Identification of common variants associated with human hippocampal and intracranial volumes

Journal name:
Nature Genetics
Volume:
44,
Pages:
552–561
Year published:
DOI:
doi:10.1038/ng.2250
Received
Accepted
Published online

Identifying genetic variants influencing human brain structures may reveal new biological mechanisms underlying cognition and neuropsychiatric illness. The volume of the hippocampus is a biomarker of incipient Alzheimer's disease1, 2 and is reduced in schizophrenia3, major depression4 and mesial temporal lobe epilepsy5. Whereas many brain imaging phenotypes are highly heritable6, 7, identifying and replicating genetic influences has been difficult, as small effects and the high costs of magnetic resonance imaging (MRI) have led to underpowered studies. Here we report genome-wide association meta-analyses and replication for mean bilateral hippocampal, total brain and intracranial volumes from a large multinational consortium. The intergenic variant rs7294919 was associated with hippocampal volume (12q24.22; N = 21,151; P = 6.70 × 10−16) and the expression levels of the positional candidate gene TESC in brain tissue. Additionally, rs10784502, located within HMGA2, was associated with intracranial volume (12q14.3; N = 15,782; P = 1.12 × 10−12). We also identified a suggestive association with total brain volume at rs10494373 within DDR2 (1q23.3; N = 6,500; P = 5.81 × 10−7).

At a glance

Figures

  1. Association results and meta-analysis of effects in individual and combined analyses.
    Figure 1: Association results and meta-analysis of effects in individual and combined analyses.

    (a) The strongest association with hippocampal volume was found for rs7294919. Fixed-effects meta-analysis P values are shown41 after controlling for intracranial volume using all subjects in the discovery sample. (b) The strongest association with intracranial volume was found for rs10784502. Fixed-effects meta-analysis P values are shown in healthy subjects only. (c,d) The effect within each sample contributing to the meta-analysis is shown in forest plots for hippocampal volume (c) and intracranial volume (d). Association data using intracranial volume as a phenotype were not available for the EPIGEN sample. Head size was not controlled for in the CHARGE Consortium association analyses.

  2. Association of rs7294919 with hippocampal volume stratified by disease and covariates.
    Figure 2: Association of rs7294919 with hippocampal volume stratified by disease and covariates.

    Effects are consistent in the discovery sample regardless of whether individuals with disease (N = 7,795) or only healthy subjects (N = 5,775) were included. The effect is also consistent whether accounting for intracranial volume (ICV), total brain volume (TBV) or without a measure of head size (Other).

  3. Regulatory effects of hippocampal-associated variant and expression of TESC within the hippocampus.
    Figure 3: Regulatory effects of hippocampal-associated variant and expression of TESC within the hippocampus.

    (ad) The locus most associated with hippocampal volume was also associated with mRNA expression of the TESC gene in brain in three independent samples, the UCL epilepsy cohort (a), the SNPExpress database (b), where a proxy SNP was used, and the UK Brain Expression Database (d), where differences in TESC expression of the directly genotyped hippocampal variant (rs7294919) were strongest in the temporal cortex (TCTX) (red box) but also found in the average expression of all cortex (AvgCTX) and average expression of all brain structures tested (AvgALL). Symbol color represents genotype in a and d. These regional gradients in expression support the hypothesis that the SNP may associate with hippocampal but not total brain volume. No effects were detected in PBMCs from the SNPExpress database (c). CRBL, cerebellar cortex; FCTX, frontal cortex; HIPP, hippocampus; MEDU, medulla (specifically the inferior olivary nucleus); OCTX, occipital cortex; PUTM, putamen; SNIG, substantia nigra; THAL, thalamus; WHMT, intralobular white matter. (e) TESC is differentially expressed within the fetal human brain (P = 1.33 × 10−12), with the highest expression in striatum (STRIAT) and hippocampus (HIPP)42. Box plots represent median and 25th to 75th percentiles. Upper and lower lines show minimum and maximum values, respectively. CBLM, cerebellum; DLPFC, dorsolateral prefrontal neocortex; MPFC, medial prefrontal neocortex; MS, motor-somatosensory neocortex; OCC, occipital visual neocortex; OFC, orbital prefrontal neocortex; PAS, parietal association neocortex; TAC, temporal association neocortex; TAU, temporal auditory neocortex; THAL, mediodorsal thalamus; VLPFC, ventrolateral prefrontal neocortex. (f) TESC has moderate to high gene expression throughout the adult human hippocampus (shown in green), as visualized in the Allen Institute Human Brain Atlas using Brain Explorer 2 software. An inferior view of the brain is shown in two subjects; the anterior portion of the brain is at the top. The colors of spheres within the hippocampus indicate the Z-scores of TESC expression normalized within each subject across brain structures. Heat maps show that expression of TESC is higher in the hippocampus (HiF) and striatum (Str) than in other brain structures.

