Journal Articles

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

March 17, 2015

A novel Alzheimer disease locus located near the gene encoding tau proteinMol Psychiatry. 2015 Mar 17, Jun G1, Ibrahim-Verbaas CA2, Vronskaya M3, Lambert JC4, Chung J5, Naj AC6, Kunkle BW7, Wang LS6, Bis JC8, Bellenguez C4, Harold D9, Lunetta KL10,Destefano AL10, Grenier-Boley B4, Sims R3, Beecham GW11, Smith AV12, Chouraki V13, Hamilton-Nelson KL7, Ikram MA14, Fievet N4, Denning N3, Martin ER11, Schmidt H15, Kamatani Y16, Dunstan ML3, Valladares O6, Laza AR17, Zelenika D18, Ramirez A19, Foroud TM20, Choi SH10, Boland A18, Becker T21,Kukull WA22, van der Lee SJ23, Pasquier F24, Cruchaga C25, Beekly D26, Fitzpatrick AL27, Hanon O28, Gill M29, Barber R30, Gudnason V12, Campion D31,Love S32, Bennett DA33, Amin N23, Berr C34, Tsolaki M35, Buxbaum JD36, Lopez OL37, Deramecourt V24, Fox NC38, Cantwell LB6, Tárraga L17, Dufouil C39,Hardy J40, Crane PK41, Eiriksdottir G42, Hannequin D43, Clarke R44, Evans D45, Mosley TH Jr46, Letenneur L39, Brayne C47, Maier W48, De Jager P49,Emilsson V50, Dartigues JF51, Hampel H52, Kamboh MI53, de Bruijn RF23, Tzourio C39, Pastor P54, Larson EB55, Rotter JI56, O’Donovan MC3, Montine TJ57,Nalls MA58, Mead S59, Reiman EM60, Jonsson PV61, Holmes C62, St George-Hyslop PH63, Boada M17, Passmore P64, Wendland JR65, Schmidt R66, Morgan K67, Winslow AR65, Powell JF68, Carasquillo M69, Younkin SG69, Jakobsdóttir J42, Kauwe JS70, Wilhelmsen KC71, Rujescu D72, Nöthen MM73, Hofman A74,Jones L3; IGAP Consortium, Haines JL75, Psaty BM76, Van Broeckhoven C77, Holmans P3, Launer LJ78, Mayeux R79, Lathrop M80, Goate AM25, Escott-Price V3, Seshadri S13, Pericak-Vance MA11, Amouyel P81, Williams J3, van Duijn CM23, Schellenberg GD6, Farrer LA82.

