Original Article

Molecular Psychiatry (2016) 21, 108–117; doi:10.1038/mp.2015.23; published online 17 March 2015

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

G Jun1,2,3, C A Ibrahim-Verbaas4,5, M Vronskaya6, J-C Lambert7,8,9, J Chung1, A C Naj10, B W Kunkle11, L-S Wang10, J C Bis12, C Bellenguez7,8,9, D Harold13, K L Lunetta3, A L Destefano3, B Grenier-Boley7,8,9, R Sims6, G W Beecham11,14, A V Smith15,16, V Chouraki17, K L Hamilton-Nelson11, M A Ikram4,18,19, N Fievet7,8,9, N Denning6, E R Martin11,14, H Schmidt20, Y Kamatani21,22, M L Dunstan6, O Valladares10, A R Laza23, D Zelenika24, A Ramirez25,26, T M Foroud27, S-H Choi3, A Boland24, T Becker28,29, W A Kukull30, S J van der Lee4, F Pasquier8,31, C Cruchaga32,33, D Beekly34, A L Fitzpatrick30,35, O Hanon36,37, M Gill38, R Barber39, V Gudnason15,16, D Campion40,41, S Love41, D A Bennett42,43, N Amin4, C Berr44, Magda Tsolaki45, J D Buxbaum46,47,48, O L Lopez49,50, V Deramecourt8,31, N C Fox51, L B Cantwell10, L Tárraga52, C Dufouil53, J Hardy54,55, P K Crane56, G Eiriksdottir16, D Hannequin40,53, R Clarke57, D Evans58, T H Mosley Jr.59, L Letenneur53, C Brayne60, W Maier25,28, P De Jager5,61,62, V Emilsson16,63, J-F Dartigues53,64, H Hampel65,66, M I Kamboh49,67, R F A G de Bruijn4, C Tzourio53, P Pastor68,69, E B Larson56,70, J I Rotter71,72, M C O'Donovan6, T J Montine73, M A Nalls74, S Mead54, E M Reiman75,76,77,78, P V Jonsson15,79, C Holmes80, P H St George-Hyslop81,82, M Boada52, P Passmore83, J R Wendland84, R Schmidt85, K Morgan86, A R Winslow84, J F Powell87, M Carasquillo88, S G Younkin88, J Jakobsdóttir16, J S K Kauwe89, K C Wilhelmsen90, D Rujescu91, M M Nöthen26,92, A Hofman4,19, L Jones6, IGAP Consortium103, J L Haines93, B M Psaty12,30,35,70, C Van Broeckhoven94,95, P Holmans6, L J Launer96, R Mayeux97,98,99, M Lathrop22,24,100, A M Goate32,33, V Escott-Price6, S Seshadri17, M A Pericak-Vance11,14, P Amouyel7,8,9,101, J Williams6, C M van Duijn4, G D Schellenberg10 and L A Farrer1,2,3,17,102

