RAINE Study research staff. We gratefully acknowledge the assistance of the Western Australian Genetic Epidemiology Resource and the Western Australian DNA Bank (both National Health and Medical Research Council of Australia National Enabling Facilities). The authors also acknowledge the support of Healthway Western Australia, the National Health and Medical Research Council of Australia (572613) and the Canadian Institutes of Health Research (MOP 82893). We gratefully acknowledge the assistance of the Wind Over Water Foundation, the Telethon Institute for Child Health Research and the RAINE Medical Research Foundation of the University of Western Australia. The authors wish to acknowledge the following: Helmholtz Zentrum Muenchen–German Research Center for Environment and Health, Institute of Epidemiology; the Department of Pediatrics, University of Leipzig; Department of Pediatrics, Marien-Hospital; Bad Honnef; the Department of Human Exposure Research and Epidemiology, UFZ-Centre for Environmental Research Leipzig–Halle; the Department of Environmental Immunology, Zentrum für Umweltforschung (UFZ)-Centre for Environmental Research Leipzig–Halle; the Institut für Umweltmedizinische Forschung (IUF) and the Department of Pediatrics, Technical University. The UK MRC (74882), the Wellcome Trust (076467) and the University of Bristol provide core support for the Avon Longitudinal Study of Parents and Children (ALSPAC). We are extremely grateful to all the families who took part in the ALSPAC study, the midwives for their help in recruiting them and the whole ALSPAC team, which includes interviewers, computer and laboratory technicians, clerical workers, research scientists, volunteers, managers, receptionists and nurses.

Author information

Author notes

    • M Arfan Ikram
    • , Myriam Fornage
    • , Albert V Smith
    • , Sudha Seshadri
    •  & Reinhold Schmidt

    These authors contributed equally to this work.

    • Thomas H Mosley Jr
    • , Helena Schmidt
    • , Lenore J Launer
    • , Monique M B Breteler
    •  & Charles DeCarli

    These authors jointly directed this work.

Affiliations

  1. Department of Epidemiology, Erasmus Medical Center University Medical Center, Rotterdam, The Netherlands.

    • M Arfan Ikram
    • , H Rob Taal
    • , Dennis O Mook-Kanamori
    • , Maksim Struchalin
    • , Albert Hofman
    • , Meike W Vernooij
    • , Vincent W V Jaddoe
    • , Cornelia M van Duijn
    • , Monique M B Breteler
    • , Nienke Bergen
    •  & Romy Gaillard
  2. Department of Radiology, Erasmus Medical Center University Medical Center, Rotterdam, The Netherlands.

    • M Arfan Ikram
    • , Henri A Vrooman
    • , Wiro J Niessen
    • , Fernando Rivadeneira
    • , Andre G Uitterlinden
    • , Aad van der Lugt
    •  & Meike W Vernooij
  3. Netherlands Consortium for Healthy Aging, Leiden, The Netherlands.

    • M Arfan Ikram
    • , Albert Hofman
    • , Cornelia M van Duijn
    •  & Monique M B Breteler
  4. Institute of Molecular Medicine, University of Texas, Houston Health Sciences Center, Houston, Texas, USA.

    • Myriam Fornage
  5. Human Genetics Center, University of Texas, Houston Health Sciences Center, Houston, Texas, USA.

    • Myriam Fornage
  6. Icelandic Heart Association, Kopavogur, Iceland.

    • Albert V Smith
    • , Sigurdur Sigurdsson
    • , Haukur Gudnason
    •  & Vilmundur Gudnason
  7. Faculty of Medicine, University of Iceland, Reykjavik, Iceland.

    • Albert V Smith
    •  & Vilmundur Gudnason
  8. Department of Neurology, Boston University School of Medicine, Boston, Massachusetts, USA.

    • Sudha Seshadri
    • , Stéphanie Debette
    • , Anita L DeStefano
    • , Alexa Beiser
    • , Rhoda Au
    •  & Philip A Wolf
  9. Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts, USA.