  • 1] Department of Medicine (Biomedical Genetics), Boston University School of Medicine, Boston, MA, USA [2] Department of Ophthalmology, Boston University School of Medicine, Boston, MA, USA [3] Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA.
  • 21] Department of Epidemiology, Erasmus University Medical Center, Erasmus, Rotterdam,The Netherlands [2] Department of Neurology, Erasmus University Medical Center, Erasmus, Rotterdam,The Netherlands.
  • 3Institute of Psychological Medicine and Clinical Neurosciences, Medical Research Council (MRC) Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, UK.
  • 41] Inserm U744, Lille, France [2] Université Lille 2, Lille, France [3] Institut Pasteur de Lille, Lille, France.
  • 5Department of Medicine (Biomedical Genetics), Boston University School of Medicine, Boston, MA, USA.
  • 6Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
  • 7The John P. Hussman Institute for Human Genomics, University of Miami, Miami, FL, USA.
  • 8Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA.
  • 9Trinity College, University of Dublin, Dublin, Ireland.
  • 10Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA.
  • 111] The John P. Hussman Institute for Human Genomics, University of Miami, Miami, FL, USA [2] Macdonald Foundation Department of Human Genetics, University of Miami, Miami, FL, USA.
  • 121] University of Iceland, Faculty of Medicine, Reykjavik, Iceland [2] Icelandic Heart Association, Kopavogur, Iceland.
  • 13Department of Neurology, Boston University School of Medicine, Boston, MA, USA.
  • 141] Department of Epidemiology, Erasmus University Medical Center, Erasmus, Rotterdam,The Netherlands [2] Netherlands Consortium for Healthy Aging, Leiden, The Netherlands [3] Department of Radiology, Erasmus University Medical Center, Erasmus, Rotterdam,The Netherlands.
  • 15Institute for Molecular Biology and Biochemistry, Medical University of Graz, Graz, Austria.
  • 161] Laboratory for Statistical Analysis, Center for Integrative Medical Sciences, Riken, Kanagawa, Japan [2] Foundation Jean Dausset-CEPH, Paris, France.
  • 17Memory Clinic of Fundació ACE, Institut Català de Neurociències Aplicades, Barcelona, Spain.
  • 18Centre National de Genotypage, Institut Genomique, Commissariat a l’energie Atomique, Evry, France.
  • 191] Department of Psychiatry and Psychotherapy, University of Bonn, Bonn, Germany [2] Institute of Human Genetics, University of Bonn, Bonn, Germany.
  • 20Department of Medical and Molecular Genetics, Indiana University, Indianapolis, IN, USA.
  • 211] German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany [2] Institute for Medical Biometry, Informatics and Epidemiology, University of Bonn, Bonn, Germany.
  • 22Department of Epidemiology, University of Washington, Seattle, WA, USA.
  • 23Department of Epidemiology, Erasmus University Medical Center, Erasmus, Rotterdam,The Netherlands.
  • 241] Université Lille 2, Lille, France [2] Centre National de Reference pour les Malades Alzheimer Jeunes (CNR-MAJ), Centre Hospitalier Régional Universitaire de Lille, Lille, France.
  • 251] Hope Center Program on Protein Aggregation and Neurodegeneration, Washington University School of Medicine, St Louis, MO, USA [2] Department of Psychiatry, Washington University School of Medicine, St Louis, MO, USA.
  • 26National Alzheimer‘s Coordinating Center, University of Washington, Seattle, WA, USA.
  • 271] Department of Epidemiology, University of Washington, Seattle, WA, USA [2] Departments of Health Services, University of Washington, Seattle, WA, USA.
  • 281] Department of Geriatrics, University Paris Descartes, Sorbonne Paris V, France [2] Geriatrics Department, Broca Hospital, Paris, France.
  • 29Mercer’s Institute for Research on Aging, St James Hospital and Trinity College, Dublin, Ireland.
  • 30Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, Fort Worth, TX, USA.
  • 311] CNR-MAJ, Inserm U1079, Rouen, France; University Hospital, 76031 Rouen, France [2] University of Bristol Institute of Clinical Neurosciences, School of Clinical Sciences, Frenchay Hospital, Bristol, UK.
  • 32University of Bristol Institute of Clinical Neurosciences, School of Clinical Sciences, Frenchay Hospital, Bristol, UK.
  • 331] Department of Neurological Sciences, Rush University Medical Center, Chicago, IL, USA [2] Rush Alzheimer‘s Disease Center, Rush University Medical Center, Chicago, IL, USA.
  • 34Inserm U888, Hôpital La Colombière, Montpellier, France.
  • 35Department of Neurology, Aristotle University of Thessaloniki, Thessaloniki, Greece.
  • 361] Department of Neuroscience, Mount Sinai School of Medicine, New York, NY, USA [2] Department of Psychiatry, Mount Sinai School of Medicine, New York, NY, USA [3] Departments of Genetics and Genomic Sciences, Mount Sinai School of Medicine, New York, NY, USA.
  • 371] University of Pittsburgh Alzheimer‘s Disease Research Center, Pittsburgh, PA, USA [2] Departments of Neurology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
  • 38Dementia Research Centre, Department of Neurodegenerative Disease, University College London Institute of Neurology, London, UK.
  • 39Inserm U897, Victor Segalen University, F-33076, Bordeaux, France.
  • 401] Department of Molecular Neuroscience, Institute of Neurology, London, UK [2] Reta Lilla Weston Laboratories, Institute of Neurology, London, UK.
  • 41Department of Medicine, University of Washington, Seattle, WA, USA.
  • 42Icelandic Heart Association, Kopavogur, Iceland.
  • 431] CNR-MAJ, Inserm U1079, Rouen, France; University Hospital, 76031 Rouen, France [2] Inserm U897, Victor Segalen University, F-33076, Bordeaux, France.
  • 44Oxford Healthy Aging Project (OHAP), Clinical Trial Service Unit, University of Oxford, Oxford, UK.
  • 45Rush Institute for Healthy Aging, Department of Internal Medicine, Rush University Medical Center, Chicago, IL, USA.
  • 46Department of Medicine (Geriatrics), University of Mississippi Medical Center, Jackson, MS, USA.
