Letter | Published:

Common variants at 12q15 and 12q24 are associated with infant head circumference

Nature Genetics volume 44, pages 532538 (2012) | Download Citation

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

This article has been updated

Abstract

To identify genetic variants associated with head circumference in infancy, we performed a meta-analysis of seven genome-wide association studies (GWAS) (N = 10,768 individuals of European ancestry enrolled in pregnancy and/or birth cohorts) and followed up three lead signals in six replication studies (combined N = 19,089). rs7980687 on chromosome 12q24 (P = 8.1 × 10−9) and rs1042725 on chromosome 12q15 (P = 2.8 × 10−10) were robustly associated with head circumference in infancy. Although these loci have previously been associated with adult height1, their effects on infant head circumference were largely independent of height (P = 3.8 × 10−7 for rs7980687 and P = 1.3 × 10−7 for rs1042725 after adjustment for infant height). A third signal, rs11655470 on chromosome 17q21, showed suggestive evidence of association with head circumference (P = 3.9 × 10−6). SNPs correlated to the 17q21 signal have shown genome-wide association with adult intracranial volume2, Parkinson's disease and other neurodegenerative diseases3,4,5, indicating that a common genetic variant in this region might link early brain growth with neurological disease in later life.

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Change history

  • 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.

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

  2. 2.

    et al. Common variants at 6q22 and 17q21 are associated with intracranial volume. Nat. Genet. 44, 539–544 (2012).

  3. 3.

    et al. Genome-wide association study reveals genetic risk underlying Parkinson's disease. Nat. Genet. 41, 1308–1312 (2009).

  4. 4.

    International Parkinson Disease Genomics Consortium. Imputation of sequence variants for identification of genetic risks for Parkinson's disease: a meta-analysis of genome-wide association studies. Lancet 377, 641–649 (2011).

  5. 5.

    et al. Role of the tau gene region chromosome inversion in progressive supranuclear palsy, corticobasal degeneration, and related disorders. Arch. Neurol. 65, 1473–1478 (2008).

  6. 6.

    et al. Head size and intelligence, learning, nutritional status and brain development. Head, IQ, learning, nutrition and brain. Neuropsychologia 42, 1118–1131 (2004).

  7. 7.

    et al. Quantitative brain magnetic resonance imaging in attention-deficit hyperactivity disorder. Arch. Gen. Psychiatry 53, 607–616 (1996).

  8. 8.

    et al. Long-term effects of severe undernutrition during the first year of life on brain development and learning in Chilean high-school graduates. Nutrition 16, 1056–1063 (2000).

  9. 9.

    et al. Fetal growth and childhood behavioral problems: results from the ALSPAC cohort. Am. J. Epidemiol. 163, 829–837 (2006).

  10. 10.

    et al. 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).

  11. 11.

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

  12. 12.

    , , & Children with superior intelligence at 7 years of age: a prospective study of the influence of perinatal, medical, and socioeconomic factors. Am. J. Dis. Child. 130, 481–487 (1976).

  13. 13.

    et al. Heritability of head size in Dutch and Australian twin families at ages 0–50 years. Twin Res. Hum. Genet. 13, 370–380 (2010).

  14. 14.

    , & Genetic disorders associated with macrocephaly. Am. J. Med. Genet. A 146A, 2023–2037 (2008).

  15. 15.

    et al. Many roads lead to primary autosomal recessive microcephaly. Prog. Neurobiol. 90, 363–383 (2010).

  16. 16.

    , , & What primary microcephaly can tell us about brain growth. Trends Mol. Med. 12, 358–366 (2006).

  17. 17.

    , , & Mutations in STIL, encoding a pericentriolar and centrosomal protein, cause primary microcephaly. Am. J. Hum. Genet. 84, 286–290 (2009).

  18. 18.

    et al. Continuing positive secular growth change in The Netherlands 1955–1997. Pediatr. Res. 47, 316–323 (2000).