    • Sudha Seshadri
    • , Stéphanie Debette
    • , Anita L DeStefano
    •  & Alexa Beiser
  10. The National Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, Massachusetts, USA.

    • Sudha Seshadri
    • , Anita L DeStefano
    • , Alexa Beiser
    •  & Philip A Wolf
  11. Department of Neurology, Medical University Graz, Graz, Austria.

    • Reinhold Schmidt
    • , Stefan Ropele
    •  & Rhoda Au
  12. Institut National de la Santé et de la Recherche Médicale (INSERM), U708, Neuroepidemiology, Paris, France.

    • Stéphanie Debette
  13. Department of Medical Informatics, Erasmus Medical Center University Medical Center, Rotterdam, The Netherlands.

    • Henri A Vrooman
    •  & Wiro J Niessen
  14. Department of Pediatrics, Erasmus Medical Center University Medical Center, Rotterdam, The Netherlands.

    • H Rob Taal
    • , Dennis O Mook-Kanamori
    •  & Vincent W V Jaddoe
  15. The Generation R Study, Erasmus Medical Center University Medical Center, Rotterdam, The Netherlands.

    • H Rob Taal
    • , Dennis O Mook-Kanamori
    • , Vincent W V Jaddoe
    • , Nienke Bergen
    •  & Romy Gaillard
  16. Department of Physiology and Biophysics, Weill Cornell Medical College–Qatar, Doha, Qatar.

    • Dennis O Mook-Kanamori
  17. Division of Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA.

    • Laura H Coker
  18. Department of Neurology and Epidemiology, University of Washington, Seattle, Washington, USA.

    • W T Longstreth Jr
  19. Faculty of Applied Sciences, Delft University of Technology, Delft, The Netherlands.

    • Wiro J Niessen
  20. Biospective Inc, Montreal, Quebec, Canada.

    • Alex P Zijdenbos
  21. Department of Radiology, Mayo Clinic, Rochester, Minnesota, USA.

    • Clifford R Jack Jr
  22. Department of Internal Medicine, Erasmus Medical Center University Medical Center, Rotterdam, The Netherlands.

    • Fernando Rivadeneira
    •  & Andre G Uitterlinden
  23. Department of Neurology, Mayo Clinic, Rochester, Minnesota, USA.

    • David S Knopman
  24. Institute of Clinical Medicine, Department of Obstetrics and Gynecology, University of Oulu, Oulu, Finland.

    • Anna-Liisa Hartikainen
  25. School of Women's & Infant's Health, University of Western Australia, Crawley, Western Australia, Australia.

    • Craig E Pennell
    • , Joachim Heinrich
    • , Wei Ang
    • , Kelly Benke
    • , Matthew Kowgier
    •  & Julie Marsh
  26. Institute of Epidemiology I, Helmholtz Zentrum Munchen–German Research Centre for Environmental Health, Neuherberg, Germany.

    • Elisabeth Thiering
    •  & Claudia Flexeder
  27. Department of Obstetrics and Gynaecology, Erasmus Medical Center University Medical Center, Rotterdam, The Netherlands.

    • Eric A P Steegers
  28. Center for Applied Genomics, Abramsom Research Center, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.

    • Hakon Hakonarson
    • , Struan F A Grant
    •  & Dexter Hadley
  29. Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

    • Hakon Hakonarson
    •  & Struan F A Grant
  30. Genetic Epidemiology and Biostatistics Platform, Ontario Institute for Cancer Research, University of Toronto, Toronto, Ontario, Canada.

    • Lyle J Palmer
  31. Department of Epidemiology and Biostatistics, School of Public Health, Medical Research Center (MRC)–Health Protection Agency (HPA) Centre for Environmental and Health, Faculty of Medicine, Imperial College London, London, UK.

