Original Article | Published:

A novel Alzheimer disease locus located near the gene encoding tau protein

Molecular Psychiatry volume 21, pages 108117 (2016) | Download Citation

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Abstract

APOE ɛ4, the most significant genetic risk factor for Alzheimer disease (AD), may mask effects of other loci. We re-analyzed genome-wide association study (GWAS) data from the International Genomics of Alzheimer’s Project (IGAP) Consortium in APOE ɛ4+ (10 352 cases and 9207 controls) and APOE ɛ4− (7184 cases and 26 968 controls) subgroups as well as in the total sample testing for interaction between a single-nucleotide polymorphism (SNP) and APOE ɛ4 status. Suggestive associations (P<1 × 10-4) in stage 1 were evaluated in an independent sample (stage 2) containing 4203 subjects (APOE ɛ4+: 1250 cases and 536 controls; APOE ɛ4−: 718 cases and 1699 controls). Among APOE ɛ4− subjects, novel genome-wide significant (GWS) association was observed with 17 SNPs (all between KANSL1 and LRRC37A on chromosome 17 near MAPT) in a meta-analysis of the stage 1 and stage 2 data sets (best SNP, rs2732703, P=5·8 × 10−9). Conditional analysis revealed that rs2732703 accounted for association signals in the entire 100-kilobase region that includes MAPT. Except for previously identified AD loci showing stronger association in APOE ɛ4+ subjects (CR1 and CLU) or APOE ɛ4− subjects (MS4A6A/MS4A4A/MS4A6E), no other SNPs were significantly associated with AD in a specific APOE genotype subgroup. In addition, the finding in the stage 1 sample that AD risk is significantly influenced by the interaction of APOE with rs1595014 in TMEM106B (P=1·6 × 10−7) is noteworthy, because TMEM106B variants have previously been associated with risk of frontotemporal dementia. Expression quantitative trait locus analysis revealed that rs113986870, one of the GWS SNPs near rs2732703, is significantly associated with four KANSL1 probes that target transcription of the first translated exon and an untranslated exon in hippocampus (P1.3 × 10-8), frontal cortex (P1.3 × 10-9) and temporal cortex (P1.2 × 10−11). Rs113986870 is also strongly associated with a MAPT probe that targets transcription of alternatively spliced exon 3 in frontal cortex (P=9.2 × 10−6) and temporal cortex (P=2.6 × 10−6). Our APOE-stratified GWAS is the first to show GWS association for AD with SNPs in the chromosome 17q21.31 region. Replication of this finding in independent samples is needed to verify that SNPs in this region have significantly stronger effects on AD risk in persons lacking APOE ɛ4 compared with persons carrying this allele, and if this is found to hold, further examination of this region and studies aimed at deciphering the mechanism(s) are warranted.

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Acknowledgements

ADGC

The National Institutes of Health, National Institute on Aging (NIH-NIA) supported this work through the following grants: ADGC, U01 AG032984, RC2 AG036528; NACC, U01 AG016976; NCRAD, U24 AG021886; NIAGADS, U24-AG041689; NIA LOAD, U24 AG026395, U24 AG026390; MIRAGE: R01 AG025259; Banner Sun Health Research Institute P30 AG019610; Boston University, P30 AG013846, U01 AG10483, R01 CA129769, R01 MH080295, R01 AG017173, R01AG33193; Columbia University, P50 AG008702, R37 AG015473; Duke University, P30 AG028377, AG05128; Emory University, AG025688; Group Health Research Institute, UO1 AG06781, UO1 HG004610; U01 HG006375; Indiana University, P30 AG10133; Johns Hopkins University, P50 AG005146, R01 AG020688; Massachusetts General Hospital, P50 AG005134; Mayo Clinic, P50 AG016574; Mount Sinai School of Medicine, P50 AG005138, P01 AG002219; New York University, P30 AG08051, MO1RR00096, and UL1 RR029893; Northwestern University, P30 AG013854; Oregon Health & Science University, P30 AG008017, R01 AG026916; Rush University, P30 AG010161, R01 AG019085, R01 AG15819, R01 AG17917, R01 AG30146; TGen, R01 NS059873; University of Alabama at Birmingham, P50 AG016582, UL1RR02777; University of Arizona, R01 AG031581; University of California, Davis, P30 AG010129; University of California, Irvine, P50 AG016573, P50, P50 AG016575, P50 AG016576, P50 AG016577; University of California, Los Angeles, P50 AG016570; University of California, San Diego, P50 AG005131; University of California, San Francisco, P50 AG023501, P01 AG019724; University of Kentucky, P30 AG028383; University of Michigan, P50 AG008671; University of Pennsylvania, P30 AG010124; University of Pittsburgh, P50 AG005133, AG030653, AG041718; University of Southern California, P50 AG005142; University of Texas Southwestern, P30 AG012300; University of Miami, R01 AG027944, AG010491, AG027944, AG021547, AG019757; University of Washington, P50 AG005136; Vanderbilt University, R01 AG019085; and Washington University, P50 AG005681, P01 AG03991. The Kathleen Price Bryan Brain Bank at Duke University Medical Center is funded by NINDS grant no. NS39764, NIMH MH60451 and by Glaxo Smith Kline. Genotyping of the TGEN2 cohort was supported by Kronos Science. The TGen series was also funded by NIA grant AG034504 to AJM, The Banner Alzheimer’s Foundation, The Johnnie B. Byrd Sr. Alzheimer’s Institute, the Medical Research Council, and the state of Arizona and also includes samples from the following sites: Newcastle Brain Tissue Resource (funding via the Medical Research Council, local NHS trusts and Newcastle University), MRC London Brain Bank for Neurodegenerative Diseases (funding via the Medical Research Council),SouthWest Dementia Brain Bank (funding via numerous sources, including the Higher Education Funding Council for England (HEFCE), Alzheimer’s Research Trust (ART), BRACE as well as North Bristol NHS Trust Research and Innovation Department and DeNDRoN), The Netherlands Brain Bank (funding via numerous sources, including Stichting MS Research, Brain Net Europe, Hersenstichting Nederland Breinbrekend Werk, International Parkinson Fonds, Internationale Stiching Alzheimer Onderzoek), Institut de Neuropatologia, Servei Anatomia Patologica, Universitat de Barcelona. Marcelle Morrison-Bogorad, PhD, Tony Phelps, PhD and Walter Kukull PhD are thanked for helping to co-ordinate this collection. ADNI Funding for ADNI is through the Northern California Institute for Research and Education by grants from Abbott, AstraZeneca AB, Bayer Schering Pharma AG, Bristol-Myers Squibb, Eisai Global Clinical Development, Elan Corporation, Genentech, GE Healthcare, GlaxoSmithKline, Innogenetics, Johnson and Johnson, Eli Lilly, Medpace, Merck, Novartis AG, Pfizer, F Homan-La Roche, Schering-Plough, Synarc, Alzheimer’s Association, Alzheimer’s Drug Discovery Foundation, the Dana Foundation, and by the National Institute of Biomedical Imaging and Bioengineering and NIA grants U01 AG024904, RC2 AG036535, K01 AG030514. We thank Dr D Stephen Snyder and Dr Marilyn Miller from NIA who are ex-officio ADGC members. Support was also from the Alzheimer’s Association (LAF, IIRG-08-89720; MP-V, IIRG-05-14147) and the US Department of Veterans Affairs Administration, Office of Research and Development, Biomedical Laboratory Research Program. P.S.G.-H. is supported by the Wellcome Trust, Howard Hughes Medical Institute, and Canadian Institute of Health.