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Author information

  1. These authors contributed equally to this work.

    • Jason L Stein,
    • Sarah E Medland,
    • Alejandro Arias Vasquez &
    • Derrek P Hibar
  2. These authors jointly directed this work.

    • Nicholas G Martin,
    • Barbara Franke,
    • Margaret J Wright &
    • Paul M Thompson
  3. These authors contributed equally to this work.

    • the Enhancing Neuro Imaging Genetics through Meta-Analysis (ENIGMA) Consortium

Affiliations

  1. Laboratory of Neuro Imaging, David Geffen School of Medicine, University of California, Los Angeles, California, USA.

    • Jason L Stein,
    • Derrek P Hibar,
    • Rudy E Senstad,
    • Kristy S Hwang,
    • Neda Jahanshad,
    • Arthur W Toga,
    • Liana G Apostolova &
    • Paul M Thompson
  2. Genetic Epidemiology Laboratory, Queensland Institute of Medical Research, Brisbane, Queensland, Australia.

    • Sarah E Medland,
    • Narelle K Hansell,
    • Miguel E Rentería,
    • Grant W Montgomery,
    • Meike W Vernooij,
    • Nicholas G Martin &
    • Margaret J Wright
  3. Quantitative Genetics Laboratory, Queensland Institute of Medical Research, Brisbane, Queensland, Australia.

    • Sarah E Medland
  4. Broad Institute of Harvard University and MIT, Cambridge, Massachusetts, USA.

    • Sarah E Medland
  5. Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.

    • Alejandro Arias Vasquez,
    • Martine Hoogman,
    • Joris A Veltman,
    • Han G Brunner &
    • Barbara Franke
  6. Department of Psychiatry, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.

    • Alejandro Arias Vasquez &
    • Barbara Franke
  7. Donders Institute for Brain, Cognition and Behaviour, Radboud University Nijmegen, Nijmegen, The Netherlands.

    • Alejandro Arias Vasquez,
    • Mark Rijpkema,
    • Martine Hoogman,
    • Peter Hagoort,
    • Guillén Fernández &
    • Barbara Franke
  8. Olin Neuropsychiatry Research Center, Institute of Living, Hartford Hospital, Hartford, Connecticut, USA.

    • Anderson M Winkler &
    • David C Glahn
  9. Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut, USA.

    • Anderson M Winkler &
    • David C Glahn
  10. Laboratory of Human Genetics and Cognitive Functions, Institut Pasteur, Paris, France.

    • Roberto Toro
  11. Centre Nationale de Recherche Scientifique (CNRS) Unité de Recherche Associée (URA) 2182 Genes, Synapses and Cognition, Institut Pasteur, Paris, France.

    • Roberto Toro
  12. Department of Neuroscience, Université Paris Diderot, Sorbonne Paris Cité, Paris, France.

    • Roberto Toro
  13. Department of Psychiatry and Psychotherapy, University of Greifswald, Greifswald, Germany.

    • Katja Appel,
    • Katharina Wittfeld &
    • Hans J Grabe
  14. Institute of Psychology, Department of Clinical Psychology and Psychotherapy, University of Heidelberg, Heidelberg, Germany.

    • Katja Appel
  15. Department of Psychiatry, Rudolf Magnus Institute, University Medical Center Utrecht, Utrecht, The Netherlands.

    • Richard Bartecek,
    • René Mandl,
    • Hugo G Schnack,
    • Martijn Van den Heuvel,
    • Neeltje E M Van Haren,
    • Hilleke E Hulshoff Pol,
    • René S Kahn &
    • Roel A Ophoff
  16. Institute of Clinical Medicine, University of Oslo, Oslo, Norway.

