Evidence map›Paper›PMID 25778476›Full record

ArticleMolecular psychiatry2016

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

G Jun, C A Ibrahim-Verbaas, M Vronskaya, J-C Lambert, J Chung, A C Naj, B W Kunkle, L-S Wang, J C Bis, C Bellenguez and 108 more

Open access · greenAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Molecular psychiatry, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 210 papers, 9 of them syntheses that pooled it.

0numbers the graph read from it
0cells of the map it votes in
210citing papers in PubMed, 9 pooled it
16.4field-weighted citation impact, top 1% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

210 citing papers in PubMed, 9 syntheses or guidelines pooled it, 305 citations in OpenAlex.

  1. International journal of molecular sciences · 2025
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  15. APOE*4 risk-modifying genes and drug targets in Alzheimer's disease through cell-type-specific genomic analyses.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2026
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  16. HiFiMAP: High-resolution fast identity-by-descent mapping test.medRxiv : the preprint server for health sciences · 2026
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  19. Promoter mutagenesis and a massively parallel reporter screen of thebioRxiv : the preprint server for biology · 2026
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150 more citing papers are in PubMed but not listed here.

4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

118 authors at 20 institutions in 13 countries.

G JunDepartment of Medicine (Biomedical Genetics), Boston University School of Medicine, Boston, MA, USA.
C A Ibrahim-VerbaasDepartment of Epidemiology, Erasmus University Medical Center, Erasmus, Rotterdam,The Netherlands.
M VronskayaInstitute of Psychological Medicine and Clinical Neurosciences, Medical Research Council (MRC) Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, UK.
J-C LambertInserm U744, Lille, France.
J ChungDepartment of Medicine (Biomedical Genetics), Boston University School of Medicine, Boston, MA, USA.
A C NajDepartment of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
B W KunkleThe John P. Hussman Institute for Human Genomics, University of Miami, Miami, FL, USA.
L-S WangDepartment of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
J C BisCardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA.
C BellenguezInserm U744, Lille, France.
D HaroldTrinity College, University of Dublin, Dublin, Ireland.
K L LunettaDepartment of Biostatistics, Boston University School of Public Health, Boston, MA, USA.
A L DestefanoDepartment of Biostatistics, Boston University School of Public Health, Boston, MA, USA.
B Grenier-BoleyInserm U744, Lille, France.
R SimsInstitute of Psychological Medicine and Clinical Neurosciences, Medical Research Council (MRC) Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, UK.
G W BeechamThe John P. Hussman Institute for Human Genomics, University of Miami, Miami, FL, USA.
A V SmithUniversity of Iceland, Faculty of Medicine, Reykjavik, Iceland.
V ChourakiDepartment of Neurology, Boston University School of Medicine, Boston, MA, USA.ORCID http://orcid.org/0000-0002-4698-1794
K L Hamilton-NelsonThe John P. Hussman Institute for Human Genomics, University of Miami, Miami, FL, USA.
M A IkramDepartment of Epidemiology, Erasmus University Medical Center, Erasmus, Rotterdam,The Netherlands.
N FievetInserm U744, Lille, France.
N DenningInstitute of Psychological Medicine and Clinical Neurosciences, Medical Research Council (MRC) Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, UK.
E R MartinThe John P. Hussman Institute for Human Genomics, University of Miami, Miami, FL, USA.
H SchmidtInstitute for Molecular Biology and Biochemistry, Medical University of Graz, Graz, Austria.