CHARGE

AGES: The AGES-Reykjavik Study is funded by NIH contract N01-AG-12100 (NIA with contributions from the NEI, NIDCD and NHLBI), the NIA Intramural Research Program, Hjartavernd (the Icelandic Heart Association) and the Althingi (the Icelandic Parliament).

ASPS/PRODEM: The Austrian Stroke Prevention Study and The Prospective Dementia Register of the Austrian Alzheimer Society was supported by The Austrian Science Fond (FWF) grant number P20545-P05 (H Schmidt) and P13180; The Austrian Alzheimer Society; The Medical University of Graz.

Cardiovascular Health Study (CHS): This research was supported by NHLBI contracts HHSN268201200036C, HHSN268200800007C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086; and NHLBI grants U01HL080295, R01HL087652, R01HL105756, R01HL103612, and R01HL120393 with additional contribution from the National Institute of Neurological Disorders and Stroke (NINDS). Additional support was provided through R01AG023629, R01AG15928, R01AG20098, R01AG027058 and R01AG033193 (Seshadri) from the National Institute on Aging (NIA). A full list of principal CHS investigators and institutions can be found at CHS-NHLBI.org. The provision of genotyping data was supported in part by the National Center for Advancing Translational Sciences, CTSI grant UL1TR000124, and the National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center (DRC) grant DK063491 to the Southern California Diabetes Endocrinology Research Center.

Framingham Heart Study (FHS): This work was supported by the National Heart, Lung and Blood Institute’s Framingham Heart Study (Contract No. N01-HC-25195) and its contract with Affymetrix, Inc for genotyping services (Contract No. N02-HL-6-4278). A portion of this research utilized the Linux Cluster for Genetic Analysis (LinGAII) funded by the Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine and Boston Medical Center. This study as also supported by grants from the National Institute on Aging: AG08122 and AG033193 (Seshadri). Dr Seshadri and Dr DeStefano were also supported by additional grants from the National Institute on Aging: (R01 AG16495; AG031287, AG033040), the National Institute of Neurological Disorders and Stroke (R01 NS17950), and the National Heart, Lung and Blood Institute (U01 HL096917, HL093029 and K24HL038444, RC2-HL102419 and UC2 HL103010.

Fundació ACE: would like to thank patients and controls who participated in this project. This work has been funded by the Fundación Alzheimur (Murcia), the Ministerio de Educación y Ciencia (PCT-010000-2007-18), (DEX-580000-2008-4), (Gobierno de España), Corporación Tecnológica de Andalucía (08/211) and Agencia IDEA (841318) (Consejería de Innovación, Junta de Andalucía). We thank Ms Trinitat Port-Carbó and her family for their generous support of Fundació ACE research programs.

Erasmus Rucphen Family Study: We thank the participants from the Genetic Research in Isolated Populations in the Erasmus Rucphen Family Study who made this work possible. This study is financially supported by the Netherlands Organization for Scientific Research (NWO), the Internationale Stichting Alzheimer Onderzoek (ISAO), the Hersenstichting Nederland (HSN) and the Centre for Medical Systems Biology (CMSB1 and CMSB2) in the framework of the Netherlands Genomics Initiative (NGI).