    • Ørjan Bergmann,
    • Andrew A Brown,
    • Morten Mattingsdal,
    • Ingrid Melle,
    • Ingrid Agartz,
    • Srdjan Djurovic &
    • Ole A Andreassen
  17. The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.

    • Manon Bernard &
    • Zdenka Pausova
  18. Institute of Basic Medical Sciences, Department of Biostatistics, University of Oslo, Oslo, Norway.

    • Andrew A Brown
  19. Clinical Neuroimaging Laboratory, Department of Anatomy, National University of Ireland Galway, Galway, Ireland.

    • Dara M Cannon
  20. Clinical Neuroimaging Laboratory, Department of Psychiatry, National University of Ireland Galway, Galway, Ireland.

    • Camilla Langan &
    • Colm McDonald
  21. Rotman Research Institute, University of Toronto, Toronto, Ontario, Canada.

    • M Mallar Chakravarty &
    • Tomas Paus
  22. Dr Einar Martens Research Group for Biological Psychiatry, Department of Clinical Medicine, University of Bergen, Bergen, Norway.

    • Andrea Christoforou,
    • Vidar M Steen &
    • Stephanie Le Hellard
  23. Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway.

    • Andrea Christoforou,
    • Vidar M Steen &
    • Stephanie Le Hellard
  24. Department of Diagnostic Radiology and Neuroradiology, University of Greifswald, Greifswald, Germany.

    • Martin Domin,
    • Norbert Hosten &
    • Ralf Puls
  25. Central Institute of Mental Health, University of Heidelberg–Medical Faculty Mannheim, Mannheim, Germany.

    • Oliver Grimm,
    • Marcella Rietschel &
    • Andreas Meyer-Lindenberg
  26. Department of Psychology, Center for Brain Science, Harvard University, Cambridge, Massachusetts, USA.

    • Marisa Hollinshead,
    • Avram J Holmes &
    • Randy L Buckner
  27. Howard Hughes Medical Institute, Cambridge, Massachusetts, USA.

    • Marisa Hollinshead &
    • Randy L Buckner
  28. Interfaculty Institute for Genetics and Functional Genomics, University of Greifswald, Greifswald, Germany.

    • Georg Homuth &
    • Alexander Teumer
  29. Department of Biological Psychology, Neuroscience Campus Amsterdam, VU University, Amsterdam, The Netherlands.

    • Jouke-Jan Hottenga,
    • Dorret I Boomsma &
    • Eco J C de Geus
  30. Centre for Cognitive Ageing and Cognitive Epidemiology, The University of Edinburgh, Edinburgh, UK.

    • Lorna M Lopez,
    • Susana Muñoz Maniega,
    • David C Liewald,
    • Natalie A Royle,
    • Maria C Valdés Hernández,
    • David J Porteous,
    • John M Starr,
    • Mark E Bastin,
    • Ian J Deary &
    • Joanna M Wardlaw
  31. Department of Psychology, The University of Edinburgh, Edinburgh, UK.

    • Lorna M Lopez,
    • Gail Davies &
    • Ian J Deary
  32. Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, California, USA.

    • Kristy S Hwang,
    • Liana G Apostolova &
    • Giovanni Coppola
  33. Department of Radiology and Imaging Sciences, Center for Neuroimaging, Indiana University School of Medicine, Indianapolis, Indiana, USA.

    • Sungeun Kim,
    • Kwangsik Nho,
    • Shannon L Risacher,
    • Li Shen &
    • Andrew J Saykin
  34. Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, Indiana, USA.

    • Sungeun Kim,
    • Li Shen,
    • Tatiana M Foroud &
    • Andrew J Saykin
  35. Mood and Anxiety Disorders Section, Human Genetics Branch, Intramural Research Program, National Institute of Mental Health (NIMH), US National Institutes of Health (NIH), US Department of Health and Human Services, Bethesda, Maryland, USA.

    • Gonzalo Laje,
    • Xinmin Liu &
    • Francis J McMahon
  36. Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, USA.