  19. 19.

    et al. Abundant quantitative trait loci exist for DNA methylation and gene expression in human brain. PLoS Genet. 6, e1000952 (2010).

  20. 20.

    et al. High-resolution mapping of expression-QTLs yields insight into human gene regulation. PLoS Genet. 4, e1000214 (2008).

  21. 21.

    et al. Genetics and beyond–the transcriptome of human monocytes and disease susceptibility. PLoS ONE 5, e10693 (2010).

  22. 22.

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

  23. 23.

    et al. p12(DOC-1) is a novel cyclin-dependent kinase 2-associated protein. Mol. Cell. Biol. 20, 6300–6307 (2000).

  24. 24.

    , , , & Identification of novel M phase phosphoproteins by expression cloning. Mol. Biol. Cell 7, 1455–1469 (1996).

  25. 25.

    , & Assessment of head size adjusted for height: an anthropometric tool for clinical use based on Argentinian data. Ann. Hum. Biol. 33, 415–423 (2006).

  26. 26.

    & The strawberry notch gene functions with Notch in common developmental pathways. Development 119, 377–395 (1993).

  27. 27.

    et al. Identification of Myc-associated protein with JmjC domain as a novel therapeutic target oncogene for lung cancer. Mol. Cancer Ther. 6, 542–551 (2007).

  28. 28.

    & The role of Notch in tumorigenesis: oncogene or tumour suppressor? Nat. Rev. Cancer 3, 756–767 (2003).

  29. 29.

    et al. Constitutional rearrangement of the architectural factor HMGA2: a novel human phenotype including overgrowth and lipomas. Am. J. Hum. Genet. 76, 340–348 (2005).

  30. 30.

    , , & Mutation responsible for the mouse pygmy phenotype in the developmentally regulated factor HMGI-C. Nature 376, 771–774 (1995).

  31. 31.

    et al. Twenty bone-mineral-density loci identified by large-scale meta-analysis of genome-wide association studies. Nat. Genet. 41, 1199–1206 (2009).

  32. 32.

    , , , & 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).

  33. 33.

    Tau mutations in neurodegenerative diseases. J. Biol. Chem. 284, 6021–6025 (2009).

  34. 34.

    et al. The effect of MAPT H1 and APOE epsilon4 on transition from mild cognitive impairment to dementia. J. Alzheimers Dis. 22, 1065–1071 (2010).

  35. 35.

    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).

  36. 36.

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

  37. 37.

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

  38. 38.

    et al. A System for Information Management in BioMedical Studies–SIMBioMS. Bioinformatics 25, 2768–2769 (2009).

  39. 39.

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

  40. 40.

    , , & Measuring inconsistency in meta-analyses. Br. Med. J. 327, 557–560 (2003).

  41. 41.

    et al. New charts for ultrasound dating of pregnancy and assessment of fetal growth: longitudinal data from a population-based cohort study. Ultrasound Obstet. Gynecol. 31, 388–396 (2008).

  42. 42.

    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).

  43. 43.