  1. 1Department of Medicine (Biomedical Genetics), Boston University School of Medicine, Boston, MA, USA
  2. 2Department of Ophthalmology, Boston University School of Medicine, Boston, MA, USA
  3. 3Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA
  4. 4Department of Epidemiology, Erasmus University Medical Center, Erasmus, Rotterdam,The Netherlands
  5. 5Department of Neurology, Erasmus University Medical Center, Erasmus, Rotterdam,The Netherlands
  6. 6Institute of Psychological Medicine and Clinical Neurosciences, Medical Research Council (MRC) Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, UK
  7. 7Inserm U744, Lille, France
  8. 8Université Lille 2, Lille, France
  9. 9Institut Pasteur de Lille, Lille, France
  10. 10Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
  11. 11The John P. Hussman Institute for Human Genomics, University of Miami, Miami, FL, USA
  12. 12Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA
  13. 13Trinity College, University of Dublin, Dublin, Ireland
  14. 14Macdonald Foundation Department of Human Genetics, University of Miami, Miami, FL, USA
  15. 15University of Iceland, Faculty of Medicine, Reykjavik, Iceland
  16. 16Icelandic Heart Association, Kopavogur, Iceland
  17. 17Department of Neurology, Boston University School of Medicine, Boston, MA, USA
  18. 18Netherlands Consortium for Healthy Aging, Leiden, The Netherlands
  19. 19Department of Radiology, Erasmus University Medical Center, Erasmus, Rotterdam,The Netherlands
  20. 20Institute for Molecular Biology and Biochemistry, Medical University of Graz, Graz, Austria
  21. 21Laboratory for Statistical Analysis, Center for Integrative Medical Sciences, Riken, Kanagawa, Japan
  22. 22Foundation Jean Dausset—CEPH, Paris, France
  23. 23Memory Clinic of Fundació ACE, Institut Català de Neurociències Aplicades, Barcelona, Spain
  24. 24Centre National de Genotypage, Institut Genomique, Commissariat a l’energie Atomique, Evry, France
  25. 25Department of Psychiatry and Psychotherapy, University of Bonn, Bonn, Germany
  26. 26Institute of Human Genetics, University of Bonn, Bonn, Germany
  27. 27Department of Medical and Molecular Genetics, Indiana University, Indianapolis, IN, USA
  28. 28German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany
  29. 29Institute for Medical Biometry, Informatics and Epidemiology, University of Bonn, Bonn, Germany
  30. 30Department of Epidemiology, University of Washington, Seattle, WA, USA
  31. 31Centre National de Reference pour les Malades Alzheimer Jeunes (CNR-MAJ), Centre Hospitalier Régional Universitaire de Lille, Lille, France
  32. 32Hope Center Program on Protein Aggregation and Neurodegeneration, Washington University School of Medicine, St Louis, MO, USA
  33. 33Department of Psychiatry, Washington University School of Medicine, St Louis, MO, USA
  34. 34National Alzheimer’s Coordinating Center, University of Washington, Seattle, WA, USA
  35. 35Departments of Health Services, University of Washington, Seattle, WA, USA
  36. 36Department of Geriatrics, University Paris Descartes, Sorbonne Paris V, France
  37. 37Geriatrics Department, Broca Hospital, Paris, France
  38. 38Mercer’s Institute for Research on Aging, St James Hospital and Trinity College, Dublin, Ireland
  39. 39Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, Fort Worth, TX, USA
  40. 40CNR-MAJ, Inserm U1079, Rouen, France; University Hospital, 76031 Rouen, France
  41. 41University of Bristol Institute of Clinical Neurosciences, School of Clinical Sciences, Frenchay Hospital, Bristol, UK
  42. 42Department of Neurological Sciences, Rush University Medical Center, Chicago, IL, USA
  43. 43Rush Alzheimer’s Disease Center, Rush University Medical Center, Chicago, IL, USA
  44. 44Inserm U888, Hôpital La Colombière, Montpellier, France
  45. 45Department of Neurology, Aristotle University of Thessaloniki, Thessaloniki, Greece
  46. 46Department of Neuroscience, Mount Sinai School of Medicine, New York, NY, USA
  47. 47Department of Psychiatry, Mount Sinai School of Medicine, New York, NY, USA
  48. 48Departments of Genetics and Genomic Sciences, Mount Sinai School of Medicine, New York, NY, USA
  49. 49University of Pittsburgh Alzheimer’s Disease Research Center, Pittsburgh, PA, USA
  50. 50Departments of Neurology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
  51. 51Dementia Research Centre, Department of Neurodegenerative Disease, University College London Institute of Neurology, London, UK
  52. 52Memory Clinic of Fundació ACE, Institut Català de Neurociències Aplicades, Barcelona, Spain
  53. 53Inserm U897, Victor Segalen University, F-33076, Bordeaux, France
  54. 54Department of Molecular Neuroscience, Institute of Neurology, London, UK
  55. 55Reta Lilla Weston Laboratories, Institute of Neurology, London, UK
  56. 56Department of Medicine, University of Washington, Seattle, WA, USA
  57. 57Oxford Healthy Aging Project (OHAP), Clinical Trial Service Unit, University of Oxford, Oxford, UK
  58. 58Rush Institute for Healthy Aging, Department of Internal Medicine, Rush University Medical Center, Chicago, IL, USA
  59. 59Department of Medicine (Geriatrics), University of Mississippi Medical Center, Jackson, MS, USA