The Rotterdam Study: The Rotterdam Study was funded by Erasmus Medical Center and Erasmus University, Rotterdam; the Netherlands Organization for Health Research and Development; the Research Institute for Diseases in the Elderly; the Ministry of Education, Culture and Science; the Ministry for Health, Welfare and Sports; the European Commission; and the Municipality of Rotterdam; by grants from the Research Institute for Diseases in the Elderly (014-93-015; RIDE2), Internationale Stichting Alzheimer Onderzoek, Hersenstichting Nederland, the Netherlands Genomics Initiative–Netherlands Organization for Scientific Research (Center for Medical Systems Biology and the Netherlands Consortium for Healthy Aging), the Seventh Framework Program (FP7/2007-2013), the ENGAGE project (grant agreement HEALTH-F4-2007-201413), MRACE-grant from the Erasmus Medical Center and the Netherlands Organization for Health Research and Development (ZonMW Veni-grant no. 916.13.054).

ARIC: The Atherosclerosis Risk in Communities Study (ARIC) is carried out as a collaborative study supported by National Heart, Lung, and Blood Institute contracts N01-HC-55015, N01-HC-55016, N01-HC-55018, N01-HC-55019, N01-HC-55020, N01-HC-55021, N01-HC-55022 and grants R01-HL087641, RC2-HL102419 (Boerwinkle, CHARGE-S), UC2 HL103010, U01 HL096917 (Mosley) and R01-HL093029; NHGRI contract U01-HG004402; and NIH contract HHSN268200625226C and NIA: R01 AG033193 (Seshadri). Infrastructure was partly supported by Grant Number UL1RR025005, a component of the National Institutes of Health and NIH Roadmap for Medical Research.

EADI

This work was supported by the National Foundation for Alzheimer’s disease and related disorders, the Institut Pasteur de Lille and the Centre National de Génotypage. The Three-City Study was performed as part of a collaboration between the Institut National de la Santé et de la Recherche Médicale (Inserm), the Victor Segalen Bordeaux II University and Sanofi-Synthélabo. The Fondation pour la Recherche Médicale funded the preparation and initiation of the study. The 3C Study was also funded by the Caisse Nationale Maladie des Travailleurs Salariés, Direction Générale de la Santé, MGEN, Institut de laLongévité, Agence Française de Sécurité Sanitaire des Produits de Santé, the Aquitaine and Bourgogne RegionalCouncils, Fondation de France and the joint French Ministry of Research/INSERM ‘Cohortes et collections de données biologiques’ programme. Lille Génopôle received an unconditional grant from Eisai.

Belgium sample collection: Research at the Antwerp site is funded in part by the Interuniversity Attraction Poles program of the Belgian Science Policy Office, the Foundation for Alzheimer Research (SAO-FRA), a Methusalem Excellence Grant of the Flemish Government, the Research Foundation Flanders (FWO), the Special Research Fund of the University of Antwerp, Belgium. KB is a postdoctoral fellow of the FWO. The Antwerp site authors thank the personnel of the VIB Genetic Service Facility, the Biobank of the Institute Born-Bunge and the Departments of Neurology and Memory Clinics at the Hospital Network Antwerp and the University Hospitals Leuven.

Finish sample collection: Financial support for this project was provided by the Health Research Council of the Academy of Finland, EVO grant 5772708 of Kuopio University Hospital and the Nordic Centre of Excellence in Neurodegeneration.

Italian sample collections: The Bologna site (FL) obtained funds from the Italian Ministry of research and University as well as Carimonte Foundation. The Florence site was supported by a grant from the Italian ministry of Health (RFPS-2006-7-334858) and grant RF-2010-2319722. The Milan site was supported by a grant from the ‘fondazione Monzino’. We thank the expert contribution of Mr. Carmelo Romano. The Roma site received financial support from Italian Ministry of Health, Grant RF07-08 and RC08-09-10-11-12. The Pisa site is grateful to Dr Annalisa LoGerfo for her technical assistance in the DNA purification studies.

Spanish sample collection: The Madrid site (MB) was supported by grants of the Ministerio de Educación y Ciencia and the Ministerio de Sanidad y Consumo (Instituto de Salud Carlos III), and an institutional grant of the FundaciónRamón Areces to the CBMSO. We thank I Sastre and Dr A Martínez-García for the preparation and control of the DNA collection, and Dr P Gil and Dr P Coria for their cooperation in the cases/controls recruitment. We are grateful to the Asociación de Familiares de Alzheimer de Madrid (AFAL) for continuous encouragement and help.

Swedish sample collection: Financially supported in part by the Swedish Brain Power network, the Marianne and Marcus Wallenberg Foundation, the Swedish Research Council (521-2010-3134), the King Gustaf V and Queen Victoria’s Foundation of Freemasons, the Regional Agreement on Medical Training and Clinical Research (ALF) between Stockholm County Council and the Karolinska Institutet, the Swedish Brain Foundation and the Swedish Alzheimer Foundation.

GERAD

Cardiff University was supported by the Wellcome Trust, Medical Research Council (MRC), Alzheimer’s Research UK (ARUK) and the Welsh Assembly Government. Cambridge University and Kings College London acknowledge support from the MRC. ARUK supported sample collections at the South West Dementia Bank and the Universities of Nottingham, Manchester and Belfast. The Belfast group acknowledges support from the Alzheimer's Society, Ulster Garden Villages, N. Ireland R&D Office and the Royal College of Physicians/Dunhill Medical Trust. The MRC and Mercer’s Institute for Research on Ageing supported the Trinity College group. The South West Dementia Brain Bank acknowledges support from Bristol Research into Alzheimer's and Care of the Elderly. The Charles Wolfson Charitable Trust supported the OPTIMA group. Washington University was funded by NIH grants, Barnes Jewish Foundation and the Charles and Joanne Knight Alzheimer's Research Initiative. Patient recruitment for the MRC Prion Unit/UCL NIHR Department of Neurodegenerative Disease collection was supported by the UCLH/UCL NIHR Biomedical Centre and Queen Square Dementia Biomedical Research Unit. LASER-AD was funded by Lundbeck SA. The Bonn group was supported by the German Federal Ministry of Education and Research (BMBF), Competence Network Dementia and Competence Network Degenerative Dementia and by the Alfried Krupp von Bohlen und Halbach-Stiftung. The GERAD1 Consortium also used samples ascertained by the NIMH AD Genetics Initiative.