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

Download references

Acknowledgements

We thank A. Sayers for helpful discussions with respect to the conducted mediation analysis. Major funding for the research in this paper is from the Academy of Finland (project grants 104781, 120315, 129269, 1114194, 134839, 129287 and Center of Excellence in Complex Disease Genetics); Biocentrum Helsinki; Biocenter, University of Oulu, Finland; the British Heart Foundation; the Canadian Institutes of Health Research (grant MOP 82893); The Children's Hospital of Philadelphia (Institute Development Award); the Cotswold Foundation (Research Development Award); the Darlington Trust; the Dutch Asthma Foundation; the Dutch Ministry of the Environment; Erasmus Medical Center Rotterdam; Erasmus University Rotterdam; The European Community's Seventh Framework Programme (FP7/2007-2013), ENGAGE project and grant agreement HEALTH-F4-2007- 201413; Exeter National Health Service (NHS) Research and Development; Fundació La Marató de TV3 (Televisió de Catalunya); Helmholtz Zentrum Muenchen, the German Research Center for Environment and Health, Institute of Epidemiology I, Neuherberg; Instituto de Salud Carlos III (FIS PI081151 and PS09/00432); Institut für Umweltmedizinische Forschung (IUF) Düsseldorf; Marien-Hospital Wesel; the UK MRC (G0500539, G0600331, PrevMetSyn/Salve/MRC and G0600705); the Municipal Health Service Rotterdam; the National Health and Medical Research Council of Australia (403981 and 003209); the National Public Health Institute, Helsinki, Finland; the Netherlands Organisation for Scientific Research (NWO) and the Netherlands Organisation for Health Research and Development (ZonMw) (grants SPI 56-464-14192, 904-61-090, 904-61-193, 912-03-031, 480-04-004 and 400-05-717); the US NHLBI (grant 5R01HL087679-02 through the STAMPEED program (1RL1MH083268-01)); the US NIH (grant 1R01HD056465-01A1); the Peninsula NIHR Clinical Research Facility; the RAINE Medical Research Foundation; the Rotterdam Homecare Foundation; South West NHS Research and Development; Stichting Astmabestrijding; Stichting Trombosedienst & Artsenlaboratorium Rijnmond (STAR) Rotterdam; Technical University Munich; the Telethon Institute for Child Health Research; UFZ–Centre for Environmental Research Leipzig–Halle; University Hospital Oulu, Finland; University of Bristol; University of Leipzig; the Wellcome Trust (project grant GR069224); the Western Australian DNA Bank; the Western Australian Genetic Epidemiology Resource and ZonMW (grant 21000074). Data exchange and deposition has been facilitated by the SIMBioMS platform. Personal funding was provided by the Dutch Kidney Foundation (C08.2251 to H.R.T.), the MRC UK (G0500539, PrevMetSyn and PS0476 to S. Das), a Sir Henry Wellcome Postdoctoral Fellowship (Wellcome Trust grant 085541/Z/08/Z to R.M.F.), a MRC New Investigator Award (MRC G0800582 to D.M.E.) and Wellcome Trust 4-year PhD studentships (WT083431MA to J.P.K. and WT088431MA to J.L.B.). I.P. and J.F.-B. are in part supported by the European Community's ENGAGE grant HEALTH-F4-2007-201413, A.T.H. is employed as a core member of the Peninsula NIHR Clinical Research Facility and V.W.V.J. is funded by the Netherlands Organisation for Health Research (ZonMw 90700303 and 916.10159). Detailed acknowledgments by study are given in the Supplementary Note.

Author information

Author notes

    • H Rob Taal
    • , Beate St Pourcain
    • , Elisabeth Thiering
    • , Shikta Das
    •  & Dennis O Mook-Kanamori

    These authors contributed equally to this work.

    • George Davey Smith
    • , Joachim Heinrich
    • , Marjo-Riitta Jarvelin
    •  & Vincent W V Jaddoe

    These authors jointly directed this work.

Affiliations

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

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

    • H Rob Taal
    • , Dennis O Mook-Kanamori
    • , Vincent W V Jaddoe
    •  & Albert J van der Heijden
  3. The Generation R Study Group, Erasmus Medical Center, Rotterdam, The Netherlands.

    • H Rob Taal
    • , Dennis O Mook-Kanamori
    • , Albert Hofman
    • , Nienke Bergen
    • , Romy Gaillard
    •  & Vincent W V Jaddoe
  4. Medical Research Council (MRC) Centre for Causal Analyses in Translational Epidemiology, School of Social and Community Medicine, University of Bristol, Bristol, UK.

    • Beate St Pourcain
    • , Rachel M Freathy
    • , Nicholas J Timpson
    • , David M Evans
    • , John P Kemp
    • , George McMahon
    • , Debbie A Lawlor
    •  & George Davey Smith
  5. Institute of Epidemiology I, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.

    • Elisabeth Thiering
    • , Carla Tiesler
    • , Marie Standl
    • , Joachim Heinrich
    • , H-Erich Wichmann
    •  & Claudia Flexeder
  6. Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK.