    • Phil H Lee,
    • David G Brohawn,
    • Jesen Fagerness &
    • Jordan W Smoller
  37. Department of Psychiatry, Massachusetts General Hospital, Boston, Massachusetts, USA.

    • Phil H Lee,
    • Joshua L Roffman,
    • Randy L Buckner &
    • Jordan W Smoller
  38. Taub Institute for Research on Alzheimer Disease and the Aging Brain, Columbia University Medical Center, New York, New York, USA.

    • Xinmin Liu
  39. Medical Research Council (MRC)–Social, Genetic and Developmental Psychiatry (SGDP) Centre, Institute of Psychiatry, King's College London, London, UK.

    • Eva Loth,
    • Anbarasu Lourdusamy &
    • Gunter Schumann
  40. Research Unit, Sørlandet Hospital, Kristiansand, Norway.

    • Morten Mattingsdal
  41. Department of Psychiatry and Psychotherapy, Charité-Universitaetsmedizin Berlin, Campus Mitte, Berlin, Germany.

    • Sebastian Mohnke,
    • Susanne Erk,
    • Nina Seiferth,
    • Andreas Heinz &
    • Henrik Walter
  42. Scottish Imaging Network, A Platform for Scientific Excellence (SINAPSE) Collaboration, UK.

    • Susana Muñoz Maniega,
    • Natalie A Royle,
    • Maria C Valdés Hernández,
    • Mark E Bastin &
    • Joanna M Wardlaw
  43. Brain Research Imaging Centre, The University of Edinburgh, Edinburgh, UK.

    • Susana Muñoz Maniega,
    • Natalie A Royle,
    • Maria C Valdés Hernández,
    • Mark E Bastin &
    • Joanna M Wardlaw
  44. Division of Medical Informatics, Regenstrief Institute, Indianapolis, Indiana, USA.

    • Kwangsik Nho
  45. Section on Neuroimaging in Mood and Anxiety Disorders, Intramural Research Program, NIMH, NIH, US Department of Health and Human Services, Bethesda, Maryland, USA.

    • Allison C Nugent,
    • Jonathan Savitz &
    • Wayne C Drevets
  46. Neuropsychiatric Genetics Research Group, Department of Psychiatry, Institute for Molecular Medicine, Trinity College, Dublin, Ireland.

    • Carol O'Brien,
    • Emma J Rose,
    • Aiden Corvin,
    • Michael Gill,
    • Gary Donohoe &
    • Derek W Morris
  47. Trinity College Institute of Neuroscience, Trinity College, Dublin, Ireland.

    • Carol O'Brien,
    • Emma J Rose,
    • Aiden Corvin,
    • Michael Gill,
    • Gary Donohoe &
    • Derek W Morris
  48. Division of Psychiatry, University of Edinburgh, Royal Edinburgh Hospital, Edinburgh, UK.

    • Martina Papmeyer,
    • Emma Sprooten,
    • Stephen M Lawrie,
    • Jeremy Hall,
    • Jessika Sussmann &
    • Andrew M McIntosh
  49. Max Planck Institute of Psychiatry, Munich, Germany.

    • Benno Pütz,
    • Christiane Wolf,
    • Elisabeth B Binder,
    • Michael Czisch,
    • David Hoehn,
    • Florian Holsboer,
    • Bertram Müller-Myhsok &
    • Philipp G Sämann
  50. Department of Medical & Molecular Genetics, King's College London, London, UK.

    • Adaikalavan Ramasamy &
    • Michael E Weale
  51. Department of Psychiatry and Human Behavior, University of California, Irvine, California, USA.

    • Jerod Rasmussen,
    • Theo G M van Erp,
    • Fabio Macciardi &
    • Steven G Potkin
  52. Department of Neurosciences, University of California, San Diego, La Jolla, California, USA.

    • Mark Rijpkema,
    • Peter Hagoort &
    • Guillén Fernández
  53. Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.

    • J Cooper Roddey &
    • Anders M Dale
  54. Department of Molecular Neuroscience, University College London, London, UK.

    • Mina Ryten,
    • Daniah Trabzuni &
    • John Hardy
  55. Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.