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Affiliations

  1. Department of Medicine (Biomedical Genetics), Boston University School of Medicine, Boston, MA, USA

    • G Jun
    • , J Chung
    •  & L A Farrer
  2. Department of Ophthalmology, Boston University School of Medicine, Boston, MA, USA

    • G Jun
    •  & L A Farrer
  3. Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA

    • G Jun
    • , K L Lunetta
    • , A L Destefano
    • , S-H Choi
    •  & L A Farrer
  4. Department of Epidemiology, Erasmus University Medical Center, Erasmus, Rotterdam,The Netherlands

    • C A Ibrahim-Verbaas
    • , M A Ikram
    • , S J van der Lee
    • , N Amin
    • , R F A G de Bruijn
    • , A Hofman
    •  & C M van Duijn
  5. Department of Neurology, Erasmus University Medical Center, Erasmus, Rotterdam,The Netherlands

    • C A Ibrahim-Verbaas
    •  & P De Jager
  6. Institute of Psychological Medicine and Clinical Neurosciences, Medical Research Council (MRC) Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, UK

    • M Vronskaya
    • , R Sims
    • , N Denning
    • , M L Dunstan
    • , M C O'Donovan
    • , L Jones
    • , P Holmans
    • , V Escott-Price
    •  & J Williams
  7. Inserm U744, Lille, France

    • J-C Lambert
    • , C Bellenguez
    • , B Grenier-Boley
    • , N Fievet
    •  & P Amouyel
  8. Université Lille 2, Lille, France

    • J-C Lambert
    • , C Bellenguez
    • , B Grenier-Boley
    • , N Fievet
    • , F Pasquier
    • , V Deramecourt
    •  & P Amouyel
  9. Institut Pasteur de Lille, Lille, France

    • J-C Lambert
    • , C Bellenguez
    • , B Grenier-Boley
    • , N Fievet
    •  & P Amouyel
  10. Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA

    • A C Naj
    • , L-S Wang
    • , O Valladares
    • , L B Cantwell
    •  & G D Schellenberg
  11. The John P. Hussman Institute for Human Genomics, University of Miami, Miami, FL, USA

    • B W Kunkle
    • , G W Beecham
    • , K L Hamilton-Nelson
    • , E R Martin
    •  & M A Pericak-Vance
  12. Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA

    • J C Bis
    •  & B M Psaty
  13. Trinity College, University of Dublin, Dublin, Ireland

    • D Harold
  14. Macdonald Foundation Department of Human Genetics, University of Miami, Miami, FL, USA

    • G W Beecham
    • , E R Martin
    •  & M A Pericak-Vance
  15. University of Iceland, Faculty of Medicine, Reykjavik, Iceland

    • A V Smith
    • , V Gudnason
    •  & P V Jonsson
  16. Icelandic Heart Association, Kopavogur, Iceland

    • A V Smith
    • , V Gudnason
    • , G Eiriksdottir
    • , V Emilsson
    •  & J Jakobsdóttir
  17. Department of Neurology, Boston University School of Medicine, Boston, MA, USA

    • V Chouraki
    • , S Seshadri
    •  & L A Farrer
  18. Netherlands Consortium for Healthy Aging, Leiden, The Netherlands

    • M A Ikram
  19. Department of Radiology, Erasmus University Medical Center, Erasmus, Rotterdam,The Netherlands

    • M A Ikram
    •  & A Hofman
  20. Institute for Molecular Biology and Biochemistry, Medical University of Graz, Graz, Austria

    • H Schmidt
  21. Laboratory for Statistical Analysis, Center for Integrative Medical Sciences, Riken, Kanagawa, Japan

    • Y Kamatani
  22. Foundation Jean Dausset—CEPH, Paris, France

    • Y Kamatani
    •  & M Lathrop
  23. Memory Clinic of Fundació ACE, Institut Català de Neurociències Aplicades, Barcelona, Spain

    • A R Laza
  24. Centre National de Genotypage, Institut Genomique, Commissariat a l’energie Atomique, Evry, France

    • D Zelenika
    • , A Boland
    •  & M Lathrop
  25. Department of Psychiatry and Psychotherapy, University of Bonn, Bonn, Germany

    • A Ramirez
    •  & W Maier
  26. Institute of Human Genetics, University of Bonn, Bonn, Germany

    • A Ramirez
    •  & M M Nöthen
  27. Department of Medical and Molecular Genetics, Indiana University, Indianapolis, IN, USA

    • T M Foroud
  28. German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany

    • T Becker
    •  & W Maier
  29. Institute for Medical Biometry, Informatics and Epidemiology, University of Bonn, Bonn, Germany

    • T Becker
  30. Department of Epidemiology, University of Washington, Seattle, WA, USA

    • W A Kukull
    • , A L Fitzpatrick
    •  & B M Psaty
  31. Centre National de Reference pour les Malades Alzheimer Jeunes (CNR-MAJ), Centre Hospitalier Régional Universitaire de Lille, Lille, France

    • F Pasquier
    •  & V Deramecourt
  32. Hope Center Program on Protein Aggregation and Neurodegeneration, Washington University School of Medicine, St Louis, MO, USA