    • Marjo-Riitta Jarvelin
    • , Ulla Sovio
    • , Lachlan Coin
    • , Paul Elliott
    • , Alex Lewin
    • , Iona Millwood
    • , Alina Rodriguez
    • , Sylvain Sebert
    •  & Beatriz Valcárcel
  32. Institute of Health Sciences, University of Oulu, Oulu, Finland.

    • Marjo-Riitta Jarvelin
    •  & Ville Huikari
  33. Biocenter Oulu, University of Oulu, Oulu, Finland.

    • Marjo-Riitta Jarvelin
    •  & Ville Huikari
  34. Department of Children, Young People and Families, National Institute of Health and Welfare, Oulu, Finland.

    • Marjo-Riitta Jarvelin
  35. Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, UK.

    • Mark I McCarthy
    •  & Momoko Horikoshi
  36. Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.

    • Mark I McCarthy
    • , Momoko Horikoshi
    • , Cecilia Lindgren
    •  & Reedik Maggi
  37. MRC Centre for Causal Analyses in Translational Epidemiology, School of Social and Community Medicine, University of Bristol, Bristol, UK.

    • Beate St Pourcain
    • , Nicholas J Timpson
    • , George Davey Smith
    •  & Debbie A Lawlor
  38. Department of Medical Statistics, London School of Hygiene and Tropical Medicine, London, UK.

    • Ulla Sovio
  39. Laboratory of Neurogenetics, National Institute on Aging, US National Institutes of Health (NIH), Bethesda, Maryland, USA.

    • Mike A Nalls
  40. Laboratory of Epidemiology, Demography, and Biometry, NIH, Bethesda, Maryland, USA.

    • Tamara B Harris
    •  & Lenore J Launer
  41. Department of Medicine (Geriatrics), University of Mississippi Medical Center, Jackson, Mississippi, USA.

    • William M Meeks
    • , B Gwen Windham
    •  & Thomas H Mosley Jr
  42. Department of Neurology, University of Mississippi Medical Center, Jackson, Mississippi, USA.

    • William M Meeks
    • , B Gwen Windham
    •  & Thomas H Mosley Jr
  43. Department of Radiology, Leiden University Medical Center, Leiden, The Netherlands.

    • Mark A van Buchem
  44. Department of Biostatistics, University of North Carolina, Chapel Hill, North Carolina, USA.

    • Diane Catellier
  45. Institute of Molecular Biology and Biochemistry, Medical University Graz, Graz, Austria.

    • Helena Schmidt
  46. German Center for Neurologic Diseases (DZNE), Bonn, Germany.

    • Monique M B Breteler
  47. Department of Neurology, University of California, Davis, Sacramento, California, USA.

    • Charles DeCarli
  48. Center of Neuroscience, University of California, Davis, Sacramento, California, USA.

    • Charles DeCarli
  49. Department of Nutrition, University of North Carolina, Chapel Hill, North Carolina, USA.

    • Linda S Adair
  50. Department of Physiology, Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland.

    • Mustafa Atalay
    • , Virpi Lindi
    •  & Timo A Lakka
  51. Department of Biological Psychology, VU University, Amsterdam, The Netherlands.

    • Toos van Beijsterveldt
    • , Maria Groen-Blokhuis
    • , Jouke Jan Hottenga
    • , Christel Middeldorp
    • , Michel Nivard
    • , Gonneke Willemsen
    •  & Dorret I Boomsma
  52. Centre for Paediatric Epidemiology and Biostatistics, MRC Centre of Epidemiology for Child Health, University College of London Institute of Child Health, London, UK.

    • Diane Berry
    • , Elina Hypponen
    •  & Chris Power
  53. MRC Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, King's College London, London, UK.

    • Oliver S P Davis
    • , Claire M A Haworth
    • , Jennifer Pararajasingham
    • , Alina Rodriguez
    •  & Thomas S Price
  54. Genetics of Complex Traits, Peninsula College of Medicine and Dentistry, University of Exeter, Exeter, UK.

    • Tim Frayling
  55. Duke–National University of Singapore (NUS) Graduate Medical School, Singapore.