    • Eric Strengman &
    • Kristel van Eijk
  56. Rudolf Magnus Institute, University Medical Center Utrecht, Utrecht, The Netherlands.

    • Eric Strengman &
    • Kristel van Eijk
  57. Department of Genetics, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.

    • Daniah Trabzuni
  58. Mind Research Network, Albuquerque, New Mexico, USA.

    • Jessica Turner
  59. Department of Psychiatry, Leiden University Medical Center, Leiden, The Netherlands.

    • Marie-Jose van Tol,
    • Nic J van der Wee &
    • Brenda W Penninx
  60. Leiden Institute for Brain and Cognition, Leiden University, Leiden, The Netherlands.

    • Marie-Jose van Tol,
    • Nic J van der Wee &
    • Brenda W Penninx
  61. Behavioural and Cognitive Neuroscience Neuroimaging Center, University Medical Center Groningen, Groningen, The Netherlands.

    • Marie-Jose van Tol &
    • Andre Aleman
  62. Department of Psychiatry, VU University Medical Center, Amsterdam, The Netherlands.

    • Saskia Woudstra,
    • Dick J Veltman &
    • Brenda W Penninx
  63. Department of Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland, Dublin, Ireland.

    • Saud Alhusaini,
    • Norman Delanty,
    • Christopher D Whelan &
    • Gianpiero L Cavalleri
  64. Department of Genetics, Texas Biomedical Research Institute, San Antonio, Texas, USA.

    • Laura Almasy,
    • Melanie A Carless,
    • Joanne E Curran,
    • Marcio A A de Almeida,
    • Ravi Duggirala,
    • Thomas D Dyer,
    • Harald H H Göring,
    • Matthew P Johnson,
    • Jack W Kent Jr,
    • Eric K Moses &
    • John Blangero
  65. Center for Neurobehavioral Genetics, University of California, Los Angeles, USA.

    • Rita M Cantor,
    • Nelson B Freimer &
    • Roel A Ophoff
  66. Division of Neurology, Beaumont Hospital, Dublin, Ireland.

    • Norman Delanty
  67. Department of Neurology, Hopital Erasme, Universite Libre de Bruxelles, Brussels, Belgium.

    • Chantal Depondt &
    • Massimo Pandolfo
  68. Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Boston, Massachusetts, USA.

    • Randy L Buckner
  69. Research Imaging Institute, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA.

    • Peter T Fox,
    • Peter Kochunov &
    • Jack L Lancaster
  70. Department of Radiology, University of California, San Diego, La Jolla, California, USA.

    • Donald J Hagler &
    • Anders M Dale
  71. Department of Cognitive Neuroscience, Radboud University Nijmegen Medical Centre, The Netherlands.

    • Martine Hoogman &
    • Guillén Fernández
  72. Max Planck Institute for Psycholinguistics, Nijmegen, The Netherlands.

    • Martine Hoogman &
    • Peter Hagoort
  73. Department of Clinical and Experimental Epilepsy, University College London, Institute of Neurology, London, UK.

    • Dalia Kasperaviciute,
    • Mar Matarin &
    • Sanjay M Sisodiya
  74. Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, Maryland, USA.

    • Peter Kochunov
  75. Department of Genomics, Life and Brain Center, University of Bonn, Bonn, Germany.

    • Manuel Mattheisen,
    • Thomas W Mühleisen,
    • Markus M Nöthen &
    • Sven Cichon
  76. Institute of Human Genetics, University of Bonn, Bonn, Germany.

    • Manuel Mattheisen,
    • Thomas W Mühleisen,
    • Markus M Nöthen &
    • Sven Cichon
  77. Institute for Genomic Mathematics, University of Bonn, Bonn, Germany

    • Manuel Mattheisen
  78. Department of Psychiatry, Ludwig-Maximilians-University (LMU), Munich, Germany.

    • Eva Meisenzahl &
    • Dan Rujescu
  79. Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway.

    • Ingrid Melle &
    • Ole A Andreassen
  80. Institute of Clinical Chemistry and Laboratory Medicine, University of Greifswald, Greifswald, Germany.

    • Matthias Nauck
  81. German Center for Neurodegenerative Disorders (DZNE), Bonn, Germany.

    • Markus M Nöthen
  82. Department of Psychiatry, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA.

