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Mol Psychiatry. 2016 Jan;21(1):108-17. doi: 10.1038/mp.2015.23. Epub 2015 Mar 17.

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

Jun G1,2,3, Ibrahim-Verbaas CA4,5, Vronskaya M6, Lambert JC7,8,9, Chung J1, Naj AC10, Kunkle BW11, Wang LS10, Bis JC12, Bellenguez C7,8,9, Harold D13, Lunetta KL3, Destefano AL3, Grenier-Boley B7,8,9, Sims R6, Beecham GW11,14, Smith AV15,16, Chouraki V17, Hamilton-Nelson KL11, Ikram MA4,18,19, Fievet N7,8,9, Denning N6, Martin ER11,14, Schmidt H20, Kamatani Y21,22, Dunstan ML6, Valladares O10, Laza AR23, Zelenika D24, Ramirez A25,26, Foroud TM27, Choi SH3, Boland A24, Becker T28,29, Kukull WA30, van der Lee SJ4, Pasquier F8,31, Cruchaga C32,33, Beekly D34, Fitzpatrick AL30,35, Hanon O36,37, Gill M38, Barber R39, Gudnason V15,16, Campion D40,41, Love S41, Bennett DA42,43, Amin N4, Berr C44, Tsolaki M45, Buxbaum JD46,47,48, Lopez OL49,50, Deramecourt V8,31, Fox NC51, Cantwell LB10, Tárraga L23, Dufouil C52, Hardy J53,54, Crane PK55, Eiriksdottir G16, Hannequin D40,52, Clarke R56, Evans D57, Mosley TH Jr58, Letenneur L52, Brayne C59, Maier W25,28, De Jager P5,60,61, Emilsson V16,62, Dartigues JF52,63, Hampel H64,65, Kamboh MI49,66, de Bruijn RF4, Tzourio C52, Pastor P67,68, Larson EB55,69, Rotter JI70,71, O'Donovan MC6, Montine TJ72, Nalls MA73, Mead S53, Reiman EM74,75,76,77, Jonsson PV15,78, Holmes C79, St George-Hyslop PH80,81, Boada M23, Passmore P82, Wendland JR83, Schmidt R84, Morgan K85, Winslow AR83, Powell JF86, Carasquillo M87, Younkin SG87, Jakobsdóttir J16, Kauwe JS88, Wilhelmsen KC89, Rujescu D90, Nöthen MM26,91, Hofman A4,19, Jones L6; IGAP Consortium, Haines JL92, Psaty BM12,30,35,69, Van Broeckhoven C93,94, Holmans P6, Launer LJ95, Mayeux R96,97,98, Lathrop M22,24,99, Goate AM32,33, Escott-Price V6, Seshadri S17, Pericak-Vance MA11,14, Amouyel P7,8,9,100, Williams J6, van Duijn CM4, Schellenberg GD10, Farrer LA1,2,3,17,101.

Collaborators (311)