Y KamataniLaboratory for Statistical Analysis, Center for Integrative Medical Sciences, Riken, Kanagawa, Japan.
M L DunstanInstitute of Psychological Medicine and Clinical Neurosciences, Medical Research Council (MRC) Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, UK.
O ValladaresDepartment of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
A R LazaMemory Clinic of Fundació ACE, Institut Català de Neurociències Aplicades, Barcelona, Spain.
D ZelenikaCentre National de Genotypage, Institut Genomique, Commissariat a l'energie Atomique, Evry, France.
A RamirezDepartment of Psychiatry and Psychotherapy, University of Bonn, Bonn, Germany.
T M ForoudDepartment of Medical and Molecular Genetics, Indiana University, Indianapolis, IN, USA.
S-H ChoiDepartment of Biostatistics, Boston University School of Public Health, Boston, MA, USA.
A BolandCentre National de Genotypage, Institut Genomique, Commissariat a l'energie Atomique, Evry, France.
T BeckerGerman Center for Neurodegenerative Diseases (DZNE), Bonn, Germany.
W A KukullDepartment of Epidemiology, University of Washington, Seattle, WA, USA.
S J van der LeeDepartment of Epidemiology, Erasmus University Medical Center, Erasmus, Rotterdam,The Netherlands.
F PasquierUniversité Lille 2, Lille, France.
C CruchagaHope Center Program on Protein Aggregation and Neurodegeneration, Washington University School of Medicine, St Louis, MO, USA.
D BeeklyNational Alzheimer's Coordinating Center, University of Washington, Seattle, WA, USA.
A L FitzpatrickDepartment of Epidemiology, University of Washington, Seattle, WA, USA.
O HanonDepartment of Geriatrics, University Paris Descartes, Sorbonne Paris V, France.
M GillMercer's Institute for Research on Aging, St James Hospital and Trinity College, Dublin, Ireland.
R BarberDepartment of Pharmacology and Neuroscience, University of North Texas Health Science Center, Fort Worth, TX, USA.
V GudnasonUniversity of Iceland, Faculty of Medicine, Reykjavik, Iceland.
D CampionCNR-MAJ, Inserm U1079, Rouen, France; University Hospital, 76031 Rouen, France.
S LoveUniversity of Bristol Institute of Clinical Neurosciences, School of Clinical Sciences, Frenchay Hospital, Bristol, UK.
D A BennettDepartment of Neurological Sciences, Rush University Medical Center, Chicago, IL, USA.
N AminDepartment of Epidemiology, Erasmus University Medical Center, Erasmus, Rotterdam,The Netherlands.
C BerrInserm U888, Hôpital La Colombière, Montpellier, France.
Magda TsolakiDepartment of Neurology, Aristotle University of Thessaloniki, Thessaloniki, Greece.
J D BuxbaumDepartment of Neuroscience, Mount Sinai School of Medicine, New York, NY, USA.
O L LopezUniversity of Pittsburgh Alzheimer's Disease Research Center, Pittsburgh, PA, USA.
V DeramecourtUniversité Lille 2, Lille, France.
N C FoxDementia Research Centre, Department of Neurodegenerative Disease, University College London Institute of Neurology, London, UK.
L B CantwellDepartment of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
L TárragaMemory Clinic of Fundació ACE, Institut Català de Neurociències Aplicades, Barcelona, Spain.
C DufouilInserm U897, Victor Segalen University, F-33076, Bordeaux, France.
J HardyDepartment of Molecular Neuroscience, Institute of Neurology, London, UK.
P K CraneDepartment of Medicine, University of Washington, Seattle, WA, USA.
G EiriksdottirIcelandic Heart Association, Kopavogur, Iceland.
D HannequinCNR-MAJ, Inserm U1079, Rouen, France; University Hospital, 76031 Rouen, France.
R ClarkeOxford Healthy Aging Project (OHAP), Clinical Trial Service Unit, University of Oxford, Oxford, UK.
D EvansRush Institute for Healthy Aging, Department of Internal Medicine, Rush University Medical Center, Chicago, IL, USA.
T H MosleyDepartment of Medicine (Geriatrics), University of Mississippi Medical Center, Jackson, MS, USA.