    • Rene L Olvera
  83. Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada.

    • G Bruce Pike
  84. Center for the Study of Human Cognition, Department of Psychology, University of Oslo, Oslo, Norway.

    • Ivar Reinvang,
    • Lars T Westlye &
    • Thomas Espeseth
  85. Centre for Advanced Study, Oslo, Norway.

    • Ivar Reinvang &
    • Thomas Espeseth
  86. School of Psychology, University of Queensland, Brisbane, Queensland, Australia.

    • Miguel E Rentería &
    • Greig I de Zubicaray
  87. Laureate Institute for Brain Research, Tulsa, Oklahoma, USA.

    • Jonathan Savitz &
    • Wayne C Drevets
  88. Department of General Psychiatry, Heidelberg University Hospital, University of Heidelberg, Heidelberg, Germany.

    • Knut Schnell
  89. Department of Psychiatry, Division of Medical Psychology, Bonn, Germany.

    • Knut Schnell &
    • Henrik Walter
  90. The MRC Sudden Death Tissue Bank in Edinburgh, Department of Pathology, University of Edinburgh, Edinburgh, UK.

    • Colin Smith &
    • Robert Walker
  91. Institute for Community Medicine, University of Greifswald, Greifswald, Germany.

    • Henry Völzke
  92. Department of Research and Development, Diakonhjemmet Hospital, Oslo, Norway.

    • Ingrid Agartz
  93. Department of Medical Genetics, Oslo University Hospital, Oslo, Norway.

    • Srdjan Djurovic
  94. Aging and Dementia Imaging Research Laboratory, Department of Radiology, Mayo Clinic and Foundation, Rochester, Minnesota, USA.

    • Clifford R Jack Jr
  95. Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana, USA.

    • Tatiana M Foroud &
    • Andrew J Saykin
  96. Neurospin, Institut d'Imagerie Biomédicale (I2BM), Commissariat à l'Energie Atomique, Gif-sur-Yvette, France.

    • Jean Baptiste Poline
  97. Medical Genetics Section, Molecular Medicine Centre, Institute of Genetics and Molecular Medicine, The University of Edinburgh, Western General Hospital, Edinburgh, UK.

    • David J Porteous
  98. Geriatric Medicine Unit, The University of Edinburgh, Royal Victoria Hospital, Edinburgh, UK.

    • John M Starr
  99. Departments of Radiology, University of California, San Francisco, California, USA.

    • Michael W Weiner
  100. Department of Medicine, University of California, San Francisco, California, USA.

    • Michael W Weiner
  101. Department of Psychiatry, University of California, San Francisco, California, USA.

    • Michael W Weiner
  102. Veterans Affairs Medical Center, San Francisco, California, USA.

    • Michael W Weiner
  103. Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, Washington, USA.

    • Joshua C Bis
  104. Department of Epidemiology, Erasmus Medical Center University Medical Center, Rotterdam, The Netherlands.

    • M Arfan Ikram
  105. Department of Radiology, Erasmus Medical Center University Medical Center, Rotterdam, The Netherlands.

    • M Arfan Ikram
  106. Netherlands Consortium for Healthy Aging, Leiden, The Netherlands.

    • M Arfan Ikram
  107. Icelandic Heart Association, Kopavogur, Iceland.

    • Albert V Smith &
    • Vilmundur Gudnason
  108. Faculty of Medicine, University of Iceland, Reykjavik, Iceland.

    • Albert V Smith &
    • Vilmundur Gudnason
  109. Center of Neuroscience, University of California, Davis, Sacramento, California, USA

    • Christophe Tzourio
  110. Institut National de la Santé et la Recherche Médicale (INSERM), Neuroepidemiology, U708, Bordeaux, France.

    • Christophe Tzourio
  111. Laboratory of Epidemiology, Demography, and Biometry, NIH, Bethesda, Maryland, USA.

    • Lenore J Launer
  112. Department of Neurology, University of California, Davis, Sacramento, California, USA.

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

    • Charles DeCarli
  114. Department of Neurology, Boston University School of Medicine, Boston, Massachusetts, USA.

    • Sudha Seshadri
  115. National Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, Massachusetts, USA.