    • Liang-Kee Goh
    •  & Seang-Mei Saw
  56. Saw Swee Hock School of Public Health, NUS, Singapore.

    • Liang-Kee Goh
    • , Yik-Ying Teo
    •  & Seang-Mei Saw
  57. Department of Child and Adolescent Psychiatry, University of Duisburg–Essen, Essen, Germany.

    • Johannes Hedebrand
    •  & Anke Hinney
  58. Division of Genetics, Children's Hospital, Boston, Massachusetts, USA.

    • Joel N Hirschhorn
    • , Emily Oken
    •  & Rany M Salem
  59. Division of Endocrinology, Children's Hospital, Boston, Massachusetts, USA.

    • Joel N Hirschhorn
    • , Emily Oken
    •  & Rany M Salem
  60. Program in Genomics, Children's Hospital, Boston, Massachusetts, USA.

    • Joel N Hirschhorn
    • , Emily Oken
    •  & Rany M Salem
  61. Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA.

    • Joel N Hirschhorn
    • , Emily Oken
    •  & Rany M Salem
  62. Metabolism Initiative, Broad Institute, Cambridge, Massachusetts, USA.

    • Joel N Hirschhorn
    • , Emily Oken
    •  & Rany M Salem
  63. Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, USA.

    • Joel N Hirschhorn
    • , Emily Oken
    •  & Rany M Salem
  64. Human Genetics and Medical Genomics, Human Development & Health, Faculty of Medicine, University of Southampton, Southampton, UK.

    • John W Holloway
  65. Clinical & Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, UK.

    • John W Holloway
    •  & Ellen Aagaard Nohr
  66. Institute of Preventive Medicine, Copenhagen University Hospital, Copenhagen, Denmark.

    • Claus Holst
  67. Department of Genomics of Common Disease, School of Public Health, Imperial College London, London, UK.

    • Elina Hypponen
  68. Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark.

    • Tuomas O Kilpeläinen
  69. Centre for Population Health Sciences, University of Edinburgh, Edinburgh, UK.

    • Mirna Kirin
    •  & James F Wilson
  70. Department of Public Health, Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland.

    • Hanna-Maaria Lakka
  71. Department of Genetics, University of North Carolina, Chapel Hill, North Carolina, USA.

    • Leslie A Lange
    •  & Karen L Mohlke
  72. Department of Clinical Chemistry, Tampere University Hospital, Tampere, Finland.

    • Terho Lehtimäki
  73. Department of Clinical Chemistry, University of Tampere School of Medicine, Tampere, Finland.

    • Terho Lehtimäki
  74. Estonian Genome Center, University of Tartu, Tartu, Estonia.

    • Reedik Maggi
  75. Clinical Trial Service Unit and Epidemiological Studies Unit (CTSU), University of Oxford, Oxford, UK.

    • Iona Millwood
  76. Department of Pediatrics, University of Iowa, Iowa City, Iowa, USA.

    • Jeffrey C Murray
  77. Department of Dietetics–Nutrition, Harokopio University of Athens, Athens, Greece.

    • Ioanna Ntalla
    •  & George V Dedoussis
  78. Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK.

    • Kalliope Panoutsopoulou
    •  & Eleftheria Zeggini
  79. Department of Psychology, Mid Sweden University, Östersund, Sweden.

    • Alina Rodriguez
  80. Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, Finland.

    • Niina Siitonen
    • , Olli T Raitakari
    •  & Olli Simell
  81. Division of Population Health Sciences and Education, St George's, University of London, London, UK.

    • David P Strachan
  82. MRC Lifecourse Epidemiology Unit, University of Southampton, Southampton, UK.

    • Cyrus Cooper
  83. Obesity Prevention Program, Department of Population Medicine, Harvard Medical School and Harvard Pilgrim Health Care Institute, Boston, Massachusetts, USA.

    • Matthew Gillman
  84. Institute of Nutritional Science, University of Potsdam, Potsdam, Germany.