    • C Cruchaga
    •  & A M Goate
  33. Department of Psychiatry, Washington University School of Medicine, St Louis, MO, USA

    • C Cruchaga
    •  & A M Goate
  34. National Alzheimer’s Coordinating Center, University of Washington, Seattle, WA, USA

    • D Beekly
  35. Departments of Health Services, University of Washington, Seattle, WA, USA

    • A L Fitzpatrick
    •  & B M Psaty
  36. Department of Geriatrics, University Paris Descartes, Sorbonne Paris V, France

    • O Hanon
  37. Geriatrics Department, Broca Hospital, Paris, France

    • O Hanon
  38. Mercer’s Institute for Research on Aging, St James Hospital and Trinity College, Dublin, Ireland

    • M Gill
  39. Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, Fort Worth, TX, USA

    • R Barber
  40. CNR-MAJ, Inserm U1079, Rouen, France; University Hospital, 76031 Rouen, France

    • D Campion
    •  & D Hannequin
  41. University of Bristol Institute of Clinical Neurosciences, School of Clinical Sciences, Frenchay Hospital, Bristol, UK

    • D Campion
    •  & S Love
  42. Department of Neurological Sciences, Rush University Medical Center, Chicago, IL, USA

    • D A Bennett
  43. Rush Alzheimer’s Disease Center, Rush University Medical Center, Chicago, IL, USA

    • D A Bennett
  44. Inserm U888, Hôpital La Colombière, Montpellier, France

    • C Berr
  45. Department of Neurology, Aristotle University of Thessaloniki, Thessaloniki, Greece

    • Magda Tsolaki
  46. Department of Neuroscience, Mount Sinai School of Medicine, New York, NY, USA

    • J D Buxbaum
  47. Department of Psychiatry, Mount Sinai School of Medicine, New York, NY, USA

    • J D Buxbaum
  48. Departments of Genetics and Genomic Sciences, Mount Sinai School of Medicine, New York, NY, USA

    • J D Buxbaum
  49. University of Pittsburgh Alzheimer’s Disease Research Center, Pittsburgh, PA, USA

    • O L Lopez
    •  & M I Kamboh
  50. Departments of Neurology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

    • O L Lopez
  51. Dementia Research Centre, Department of Neurodegenerative Disease, University College London Institute of Neurology, London, UK

    • N C Fox
  52. Memory Clinic of Fundació ACE, Institut Català de Neurociències Aplicades, Barcelona, Spain

    • L Tárraga
    •  & M Boada
  53. Inserm U897, Victor Segalen University, F-33076, Bordeaux, France

    • C Dufouil
    • , D Hannequin
    • , L Letenneur
    • , J-F Dartigues
    •  & C Tzourio
  54. Department of Molecular Neuroscience, Institute of Neurology, London, UK

    • J Hardy
    •  & S Mead
  55. Reta Lilla Weston Laboratories, Institute of Neurology, London, UK

    • J Hardy
  56. Department of Medicine, University of Washington, Seattle, WA, USA

    • P K Crane
    •  & E B Larson
  57. Oxford Healthy Aging Project (OHAP), Clinical Trial Service Unit, University of Oxford, Oxford, UK

    • R Clarke
  58. Rush Institute for Healthy Aging, Department of Internal Medicine, Rush University Medical Center, Chicago, IL, USA

    • D Evans
  59. Department of Medicine (Geriatrics), University of Mississippi Medical Center, Jackson, MS, USA

    • T H Mosley Jr.
  60. Institute of Public Health, University of Cambridge, Cambridge, UK

    • C Brayne
  61. Program in Translational NeuroPsychiatric Genomics, Institute for the Neurosciences, Department of Neurology and Psychiatry, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA

    • P De Jager
  62. Program in Medical and Population Genetics, Broad Institute, Cambridge, MA, USA

    • P De Jager
  63. Faculty of Pharmaceutical Sciences, University of Iceland, Reykjavik, Iceland

    • V Emilsson
  64. Centre de Mémoire de Ressources et de Recherche de Bordeaux, CHU de Bordeaux, Bordeaux, France

    • J-F Dartigues
  65. Department of Psychiatry, University of Frankfurt, Frankfurt am Main, Germany

    • H Hampel
  66. Department of Psychiatry, Ludwig Maximilians University, Munich, Germany

    • H Hampel
  67. Department of Human Genetics, University of Pittsburgh, Pittsburgh, PA, USA

    • M I Kamboh
  68. Neurogenetics Laboratory, Division of Neurosciences, Center for Applied Medical Research, University of Navarra School of Medicine, Pamplona, Spain

    • P Pastor
  69. CIBERNED, Instituto de Salud Carlos III, Madrid, Spain

    • P Pastor
  70. Group Health, Group Health Research Institute, Seattle, WA, USA

    • E B Larson
    •  & B M Psaty
  71. Institute for Translational Genomics and Population Sciences, Los Angeles BioMedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA, USA

    • J I Rotter
  72. Division of Genetic Outcomes, Department of Pediatrics, Harbor-UCLA Medical Center, Torrance, CA, USA

    • J I Rotter
  73. Department of Pathology, University of Washington, Seattle, WA, USA

    • T J Montine
  74. Laboratory of Neurogenetics, Intramural Research Program, National Institute on Aging, Bethesda, MD, USA

    • M A Nalls
  75. Arizona Alzheimer’s Consortium, Phoenix, AZ, USA

    • E M Reiman
  76. Department of Psychiatry, University of Arizona, Phoenix, AZ, USA

    • E M Reiman
  77. Banner Alzheimer's Institute, Phoenix, AZ, USA

    • E M Reiman
  78. Neurogenomics Division, Translational Genomics Research Institute, Phoenix, Arizona