    • Shikta Das
    • , Pimphen Charoen
    • , Paul F O'Reilly
    • , Lachlan Coin
    • , Alex Lewin
    • , Iona Millwood
    • , Alina Rodriguez
    • , Sylvain Sebert
    • , Ulla Sovio
    •  & Beatriz Valcárcel
  7. Department of Physiology and Biophysics, Weill Cornell Medical College–Qatar, Doha, Qatar.

    • Dennis O Mook-Kanamori
  8. School of Women's and Infants' Health, The University of Western Australia, Perth, Western Australia, Australia.

    • Nicole M Warrington
    • , Wei Ang
    • , Kelly Benke
    • , Matthew Kowgier
    • , Julie Marsh
    • , Scott White
    • , Craig E Pennell
    •  & John P Newnham
  9. Samuel Lunenfeld Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada.

    • Nicole M Warrington
    • , Stephen J Lye
    •  & Lyle J Palmer
  10. Institute of Health Sciences, University of Oulu, Oulu, Finland.

    • Marika Kaakinen
    • , Ville Huikari
    •  & Marjo-Riitta Jarvelin
  11. Biocenter Oulu, University of Oulu, Oulu, Finland.

    • Marika Kaakinen
    • , Ville Huikari
    • , Marjo-Riitta Jarvelin
    •  & Annneli Pouta
  12. Copenhagen Prospective Studies on Asthma in Childhood (COSPAC), Health Sciences, University of Copenhagen, Copenhagen University Hospital, Gentofte, Denmark.

    • Eskil Kreiner-Møller
    • , Klaus Bønnelykke
    • , Bo Lund Krogsgaard Chawes
    • , Anne Mølgaard
    • , Nadja Hawwa Vissing
    •  & Hans Bisgaard
  13. Center for Applied Genomics, Abramson Research Center, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.

    • Jonathan P Bradfield
    • , Cecilia E Kim
    • , Frank D Mentch
    • , Dexter Hadley
    • , Struan F A Grant
    • , Hakon Hakonarson
    •  & Rosetta M Chiavacci
  14. Genetics of Complex Traits, Peninsula College of Medicine and Dentistry, University of Exeter, Exeter, UK.

    • Rachel M Freathy
    • , Hanieh Yaghootkar
    •  & Tim Frayling
  15. Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark.

    • Frank Geller
    • , Bjarke Feenstra
    •  & Mads Melbye
  16. Center for Research in Environmental Epidemiology (CREAL), Barcelona, Spain.

    • Mònica Guxens
    •  & Jordi Sunyer
  17. Hospital del Mar Research Institute (IMIM), Barcelona, Spain.

    • Mònica Guxens
    •  & Jordi Sunyer
  18. Centro de Investigación Biomédica en Red en Epidemiologia y Salud Pública (CIBERESP), Barcelona, Spain.

    • Mònica Guxens
    • , Jordi Sunyer
    • , Xavier Estivill
    •  & Carmen Iñiguez
  19. Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland.

    • Diana L Cousminer
    • , Elisabeth Widen
    •  & Aarno Palotie
  20. Department of Epidemiology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.

    • Marjan Kerkhof
  21. Department of Radiology, Erasmus Medical Center, Rotterdam, The Netherlands.

    • M Arfan Ikram
    • , Henri A Vrooman
    • , Wiro J Niessen
    • , Aad van der Lugt
    •  & Meike W Vernooij
  22. Netherlands Consortium for Healthy Aging, Rotterdam, The Netherlands.

    • M Arfan Ikram
    • , Albert Hofman
    • , Cornelia M van Duijn
    •  & Monique M B Breteler
  23. School of Medicine and Pharmacology, The University of Western Australia, Perth, Western Australia, Australia.

    • Lawrence J Beilin
  24. Section of Investigative Medicine, Imperial College London, London, UK.