  • 47Institute of Public Health, University of Cambridge, Cambridge, UK.
  • 481] Department of Psychiatry and Psychotherapy, University of Bonn, Bonn, Germany [2] German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany.
  • 491] Department of Neurology, Erasmus University Medical Center, Erasmus, Rotterdam,The Netherlands [2] 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 [3] Program in Medical and Population Genetics, Broad Institute, Cambridge, MA, USA.
  • 501] Icelandic Heart Association, Kopavogur, Iceland [2] Faculty of Pharmaceutical Sciences, University of Iceland, Reykjavik, Iceland.
  • 511] Inserm U897, Victor Segalen University, F-33076, Bordeaux, France [2] Centre de Mémoire de Ressources et de Recherche de Bordeaux, CHU de Bordeaux, Bordeaux, France.
  • 521] Department of Psychiatry, University of Frankfurt, Frankfurt am Main, Germany [2] Department of Psychiatry, Ludwig Maximilians University, Munich, Germany.
  • 531] University of Pittsburgh Alzheimer‘s Disease Research Center, Pittsburgh, PA, USA [2] Department of Human Genetics, University of Pittsburgh, Pittsburgh, PA, USA.
  • 541] Neurogenetics Laboratory, Division of Neurosciences, Center for Applied Medical Research, University of Navarra School of Medicine, Pamplona, Spain [2] CIBERNED, Instituto de Salud Carlos III, Madrid, Spain.
  • 551] Department of Medicine, University of Washington, Seattle, WA, USA [2] Group Health, Group Health Research Institute, Seattle, WA, USA.
  • 561] Institute for Translational Genomics and Population Sciences, Los Angeles BioMedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA, USA [2] Division of Genetic Outcomes, Department of Pediatrics, Harbor-UCLA Medical Center, Torrance, CA, USA.
  • 57Department of Pathology, University of Washington, Seattle, WA, USA.
  • 58Laboratory of Neurogenetics, Intramural Research Program, National Institute on Aging, Bethesda, MD, USA.
  • 59Department of Molecular Neuroscience, Institute of Neurology, London, UK.
  • 601] Arizona Alzheimer‘s Consortium, Phoenix, AZ, USA [2] Department of Psychiatry, University of Arizona, Phoenix, AZ, USA [3] BannerAlzheimer‘s Institute, Phoenix, AZ, USA [4] Neurogenomics Division, Translational Genomics Research Institute, Phoenix, Arizona.
  • 611] University of Iceland, Faculty of Medicine, Reykjavik, Iceland [2] Department of Geriatrics, Landspitali National University Hospital, Reykjavik, Iceland.
  • 62Division of Clinical Neurosciences, School of Medicine, University of Southampton, Southampton, UK.
  • 631] Tanz Centre for Research in Neurodegenerative Disease, University of Toronto, Toronto, ON, Canada [2] Cambridge Institute for Medical Research and Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK.
  • 64Ageing Group, Centre for Public Health, School of Medicine, Dentistry and Biomedical Sciences, Queen’s University, Belfast, UK.
  • 65PharmaTherapeutics Clinical Research, Pfizer Worldwide Research and Development, Cambridge, MA, USA.
  • 66Department of Neurology, Medical University of Graz, Graz, Austria.
  • 67Institute of Genetics, Queen’s Medical Centre, University of Nottingham, Nottingham, UK.
  • 68King’s College London, Institute of Psychiatry, Department of Neuroscience, De Crespigny Park, Denmark Hill, London, UK.
  • 69Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
  • 70Department of Biology, Brigham Young University, Provo, Utah, USA.
  • 71Department of Genetics, University of North Carolina Chapel Hill, Chapel Hill, NC, USA.
  • 72Department of Psychiatry, Psychotherapy and Psychosomatics Martin-Luther-University Halle-Wittenberg, Halle, Germany.
  • 731] Institute of Human Genetics, University of Bonn, Bonn, Germany [2] Institute of Human Genetics, Department of Genomics, Life and Brain Center, University of Bonn, Bonn, Germany.
  • 741] Department of Epidemiology, Erasmus University Medical Center, Erasmus, Rotterdam,The Netherlands [2] Department of Radiology, Erasmus University Medical Center, Erasmus, Rotterdam,The Netherlands.
  • 75Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, OH, USA.
  • 761] Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA [2] Department of Epidemiology, University of Washington, Seattle, WA, USA [3] Departments of Health Services, University of Washington, Seattle, WA, USA [4] Group Health, Group Health Research Institute, Seattle, WA, USA.
  • 771] Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, VIB, Antwerp, Belgium [2] Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.
  • 78Laboratory of Epidemiology, Demography, and Biometry, National Institute of Health, Bethesda, MD, USA.
  • 791] Taub Institute on Alzheimer‘s Disease and the Aging Brain, Columbia University, New York, NY, USA [2] Gertrude H. Sergievsky Center, Columbia University, New York, NY, USA [3] Department of Neurology, Columbia University, New York, NY, USA.
  • 801] Foundation Jean Dausset-CEPH, Paris, France [2] Centre National de Genotypage, Institut Genomique, Commissariat a l’energie Atomique, Evry, France [3] McGill University and Génome Québec Innovation Centre, Montreal, QC, Canada.
  • 811] Inserm U744, Lille, France [2] Université Lille 2, Lille, France [3] Institut Pasteur de Lille, Lille, France [4] University Hospital, CHRU Lille, Lille, France.
  • 821] Department of Medicine (Biomedical Genetics), Boston University School of Medicine, Boston, MA, USA [2] Department of Ophthalmology, Boston University School of Medicine, Boston, MA, USA [3] Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA [4] Department of Neurology, Boston University School of Medicine, Boston, MA, USA [5] Department of Epidemiology, Boston University School of Public Health, Boston, MA, USA.

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, novelgenome-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.Molecular Psychiatry advance online publication, 17 March 2015; doi:10.1038/mp.2015.23.

PMID:
25778476
[PubMed – as supplied by publisher]

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