    • E M Reiman
  79. Department of Geriatrics, Landspitali National University Hospital, Reykjavik, Iceland

    • P V Jonsson
  80. Division of Clinical Neurosciences, School of Medicine, University of Southampton, Southampton, UK

    • C Holmes
  81. Tanz Centre for Research in Neurodegenerative Disease, University of Toronto, Toronto, ON, Canada

    • P H St George-Hyslop
  82. Cambridge Institute for Medical Research and Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK

    • P H St George-Hyslop
  83. Ageing Group, Centre for Public Health, School of Medicine, Dentistry and Biomedical Sciences, Queen’s University, Belfast, UK

    • P Passmore
  84. PharmaTherapeutics Clinical Research, Pfizer Worldwide Research and Development, Cambridge, MA, USA

    • J R Wendland
    •  & A R Winslow
  85. Department of Neurology, Medical University of Graz, Graz, Austria

    • R Schmidt
  86. Institute of Genetics, Queen’s Medical Centre, University of Nottingham, Nottingham, UK

    • K Morgan
  87. King’s College London, Institute of Psychiatry, Department of Neuroscience, De Crespigny Park, Denmark Hill, London, UK

    • J F Powell
  88. Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA

    • M Carasquillo
    •  & S G Younkin
  89. Department of Biology, Brigham Young University, Provo, Utah, USA

    • J S K Kauwe
  90. Department of Genetics, University of North Carolina Chapel Hill, Chapel Hill, NC, USA

    • K C Wilhelmsen
  91. Department of Psychiatry, Psychotherapy and Psychosomatics Martin-Luther-University Halle-Wittenberg, Halle, Germany

    • D Rujescu
  92. Institute of Human Genetics, Department of Genomics, Life and Brain Center, University of Bonn, Bonn, Germany

    • M M Nöthen
  93. Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, OH, USA

    • J L Haines
  94. Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, VIB, Antwerp, Belgium

    • C Van Broeckhoven
  95. Institute Born-Bunge, University of Antwerp, Antwerp, Belgium

    • C Van Broeckhoven
  96. Laboratory of Epidemiology, Demography, and Biometry, National Institute of Health, Bethesda, MD, USA

    • L J Launer
  97. Taub Institute on Alzheimer's Disease and the Aging Brain, Columbia University, New York, NY, USA

    • R Mayeux
  98. Gertrude H. Sergievsky Center, Columbia University, New York, NY, USA

    • R Mayeux
  99. Department of Neurology, Columbia University, New York, NY, USA

    • R Mayeux
  100. McGill University and Génome Québec Innovation Centre, Montreal, QC, Canada

    • M Lathrop
  101. University Hospital, CHRU Lille, Lille, France

    • P Amouyel
  102. Department of Epidemiology, Boston University School of Public Health, Boston, MA, USA