    • Jessica L Buxton
    • , Elina Hypponen
    •  & Alexandra I F Blakemore
  25. Department of Tropical Hygiene, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.

    • Pimphen Charoen
  26. Department of Chronic Disease Prevention, National Institute for Health and Welfare, Helsinki, Finland.

    • Johan Eriksson
  27. Department of General Practice and Primary Health Care, University of Helsinki, Helsinki, Finland.

    • Johan Eriksson
  28. Folkhalsan Research Centre, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland.

    • Johan Eriksson
  29. Research Unit for Molecular Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.

    • Norman Klopp
  30. Hannover Unified Biobank, Hannover Medical School, Hannover, Germany.

    • Norman Klopp
  31. Institute of Behavioural Sciences, University of Helsinki, Helsinki, Finland.

    • Jari Lahti
  32. Chair of Epidemiology, Institute of Medical Informatics, Biometry and Epidemiology, Ludwig-Maximilians-Universität, Munich, Germany.

    • Martina Müller-Nurasyid
    •  & H-Erich Wichmann
  33. Institute of Genetic Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.

    • Martina Müller-Nurasyid
  34. Department of Medicine I, University Hospital Grosshadern, Ludwig-Maximilians-Universität, Munich, Germany.

    • Martina Müller-Nurasyid
    •  & H-Erich Wichmann
  35. Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Churchill Hospital, Oxford, UK.

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

    • Inga Prokopenko
    • , Mark I McCarthy
    •  & Momoko Horikoshi
  37. Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands.

    • Fernando Rivadeneira
    •  & Andre G Uitterlinden
  38. Department of Obstetrics & Gynecology, Erasmus Medical Center, Rotterdam, The Netherlands.

    • Eric A P Steegers
  39. Department of Experimental and Health Sciences, Pompeu Fabra University (UPF), Barcelona, Spain.

    • Jordi Sunyer
    •  & Xavier Estivill
  40. Division of Metabolic Diseases and Nutritional Medicine, Dr Von Hauner Children's Hospital, Ludwig-Maximilians-Universität, Munich, Germany.

    • Carla Tiesler
  41. German Center for Neurologic Diseases (DZNE), Bonn, Germany.

    • Monique M B Breteler
  42. 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
  43. Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts, USA.

    • Sudha Seshadri
    • , Stéphanie Debette
    • , Anita L DeStefano
    •  & Alexa Beiser
  44. Institut de la Santé et la Recherche Médicale (INSERM), U708, Neuroepidemiology, Paris, France.

    • Stéphanie Debette
  45. Institute of Molecular Medicine, School of Public Health, University of Texas, Houston Health Sciences Center, Houston, Texas, USA.

    • Myriam Fornage
  46. Human Genetics Center, School of Public Health, University of Texas, Houston Health Sciences Center, Houston, Texas, USA.

    • Myriam Fornage
  47. Division of Epidemiology, School of Public Health, University of Texas, Houston Health Sciences Center, Houston, Texas, USA.

    • Myriam Fornage
  48. Icelandic Research Institute, Kopavogur, Iceland.

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

    • Albert V Smith
    •  & Vilmundur Gudnason
  50. Laboratory of Epidemiology, Demography and Biometry, National Institute on Aging, National Institutes of Health (NIH), Bethesda, Maryland, USA.

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

    • William M Meeks
    • , B Gwen Windham
    •  & Thomas H Mosley Jr
  52. The National Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, Massachusetts, USA.

    • Sudha Seshadri
    • , Anita L DeStefano
    • , Alexa Beiser
    •  & Philip A Wolf
  53. European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK.

    • Julio Fernandez-Banet
  54. Division of Human Genetics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.

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

    • Struan F A Grant
    •  & Hakon Hakonarson
  56. Institute of Clinical Medicine/Obstetrics and Gynecology, University of Oulu, Oulu, Finland.

    • Anna-Liisa Hartikainen
  57. Division of Environment and Health, Center for Public Health Research (CSISP), Valencia, Spain.