  60. 60Institute of Public Health, University of Cambridge, Cambridge, UK
  61. 61Program 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
  62. 62Program in Medical and Population Genetics, Broad Institute, Cambridge, MA, USA
  63. 63Faculty of Pharmaceutical Sciences, University of Iceland, Reykjavik, Iceland
  64. 64Centre de Mémoire de Ressources et de Recherche de Bordeaux, CHU de Bordeaux, Bordeaux, France
  65. 65Department of Psychiatry, University of Frankfurt, Frankfurt am Main, Germany
  66. 66Department of Psychiatry, Ludwig Maximilians University, Munich, Germany
  67. 67Department of Human Genetics, University of Pittsburgh, Pittsburgh, PA, USA
  68. 68Neurogenetics Laboratory, Division of Neurosciences, Center for Applied Medical Research, University of Navarra School of Medicine, Pamplona, Spain
  69. 69CIBERNED, Instituto de Salud Carlos III, Madrid, Spain
  70. 70Group Health, Group Health Research Institute, Seattle, WA, USA
  71. 71Institute for Translational Genomics and Population Sciences, Los Angeles BioMedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA, USA
  72. 72Division of Genetic Outcomes, Department of Pediatrics, Harbor-UCLA Medical Center, Torrance, CA, USA
  73. 73Department of Pathology, University of Washington, Seattle, WA, USA
  74. 74Laboratory of Neurogenetics, Intramural Research Program, National Institute on Aging, Bethesda, MD, USA
  75. 75Arizona Alzheimer’s Consortium, Phoenix, AZ, USA
  76. 76Department of Psychiatry, University of Arizona, Phoenix, AZ, USA
  77. 77Banner Alzheimer's Institute, Phoenix, AZ, USA
  78. 78Neurogenomics Division, Translational Genomics Research Institute, Phoenix, Arizona
  79. 79Department of Geriatrics, Landspitali National University Hospital, Reykjavik, Iceland
  80. 80Division of Clinical Neurosciences, School of Medicine, University of Southampton, Southampton, UK
  81. 81Tanz Centre for Research in Neurodegenerative Disease, University of Toronto, Toronto, ON, Canada
  82. 82Cambridge Institute for Medical Research and Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK
  83. 83Ageing Group, Centre for Public Health, School of Medicine, Dentistry and Biomedical Sciences, Queen’s University, Belfast, UK
  84. 84PharmaTherapeutics Clinical Research, Pfizer Worldwide Research and Development, Cambridge, MA, USA
  85. 85Department of Neurology, Medical University of Graz, Graz, Austria
  86. 86Institute of Genetics, Queen’s Medical Centre, University of Nottingham, Nottingham, UK
  87. 87King’s College London, Institute of Psychiatry, Department of Neuroscience, De Crespigny Park, Denmark Hill, London, UK
  88. 88Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA
  89. 89Department of Biology, Brigham Young University, Provo, Utah, USA
  90. 90Department of Genetics, University of North Carolina Chapel Hill, Chapel Hill, NC, USA
  91. 91Department of Psychiatry, Psychotherapy and Psychosomatics Martin-Luther-University Halle-Wittenberg, Halle, Germany
  92. 92Institute of Human Genetics, Department of Genomics, Life and Brain Center, University of Bonn, Bonn, Germany
  93. 93Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, OH, USA
  94. 94Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, VIB, Antwerp, Belgium
  95. 95Institute Born-Bunge, University of Antwerp, Antwerp, Belgium
  96. 96Laboratory of Epidemiology, Demography, and Biometry, National Institute of Health, Bethesda, MD, USA
  97. 97Taub Institute on Alzheimer's Disease and the Aging Brain, Columbia University, New York, NY, USA
  98. 98Gertrude H. Sergievsky Center, Columbia University, New York, NY, USA
  99. 99Department of Neurology, Columbia University, New York, NY, USA
  100. 100McGill University and Génome Québec Innovation Centre, Montreal, QC, Canada
  101. 101University Hospital, CHRU Lille, Lille, France
  102. 102Department of Epidemiology, Boston University School of Public Health, Boston, MA, USA

Correspondence: Dr LA Farrer, Biomedical Genetics E200, Boston University Schools of Medicine and Public Health, 72 East Concord Street, Boston, MA 02118, USA. E-mail: farrer@bu.edu

103IGAP Consortium members are listed before the Conflict of Interest section.

Received 19 October 2014; Revised 5 December 2014; Accepted 8 January 2015
Advance online publication 17 March 2015

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Abstract

APOE ε4, 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 ε4+ (10352 cases and 9207 controls) and APOE ε4− (7184 cases and 26968 controls) subgroups as well as in the total sample testing for interaction between a single-nucleotide polymorphism (SNP) and APOE ε4 status. Suggestive associations (P<1 × 10-4) in stage 1 were evaluated in an independent sample (stage 2) containing 4203 subjects (APOE ε4+: 1250 cases and 536 controls; APOE ε4−: 718 cases and 1699 controls). Among APOE ε4− 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 ε4+ subjects (CR1 and CLU) or APOE ε4− 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 (Pless than or equal to1.3 × 10-8), frontal cortex (Pless than or equal to1.3 × 10-9) and temporal cortex (Pless than or equal to1.2 × 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 ε4 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.