    • L A Farrer

Consortia

  1. IGAP Consortium

    International Genomics of Alzheimer’s Project Members Alzheimer Disease Genetics Consortium (ADGC) Perrie M Adams, PhD; Marilyn S Albert, PhD; Roger L Albin, MD; Liana G Apostolova, MD; Steven E Arnold, MD; Sanjay Asthana, MD; Craig S Atwood, PhD; Clinton T Baldwin, PhD; Michjael M Barmada, PhD; Lisa L Barnes, PhD; Thomas G Beach, MD PhD; James T Becker, PhD; Eileen H Bigio, MD; Thomas D Bird, MD; Deborah Blacker, MD; Bradley F Boeve, MD; James D Bowen, MD; Adam Boxer, MD PhD, James R Burke, MD PhD; Nigel J Cairns, PhD FRCPath; Chuanhai Cao, PhD; Chris S Carlson; PhD; Cynthia M Carlsson, MD; Regina M Carney, MD; Minerva M Carrasquillo, PhD; Steven L Carroll, MD PhD; Helena C Chui, MD; David G Clark, MD; Jason Corneveaux, BS; David H Cribbs, PhD; Elizabeth A Crocco, MD; Carlos Cruchaga, PhD; Philip L De Jager, MD PhD; Charles DeCarli, MD; Steven T DeKosky, MD; F Yesim Demirci, MD; Malcolm Dick, PhD; Dennis W Dickson, MD; Rachelle S Doody, MD PhD; Ranjan Duara, MD; Nilufer Ertekin-Taner, MD PhD; Kelley M Faber, MS; Thomas J Fairchild, PhD; Kenneth B Fallon, MD; Martin R Farlow, MD; Steven Ferris, PhD; Matthew P Frosch, MD PhD; Douglas R Galasko, MD; Marla Gearing, PhD; Daniel H Geschwind, MD PhD; Bernardino Ghetti, MD; John R Gilbert PhD; Jonathan D Glass, MD; Neill R Graff-Radford, MD; Robert C Green, MD MPH; John H Growdon, MD; Hakon Hakonarson, MD PhD; Ronald L Hamilton, MD; John Hardy, PhD; Lindy E Harrell, MD PhD; Elizabeth Head, PhD; Lawrence S Honig, MD PhD; Ryan M Huebinger, PhD, Matthew J Huentelman, PhD; Christine M Hulette, MD; Bradley T Hyman, MD PhD; Gail P Jarvik, MD PhD; Gregory A Jicha, MD PhD; Lee-Way Jin, MD PhD; Anna Karydas, BA; John SK Kauwe, PhD; Jeffrey A Kaye, MD; Ronald Kim, MD; Edward H Koo, MD; Neil W Kowall, MD; Joel H Kramer, PsyD; Frank M LaFerla, PhD; James J Lah, MD PhD; James B Leverenz, MD; Allan I Levey, MD PhD; Ge Li, MD PhD; Andrew P Lieberman, MD PhD; Chiao-Feng Lin, PhD; Oscar L Lopez, MD; Constantine G Lyketsos, MD MHS; Wendy J Mack, PhD; Daniel C Marson, JD PhD; Frank Martiniuk, PhD; Deborah C Mash, PhD; Eliezer Masliah, MD; Wayne C McCormick, MD MPH; Susan M McCurry, PhD; Andrew N McDavid, BA; Ann C McKee, MD; Marsel Mesulam, MD; Bruce L Miller, MD; Carol A Miller, MD; Joshua W Miller, PhD; John C Morris, MD; Shubhabrata Mukherjee, PhD; Jill R Murrell, PhD, Amanda J Myers, PhD; Sid O’Bryant, PhD; John M Olichney, MD; Vernon S Pankratz, PhD; Joseph E Parisi, MD; Amanda Partch, MS; Henry L Paulson, MD PhD; William Perry, MPH; Elaine Peskind, MD; Ronald C Petersen, MD PhD; Aimee Pierce, MD; Wayne W Poon, PhD; Huntington Potter, PhD; Joseph F Quinn, MD; Ashok Raj, MD; Murray Raskind, MD; Barry Reisberg, MD; Joan S Reisch, PhD; Christiane Reitz, MD PhD; John M Ringman; MD; Erik D Roberson, MD PhD; Ekaterina Rogaeva, PhD; Howard J Rosen, MD; Roger N Rosenberg, MD; Donald R Royall, MD; Mark A Sager, MD; Mary Sano, PhD; Andrew J Saykin, PsyD; Julie A Schneider, MD; Lon S Schneider, MD; William W Seeley, MD; Amanda G Smith, MD; Joshua A Sonnen, MD; Salvatore Spina, MD; Robert A Stern, PhD; Rudolph E Tanzi, PhD; Tricia A Thornton-Wells, PhD; John Q Trojanowski, MD PhD; Juan C Troncoso, MD; Debby W Tsuang, MD; Vivianna M Van Deerlin, MD PhD; Linda J Van Eldik, PhD; Badri N Vardarajan, PhD; Harry V Vinters, MD; Jean Paul Vonsattel, MD; Sandra Weintraub, PhD; Kathleen A Welsh-Bohmer, PhD; Jennifer Williamson, MS; Sarah Wishnek, MPH; Randall L Woltjer, MD PhD; Clinton B Wright, MD MS; Chuang-Kuo Wu, MD PhD; Chang-En Yu, PhD; Lei Yu, PhD. Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium Rhoda Au, PhD; Philip A Wolf, MD; Alexa Beiser, PhD; Claudia Satizabal, PhD; Andre G Uitterlinden, PhD; Fernando Rivadeneira, MD, PhD; Peter J Koudstaal, MD, PhD; William T Longstreth, Jr, MD; James T Becker, PhD; Lewis H Kuller, MD; Thomas Lumley, PhD; Kenneth Rice, PhD; Tamara B Harris, MD; Michael Nalls, PhD; Josef JM Marksteiner, MD; Peter Dal-Bianco, MD; Anna Maria Töglhofer, BSc; Paul Freudenberger, MSc; Gerhard Ransmayr, MD; Thomas Benke, MD; Anna M Toeglhofer, MSc; Eric Boerwinkle, PhD; Jan Bressler, PhD; Myriam Fornage, PhD; Francisco J Morón, PhD; Isabel Hernández, MD; Maitee Rosende Roca, MD; Ana Mauleón, MD; Montserrat Alegret, PhD; Reposo Ramírez-Lorca, PhD; Antonio González-Perez, MS. European Alzheimer’s Disease Initiative (EADI) Annick, Alpérovitch, MD, PhD; Victoria Alvarez, PhD; Pascale Barberger-Gateau, MD; Karolien Bettens, PhD; Paola Bossù, MD; Alexis Brice, MD, PhD; Maria Bullido, MD; Paolo Caffara, MD; Jordi Clarimon, MD; Onofre Combarros, MD; Eliecer Coto, PhD; Maria del Zampo, PhD; Marc Delepine, PhD; Maria Candida Deniz Naranjo, PhD; Jacques Epelbaum, PhD; Laura Fratiglioni, MD, PhD; Daniela Galimberti, PhD; Caroline Graff, MD, PhD; Mikko Hiltunen, MD, PhD; Martin Ingelsson, MD, PhD; Lina Keller, MD; Lars Lannfelt, MD; Alberto Llèo, MD; Michelangelo Mancuso, MD; Ignacio Mateo, MD; Patrizia Mecocci, MD; Benedetta Nacmias, PhD; Francesco Panza, MD; Alberto Pilotto, MD; Florentino Sanchez Garcia, MD; Elio Scarpini, MD; Davide Seripa, PhD; Kristel Sleegers, PhD; Hlikka Soininen, MD; Sandro Sorbi, MD; Gianfranco Spalletta, MD; David Wallon, MD, PhD. Genetic and Environmental Risk in Alzheimer's Disease (GERAD) Consortium Charlene Thomas, BSc; Amy Gerrish, PhD; Jade Chapman, PhD; Alexandra Stretton, PhD; Angharad Morgan; Harriet Oldham, PhD; Michael J Owen, MD, PhD; Patrick G Kehoe, PhD; Christopher Medway, PhD; Kristelle Brown, PhD; Jenny Lord; James Turton; Nigel M Hooper; Emma Vardy; Jason D Warren; Jonathan M Schott; James Uphill; Paul Hollingworth, PhD, DClinPsy; Natalie Ryan; Martin Rossor, MD PhD; John Collinge, MD, PhD; Yoav Ben-Shlomo; Daniilidou Makrina; Olymbia Gkatzima; Michelle Lupton, PhD; Maria Koutroumani; Despoina Avramidou; Antonia Germanou; Frank Jessen, PhD; Steffi Riedel-Heller; Martin Dichgans, MD, PhD; Reiner Heun; Heike Kölsch; Britta Schürmann, PhD; Christine Herold; André Lacour; Dmitriy Drichel; Per Hoffmann; Johannes Kornhuber, MD, PhD; Wei Gu; Thomas Feulner; Manuel Mayhaus, PhD; Sabrina Pichler, PhD; Matthias Riemenschneider, MD; Hendrik van den Bussche, PhD; Brian Lawlor, MD, PhD; Aoibhinn Lynch, MD; David Mann, PhD; A David Smith, DPhil; Donald Warden; Gordon Wilcock; Isabella Heuser, PhD; Jens Wiltfang, MD, PhD; Lutz Frölich, PhD; Michael Hüll, MD, PhD; Kevin Mayo, PhD; Gill Livingston, MD, PhD; Nicholas J Bass, MD, PhD; Hugh Gurling, MD, PhD; Andrew McQuillin, PhD; Rhian Gwilliam; Panagiotis Deloukas; Ammar Al-Chalabi, MB ChB; Christopher E Shaw, MD, PhD; Andrew B Singleton, PhD; Rita Guerreiro, PhD; Giancarlo Russo; Karl-Heinz Jöckel, PhD; Susanne Moebus, PhD; Norman Klopp, PhD; H-Erich Wichmann, MD, PhD; Dennis W Dickson; Neill R Graff-Radford; Li Ma; Gina Bisceglio; Elizabeth Fisher, PhD; Nick Warner MB ChB; Stuart Pickering-Brown, PhD; David Craig, MD; Janet A Johnston, PhD; Bernadette McGuinness, MD, PhD; Stephen Todd, MD, PhD; David C Rubinsztein, MB ChB, PhD; Simon Lovestone, PhD; Anthony Bayer, MD; John Gallacher, MD; Petroula Proitsi, PhD; Sara Ortega-Cubero, MD.