    • Carmen Iñiguez
  58. Comissariat à l'Energie Atomique, Centre National de Génotypage, Evry, France.

    • Mark Lathrop
  59. Foundation Jean Dausset, Centre d'Etude du Polymorphisme Humain (CEPH), Paris, France.

    • Mark Lathrop
  60. School of Social and Community Medicine, University of Bristol, Bristol, UK.

    • Wendy L McArdle
    •  & Susan M Ring
  61. Genetic Epidemiology and Biostatistics Platform, Ontario Institute for Cancer Research, Toronto, Ontario, Canada.

    • Lyle J Palmer
  62. Department of Medical Genetics, University of Helsinki, Helsinki, Finland.

    • Aarno Palotie
  63. Broad Institute of Harvard University and MIT, Cambridge, Massachusetts, USA.

    • Aarno Palotie
  64. Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK.

    • Aarno Palotie
    • , Kalliope Panoutsopoulou
    •  & Eleftheria Zeggini
  65. Department of Lifecourse and Services, National Institute for Health and Welfare, Oulu, Finland.

    • Marjo-Riitta Jarvelin
    •  & Annneli Pouta
  66. Department of Medical Statistics, London School of Hygiene and Tropical Medicine, London, UK.

    • Ulla Sovio
  67. Department of Neurology, University of California, Davis, Sacramento, California, USA.

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

    • Charles DeCarli
  69. Oxford National Institute for Health Research (NIHR) Biomedical Research Centre, Churchill Hospital, Oxford, UK.

    • Mark I McCarthy
  70. Department of Pediatric Pulmonology and Pediatric Allergology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.

    • Gerard H Koppelman
  71. Genes and Disease Program, Center for Genomic Regulation (CRG), UPF, Barcelona, Spain.

    • Xavier Estivill
  72. Peninsula NIHR Clinical Research Facility, Peninsula College of Medicine and Dentistry, University of Exeter, Exeter, UK.

    • Andrew T Hattersley
  73. MRC Health Protection Agency (HPA) Centre for Environment and Health, Imperial College London, London, UK.

    • Paul Elliott
    •  & Marjo-Riitta Jarvelin
  74. Department of Nutrition, University of North Carolina, Chapel Hill, North Carolina, USA.

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

    • Mustafa Atalay
    • , Virpi Lindi
    •  & Timo A Lakka
  76. Department of Biological Psychology, Vrije Universiteit (VU), Amsterdam, The Netherlands.

    • Toos van Beijsterveldt
    • , Maria Groen-Blokhuis
    • , Jouke Jan Hottenga
    • , Christel Middeldorp
    • , Michel Nivard
    • , Gonneke Willemsen
    •  & Dorret I Boomsma
  77. 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
  78. MRC Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, King's College London, London, UK.

    • Alina Rodriguez
    • , Oliver S P Davis
    • , Claire M A Haworth
    • , Jennifer Pararajasingham
    •  & Thomas S Price
  79. Duke–National University of Singapore (NUS) Graduate Medical School, Singapore.

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

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

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

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

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

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

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

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

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

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

    • John W Holloway
  90. Institute of Preventive Medicine, Copenhagen University Hospital, Copenhagen, Denmark.

    • Claus Holst
    •  & Ellen Aagaard Nohr
  91. Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark.

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

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

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

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

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

    • Terho Lehtimäki
  97. Genetic and Genomic Epidemiology Unit, The Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.

    • Cecilia Lindgren
    •  & Reedik Maggi
  98. Estonian Genome Center, University of Tartu, Tartu, Estonia.

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

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

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

    • Ioanna Ntalla
    •  & George V Dedoussis
  102. Department of Psychology, Mid Sweden University, Östersund, Sweden.

    • Alina Rodriguez
    •  & Olli Simell
  103. Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, Finland.

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

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

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

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

    • Berthold Hocher
  108. Center for Cardiovascular Research, Institute of Pharmacology, Charité–Universitätsmedizin Berlin, Berlin, Germany.