    • Sudha Seshadri
  116. Division of Health Sciences (Medical Physics), The University of Edinburgh, Edinburgh, UK.

    • Mark E Bastin
  117. Institute for Neuroscience and Medicine (INM-1), Research Center Juelich, Juelich, Germany.

    • Sven Cichon
  118. Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine, University of California, Los Angeles, California, USA.

    • Giovanni Coppola
  119. Department of Biological and Medical Psychology, Faculty of Psychology, University of Bergen, Bergen, Norway.

    • Thomas Espeseth
  120. German Center for Neurodegenerative Diseases (DZNE), Rostock/Greifswald, Greifswald, Germany.

    • Hans J Grabe
  121. Functional Magnetic Resonance Imaging of the Brain (FMRIB) Centre, Oxford University, Oxford, UK.

    • Mark Jenkinson &
    • Thomas E Nichols
  122. Centre for Advanced Imaging, University of Queensland, Brisbane, Queensland, Australia.

    • Katie L McMahon
  123. Department of Statistics, University of Warwick, Coventry, UK.

    • Thomas E Nichols
  124. Department of Psychiatry, University Medical Center Groningen, Groningen, The Netherlands.

    • Brenda W Penninx

Consortia

  1. the Alzheimer's Disease Neuroimaging Initiative (ADNI)

  2. A full list of members is provided in the Supplementary Note.

  3. EPIGEN Consortium

  4. A full list of members is provided in the Supplementary Note.

  5. IMAGEN Consortium

  6. A full list of members is provided in the Supplementary Note.

  7. Saguenay Youth Study Group (SYS)

  8. A full list of members is provided in the Supplementary Note.

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

  10. A full list of members is provided in the Supplementary Note.

  11. the Enhancing Neuro Imaging Genetics through Meta-Analysis (ENIGMA) Consortium

    • Ole A Andreassen,
    • Liana G Apostolova,
    • Mark E Bastin,
    • John Blangero,
    • Han G Brunner,
    • Randy L Buckner,
    • Sven Cichon,
    • Giovanni Coppola,
    • Greig I de Zubicaray,
    • Ian J Deary,
    • Gary Donohoe,
    • Eco J C de Geus,
    • Thomas Espeseth,
    • Guillén Fernández,
    • David C Glahn,
    • Hans J Grabe,
    • John Hardy,
    • Hilleke E Hulshoff Pol,
    • Mark Jenkinson,
    • René S Kahn,
    • Colm McDonald,
    • Andrew M McIntosh,
    • Francis J McMahon,
    • Katie L McMahon,
    • Andreas Meyer-Lindenberg,
    • Derek W Morris,
    • Bertram Müller-Myhsok,
    • Thomas E Nichols,
    • Roel A Ophoff,
    • Tomas Paus,
    • Zdenka Pausova,
    • Brenda W Penninx,
    • Steven G Potkin,
    • Philipp G Sämann,
    • Andrew J Saykin,
    • Gunter Schumann,
    • Jordan W Smoller,
    • Joanna M Wardlaw,
    • Michael E Weale,
    • Nicholas G Martin,
    • Barbara Franke,
    • Margaret J Wright &
    • Paul M Thompson