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Competing interests

Celine Bellenguez received personal fees from Genoscrenn unrelated to current study. HS reports grants from Austrian Science Fond (FWF) and Österreichische Nationalbank Anniversary Fund during the conduct of the study. FP reports grants from DISTALZ Labex of Excellence (ANR). NF reports payment from Janessen Alzheimer’s Immunotherapty and Pfizer to University College London for contracted image analyses and payment from Bristol Myers Squibb, Eli Lilly, GE Healthcare, Novartis and Sanofi to University College London for consultant services. JH received personal fees from Eisai, Eli Lilly and Roche, outside the current study. AMG received grants from NIA, Genentech, Pfizer and Astra Zeneca, as well as personal fees from Finnegan HC, Cognition Therapeutics, Dickstein Shapiro, Genentech and Amgen, all unrelated to the current study. In addition, AMG has a patent (US20070258898) issued and a patent with royalties paid by Taconic. WM received grants from Eli Lilly and Lundbeck. J-FD received grants and personal fees from IPSEN and Novartis and personal fees from Newron. HH reports personal fees and non-financial support from Boehringer-Ingelheim, Bristol-Myers-Squibb, Elan Corporation, Novartis, Eisai Inc., Pfizer, Sanofi-Aventis, Roche Pharmaceutical Diagnostics, GlaxoSmithKline-Biologicals, Jung-Diagnostics, Avid, Eli Lilly and Cytox and personal fees from GE Healthcare. In addition, HH has pending patents entitled ‘Method for predicting whether subjects with mild cognitive impairment (MCI) will develop Alzheimer's disease’, ‘3-Hydroxykynurenin im Serum als diagnostischer Marker fUr die Demenz vom Alzheimer-Typ’, ‘Neurodegenerative markers for psychiatric conditions’, ‘Ratio A~2/40 im Plasma in der Fruh- und Differentialdiagnose der Alzheimer Krankheit’, Liquordiagnostisches in vitro Verfahren zur Diagnose von Demenz-ErkrankUngen und neuroinfJammatorischen Erkrankungen’, ‘In vitro Verfahren zur Diagnose von neurodegenerativen Erkrankungen’ and ‘In vitro Verfahren zur Diagnose und Fruhdiagnose von neurodegenerativen Erkrankungen’. EBL received personal fees from Up to Date unrelated to the current study. MO received research grants from the Medical Research Council during the course of, but unrelated to, the current study. EMR received personal fees from AstraZeneca, CereSpir, Eisai, Eli Lilly, GlaxoSmithKline and Sanofi and research contracts from Avid/Eli Lilly and Genetech, all unrelated to the current study. JW is a full-time employee and shareholder of Pfizer (2012–present) and a former full-time employee of F. Hoffmann-La Roche (2010–2012). AW is a full-time employee and shareholder of Pfizer (2013–present). MAP-V received personal fees from Athena Neurosciences unrelated to the current study. The other authors declare no conflict of interest.

Corresponding author

Correspondence to L A Farrer.

Supplementary information

About this article

Publication history

Received

Revised

Accepted

Published

DOI

https://doi.org/10.1038/mp.2015.23

Supplementary Information accompanies the paper on the Molecular Psychiatry website (http://www.nature.com/mp)

Further reading