    • Berthold Hocher
  85. Center for Cardiovascular Research, Institute of Pharmacology, Charité, Berlin, Germany.

    • Berthold Hocher
  86. MRC Epidemiology Unit, Institute of Metabolic Science, Cambridge, UK.

    • Ken K Ong
  87. Biomedical Research Institute, University of Dundee, Dundee, UK.

    • Ewan R Pearson
  88. Department of Clinical Physiology, University of Turku and Turku University Hospital, Turku, Finland.

    • Olli T Raitakari
  89. Singapore Eye Research Institute, Singapore.

    • Seang-Mei Saw
  90. Institute for Medical Informatics, Biometry and Epidemiology, University of Duisburg–Essen, Essen, Germany.

    • Andre Scherag
  91. Department of Pediatrics, University of Turku and Turku University Hospital, Turku, Finland.

    • Olli Simell
  92. MRC Institute of Genetics and Molecular Medicine at the University of Edinburgh, Western General Hospital, Edinburgh, UK.

    • James F Wilson

Consortia

  1. the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium

  2. Early Growth Genetics (EGG) Consortium

Authors

    Contributions

    Study concept and design was carried out by M.A.I., M.F., S. Seshadri, R.S., W.T.L., A.G.U., A.-L.H., E.A.P.S., J.H., L.J.P., S.F.A.G., N.J.T., G.D.S., A.H., A.v.d.L., M.A.v.B., V.W.V.J., V.G., P.A.W., C.M.v.D., T.H.M., H.S., L.J.L., M.M.B.B. and C.D. Acquisition of data was carried out by M.A.I., M.F., A.V.S., S.D., H.A.V., S. Sigurdsson, S.R., H.R.T., D.O.M.-K., L.H.C., W.J.N., A.B., A.P.Z., M.S., C.R.J., F.R., D.S.K., C.E.P., E.A.P.S., H.H., L.J.P., M.-R.J., S.F.A.G., B.S.P., M.A.N., R.A., H.G., T.B.H., W.M.M., M.W.V., M.A.v.B., D.C., B.G.W. and T.H.M. Statistical analysis and interpretation of the findings were performed by M.A.I., M.F., A.V.S., S. Seshadri, R.S., S.D., H.R.T., D.O.M.-K., A.L.D., F.R., E.T., S.F.A.G., M.A.N., R.A., V.W.V.J., C.M.v.D., H.S., L.J.L., M.M.B.B. and C.D. The manuscript was drafted by M.A.I., M.F., S. Seshadri, R.S., H.R.T., D.O.M.-K., L.J.L. and C.D. Critical revision of the manuscript was performed by A.V.S., S.D., H.A.V., S. Sigurdsson, S.R., L.H.C., W.T.L., W.J.N., A.L.D., A.B., A.P.Z., M.S., C.R.J., F.R., A.G.U., D.S.K., A.-L.H., C.E.P., E.T., E.A.P.S., H.H., J.H., L.J.P., M.-R.J., M.I.M., B.S.P., N.J.T., G.D.S., U.S., M.A.N., R.A., A.H., H.G., A.v.d.L., T.B.H., W.M.M., M.W.V., M.A.v.B., V.G., B.G.W., P.A.W., C.M.v.D., T.H.M., H.S. and M.M.B.B. A.V.S., S. Seshadri, R.S., W.T.L., W.J.N., A.G.U., M.-R.J., M.I.M., S.F.A.G., N.J.T., U.S., A.H., A.v.d.L., M.A.v.B., D.C., V.W.V.J., V.G., P.A.W., C.M.v.D., T.H.M., H.S., L.J.L., M.M.B.B. and C.D. obtained funding and supervised the studies.

    Competing interests

    The author declare no competing financial interests.

    Corresponding authors

    Correspondence to M Arfan Ikram or Charles DeCarli.

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    DOI

    https://doi.org/10.1038/ng.2245

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