Contributions

The ENIGMA support group designed the project, established the consortium, determined the analysis and quality control procedures, offered analytical support and performed and coordinated cross-site and replication analyses. This group included J.L.S., S.E.M., A.A.V., D.P.H., M.J.W., B.F., N.G.M. and P.M.T. The imaging protocols group determined and refined protocols for computing brain measures from the MRI scans and helped sites implement them as needed. This group included J.L.S., R.T., A.M.W., T.E.N., M.J. and M. Rijpkema. The genetics protocols group created analysis methods for imputation, quality control and association testing of genome-wide data and helped to ensure that protocols were implemented consistently across all sites. This group included S.E.M., J.L.S., A.A.V. and D.P.H. The meta-analysis was carried out by the meta-analysis group, consisting of S.E.M., R.E.S., J.L.S., D.P.H., A.A.V., M.J.W., N.G.M., B.F. and P.M.T. The first draft was written by J.L.S., S.E.M., A.A.V., D.P.H., M.J.W., B.F., N.G.M. and P.M.T. Local image processing, involving statistical analysis and analysis of the data, was performed by J.L.S., A.M.W., D.P.H., R.B., Ø.B., M.M.C., O.G., M. Hollinshead, A.J.H., S.M.M., A.C.N., M. Rijpkema, N.A.R., M.C.V.H., T.G.M.v.E., S.W., D.G.B., S.L.R., J.L.R., M.-J.v.T., S.E., P.T.F., P.K., J.L.L., R.M., G.B.P., J. Savitz, H.G.S., K.S., A.W.T., M.V.d.H., N.J.v.d.W., N.E.M.V.H., H.W., A.M.D., C.R.J., D.J.V., E.J.C.d.G., G.I.d.Z., T.E., G.F., P.H., H.E.H.P., K.L.M., A.J.S., L.S., J.B., D.C.G., K.N., E.L., A.M.-L., P.G.S., L.G.A., K.S.H., T.P., M.D., R.P., N.H., K.W., I.A., Ø.B., A.M.D., D.H., M.C., S.A., N.D., C. Depondt, M. Pandolfo, E.J.R., D.M.C., J.C.R., J.R., J.T., R.T., C.L., S.M., A.H., C.D.W., N.J., D.J.H., L.T.W. and M. Hoogman. Local genetics processing, involving statistical analysis and analysis of the data, was performed by J.L.S., S.E.M., A.A.V., A.M.W., D.P.H., M.B., A.A.B., A. Christoforou, G. Davies, J.-J.H., L.M.L., G.L., P.H.L., D.C.L., X.L., M. Mattingsdal, K.N., E. Strengman, K.v.E., T.G.M.v.E., S.W., S.K., L.A., R.M.C., M.A.C., J.E.C., R.D., T.D.D., N.B.F., H.H.H.G., M.P.J., J.W.K., M. Mattheisen, E.K.M., T.W.M., M.M.N., M. Rietschel, V.M.S., A.W.T., J.A.V., S.C., S.D., T.M.F., P.H., S.L.H., G.W.M., O.A.A., H.G.B., R.A.O., B.W.P., A.J.S., L.S., J.B., D.C.G., M.J.W., N.G.M., A.L., E.B.B., C.W., B.P., B.M.-M., G.C., Z.P., G.H., M.N., A.T., D.K., M. Matarin, S.M.S., G.L.C., N.K.H., M.E.R., D.W.M., C.O., A. Corvin, M.G., J.F., J.C.R., A.R., M. Ryten, D.T., N.S., C.S., R.W., J. Hardy, M.E.W. and M.A.A.d.A. Local study oversight and management, involving joint supervision of research, contribution of reagents, materials and/or analysis tools, was carried out by R.L.B., R.D., P.T.F., R.S.K., I.M., R.L.O., I.R., I.A., W.C.D., P.H., F.M., A.M.-L., D.J.P., S.G.P., J.M.S., M.W.W., O.A.A., M.E.B., H.G.B., E.J.C.d.G., I.J.D., G.I.d.Z., T.E., G.F., H.E.H.P., F.J.M., K.L.M., R.A.O., T.P., Z.P., B.W.P., A.J.S., L.S., J.W.S., J.M.W., J.B., D.C.G., M.J.W., B.F., P.M.T., A.M.M., J. Hall, M. Papmeyer, E. Sprooten, J. Sussmann, S.M.L., J.B.P., L.G.A., G.C., D.R., E.M., G.S., K.S.H., P.G.S., E.B.B., D.I.B., H.J.G., H.V., K.A., C.M., G. Donohoe, F.H., A.V.S., V.G., C.T., M.W.V., L.J.L., C. DeCarli, S.S., J.C.B., M.A.I., A.A. and J. Hardy.

A full list of members is provided in the Supplementary Note.

the Alzheimer's Disease Neuroimaging Initiative (ADNI)

EPIGEN Consortium

IMAGEN Consortium

Saguenay Youth Study Group (SYS)

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

Competing financial interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to:

Author details

Supplementary information

PDF files

  1. Supplementary Text and Figures (26M)

    Supplementary Note, Supplementary Figures 1–44 and Supplementary Tables 1–27

Additional data