Adams PM, Albert MS, Albin RL, Apostolova LG, Arnold SE, Asthana S, Atwood CS, Baldwin CT, Barmada MM, Barnes LL, Beach TG, Becker JT, Bigio EH, Bird TD, Blacker D, Boeve BF, Bowen JD, Boxer A, Burke JR, Cairns NJ, Cao C, Carlson CS, Carlsson CM, Carney RM, Carrasquillo MM, Carroll SL, Chui HC, Clark DG, Corneveaux J, Cribbs DH, Crocco EA, Cruchaga C, De Jager PL, DeCarli C, DeKosky ST, Demirci FY, Dick M, Dickson DW, Doody RS, Duara R, Ertekin-Taner N, Faber KM, Fairchild TJ, Fallon KB, Farlow MR, Ferris S, Frosch MP, Galasko DR, Gearing M, Geschwind DH, Ghetti B, Gilbert JR, Glass JD, Graff-Radford NR, Green RC, Growdon JH, Hakonarson H, Hamilton RL, Hardy J, Harrell LE, Head E, Honig LS, Huebinger RM, Huentelman MJ, Hulette CM, Hyman BT, Jarvik GP, Jicha GA, Jin LW, Karydas A, Kauwe JS, Kaye JA, Kim R, Koo EH, Kowall NW, Kramer JH, LaFerla FM, Lah JJ, Leverenz JB, Levey AI, Li G, Lieberman AP, Lin CF, Lopez OL, Lyketsos CG, Mack WJ, Marson DC, Martiniuk F, Mash DC, Masliah E, McCormick WC, McCurry SM, McDavid AN, McKee AC, Mesulam M, Miller BL, Miller CA, Miller JW, Morris JC, Mukherjee S, Murrell JR, Myers AJ, O'Bryant S, Olichney JM, Pankratz VS, Parisi JE, Partch A, Paulson HL, Perry W, Peskind E, Petersen RC, Pierce A, Poon WW, Potter H, Quinn JF, Raj A, Raskind M, Reisberg B, Reisch JS, Reitz C, Ringman JM, Roberson ED, Rogaeva E, Rosen HJ, Rosenberg RN, Royall DR, Sager MA, Sano M, Saykin AJ, Schneider JA, Schneider LS, Seeley WW, Smith AG, Sonnen JA, Spina S, Stern RA, Tanzi RE, Thornton-Wells TA, Trojanowski JQ, Troncoso JC, Tsuang DW, Van Deerlin VM, Van Eldik LJ, Vardarajan BN, Vinters HV, Vonsattel JP, Weintraub S, Welsh-Bohmer KA, Williamson J, Wishnek S, Woltjer RL, Wright CB, Wu CK, Yu CE, Yu L, Au R, Wolf PA, Beiser A, Satizabal C, Uitterlinden AG, Rivadeneira F, Koudstaal PJ, Longstreth WT Jr, Becker JT, Kuller LH, Lumley T, Rice K, Harris TB, Nalls M, Marksteiner JJ, Dal-Bianco P, Töglhofer AM, Freudenberger P, Ransmayr G, Benke T, Toeglhofer AM, Boerwinkle E, Bressler J, Fornage M, Morón FJ, Hernández I, Roca MR, Mauleón A, Alegret M, Ramírez-Lorca R, González-Perez A, Alpérovitch A, Alvarez V, Barberger-Gateau P, Bettens K, Bossù P, Brice A, Bullido M, Caffara P, Clarimon J, Combarros O, Coto E, Del Zampo M, Delepine M, Deniz Naranjo MC, Epelbaum J, Fratiglioni L, Galimberti D, Graff C, Hiltunen M, Ingelsson M, Keller L, Lannfelt L, Llèo A, Mancuso M, Mateo I, Mecocci P, Nacmias B, Panza F, Pilotto A, Garcia FS, Scarpini E, Seripa D, Sleegers K, Soininen H, Sorbi S, Spalletta G, Wallon D, Thomas C, Gerrish A, Chapman J, Stretton A, Morgan A, Oldham H, Owen MJ, Kehoe PG, Medway C, Brown K, Lord J, Turton J, Hooper NM, Vardy E, Warren JD, Schott JM, Uphill J, Hollingworth P, Ryan N, Rossor M, Collinge J, Ben-Shlomo Y, Makrina D, Gkatzima O, Lupton M, Koutroumani M, Avramidou D, Germanou A, Jessen F, Riedel-Heller S, Dichgans M, Heun R, Kölsch H, Schürmann B, Herold C, Lacour A, Drichel D, Hoffmann P, Kornhuber J, Gu W, Feulner T, Mayhaus M, Pichler S, Riemenschneider M, van den Bussche H, Lawlor B, Lynch A, Mann D, Smith AD, Warden D, Wilcock G, Heuser I, Wiltfang J, Frölich L, Hüll M, Mayo K, Livingston G, Bass NJ, Gurling H, McQuillin A, Gwilliam R, Deloukas P, Al-Chalabi A, Shaw CE, Singleton AB, Guerreiro R, Russo G, Jöckel KH, Moebus S, Klopp N, Wichmann HE, Dickson DW, Graff-Radford NR, Ma L, Bisceglio G, Fisher E, Warner N, Pickering-Brown S, Craig D, Johnston JA, McGuinness B, Todd S, Rubinsztein DC, Lovestone S, Bayer A, Gallacher J, Proitsi P, Ortega-Cubero S.

Author information

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

PMID:
25778476
PMCID:
PMC4573764
DOI:
10.1038/mp.2015.23
[Indexed for MEDLINE]
Free PMC Article

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