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

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

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

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

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

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

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

    • James F Wilson
  116. Department of Neurology, Medical University Graz, Graz, Austria.

    • Reinhold Schmidt
    • , Stefan Ropele
    •  & Rhoda Au
  117. Department of Medical Informatics, Erasmus Medical Center University Medical Center, Rotterdam, The Netherlands.

    • Henri A Vrooman
    •  & Wiro J Niessen
  118. Division of Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA.

    • Laura H Coker
  119. Department of Epidemiology, University of Washington, Seattle, Washington, USA.

    • W T Longstreth Jr
  120. Department of Neurology, University of Washington, Seattle, Washington, USA.

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

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

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

    • Clifford R Jack Jr
  124. Laboratory of Neurogenetics, National Institute on Aging, NIH, Bethesda, Maryland, USA.

    • Mike A Nalls
  125. Department of Radiology, Leiden University Medical Center, Leiden, The Netherlands.

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

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

    • Helena Schmidt

Consortia

  1. The Cohorts for Heart and Aging Research in Genetic Epidemiology (CHARGE) Consortium

  2. Early Genetics & Lifecourse Epidemiology (EAGLE) Consortium

  3. Early Growth Genetics (EGG) Consortium

Authors

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Contributions

Project design was carried out by H.R.T., J.P.B., F.G., M. Kerkhof, A.H., E.A.P.S., J.S., M.M.B.B., L.J.L., A.v.d.L., T.H.M., S.S., A.V.S., B.F., S.F.A.G., A.J.v.d.H., J.P.N., L.J.P., H.-E.W., C.D., M.I.M., G.H.K., X.E., A.T.H., M. Melbye, H.B., C.E.P., H.H., G.D.S., J.H., M.-R.J. and V.W.V.J. Sample collection and phenotyping was performed by H.R.T., M. Kaakinen, M.G., M. Kerkhof, M.A.I., K.B., B.L.K.C., J.E., F.D.M., I.P., J.S., S. Debette, M.F., V.G., S.S., M.W.V., J.F.-B., R.M.C., A.-L.H., C.I., A.M., J.P.N., A. Pouta., U.S., M.S., N.H.V., G.H.K., A.T.H., H.H., M.-R.J. and V.W.V.J. Genotyping was performed by R.M.F., L.J.B., J.L.B., C.E.K., S.J.L., N.K., M.M.-N., F.R., C.T., A.I.F.B., A.-L.H., M.L., W.L.M., J.P.N., L.J.P., A. Palotie, S.M.R., A.G.U., C.M.v.D., X.E., C.E.P., E.W. and M.-R.J. Statistical analysis was performed by H.R.T., B.S.P., E.T., S. Das, D.O.M.-K., N.M.W., M. Kaakinen, E.K.-M., J.P.B., R.M.F., F.G., D.L.C., M. Kerkhof, N.J.T., M.A.I., P.C., D.M.E., J.P.K., J.L., G.M., P.F.O., H.Y., S.S., B.F., S.F.A.G., U.S. and C.D. The manuscript was written by H.R.T., B.S.P., E.T., S. Das, D.O.M.-K., G.D.S., J.H., M.-R.J. and V.W.V.J. The EGG, EAGLE and CHARGE consortia provided the infrastructure for conducting the genome-wide association meta-analysis, collaboration and discussion.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to George Davey Smith or Joachim Heinrich or Marjo-Riitta Jarvelin or Vincent W V Jaddoe.

Supplementary information

PDF files

  1. 1.

    Supplementary Text and Figures

    Supplementary Tables 3–12, Supplementary Figures 1–3 and Supplementary Note

Excel files

  1. 1.

    Supplementary Table 1

    Basic characteristics, exclusions, genotyping, quality control and imputation in discovery studies

  2. 2.

    Supplementary Table 2

    Basic characteristics, exclusions, genotyping, quality control and imputation in replication studies

About this article

Publication history

Received

Accepted

Published

DOI

https://doi.org/10.1038/ng.2238

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