L LetenneurInserm U897, Victor Segalen University, F-33076, Bordeaux, France.
C BrayneInstitute of Public Health, University of Cambridge, Cambridge, UK.
W MaierDepartment of Psychiatry and Psychotherapy, University of Bonn, Bonn, Germany.
P De JagerDepartment of Neurology, Erasmus University Medical Center, Erasmus, Rotterdam,The Netherlands.
V EmilssonIcelandic Heart Association, Kopavogur, Iceland.
J-F DartiguesInserm U897, Victor Segalen University, F-33076, Bordeaux, France.
H HampelDepartment of Psychiatry, University of Frankfurt, Frankfurt am Main, Germany.
M I KambohUniversity of Pittsburgh Alzheimer's Disease Research Center, Pittsburgh, PA, USA.
R F A G de BruijnDepartment of Epidemiology, Erasmus University Medical Center, Erasmus, Rotterdam,The Netherlands.
C TzourioInserm U897, Victor Segalen University, F-33076, Bordeaux, France.
P PastorNeurogenetics Laboratory, Division of Neurosciences, Center for Applied Medical Research, University of Navarra School of Medicine, Pamplona, Spain.
E B LarsonDepartment of Medicine, University of Washington, Seattle, WA, USA.
J I RotterInstitute for Translational Genomics and Population Sciences, Los Angeles BioMedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA, USA.
M C O'DonovanInstitute of Psychological Medicine and Clinical Neurosciences, Medical Research Council (MRC) Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, UK.
T J MontineDepartment of Pathology, University of Washington, Seattle, WA, USA.
M A NallsLaboratory of Neurogenetics, Intramural Research Program, National Institute on Aging, Bethesda, MD, USA.
S MeadDepartment of Molecular Neuroscience, Institute of Neurology, London, UK.
E M ReimanArizona Alzheimer's Consortium, Phoenix, AZ, USA.
P V JonssonUniversity of Iceland, Faculty of Medicine, Reykjavik, Iceland.
C HolmesDivision of Clinical Neurosciences, School of Medicine, University of Southampton, Southampton, UK.
P H St George-HyslopTanz Centre for Research in Neurodegenerative Disease, University of Toronto, Toronto, ON, Canada.
M BoadaMemory Clinic of Fundació ACE, Institut Català de Neurociències Aplicades, Barcelona, Spain.
P PassmoreAgeing Group, Centre for Public Health, School of Medicine, Dentistry and Biomedical Sciences, Queen's University, Belfast, UK.
J R WendlandPharmaTherapeutics Clinical Research, Pfizer Worldwide Research and Development, Cambridge, MA, USA.
R SchmidtDepartment of Neurology, Medical University of Graz, Graz, Austria.
K MorganInstitute of Genetics, Queen's Medical Centre, University of Nottingham, Nottingham, UK.
A R WinslowPharmaTherapeutics Clinical Research, Pfizer Worldwide Research and Development, Cambridge, MA, USA.
J F PowellKing's College London, Institute of Psychiatry, Department of Neuroscience, De Crespigny Park, Denmark Hill, London, UK.
M CarasquilloDepartment of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
S G YounkinDepartment of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
J JakobsdóttirIcelandic Heart Association, Kopavogur, Iceland.
J S K KauweDepartment of Biology, Brigham Young University, Provo, Utah, USA.
K C WilhelmsenDepartment of Genetics, University of North Carolina Chapel Hill, Chapel Hill, NC, USA.
D RujescuDepartment of Psychiatry, Psychotherapy and Psychosomatics Martin-Luther-University Halle-Wittenberg, Halle, Germany.
M M NöthenInstitute of Human Genetics, University of Bonn, Bonn, Germany.
A HofmanDepartment of Epidemiology, Erasmus University Medical Center, Erasmus, Rotterdam,The Netherlands.
L JonesInstitute of Psychological Medicine and Clinical Neurosciences, Medical Research Council (MRC) Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, UK.
IGAP Consortium
J L HainesDepartment of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, OH, USA.
B M PsatyCardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA.
C Van BroeckhovenNeurodegenerative Brain Diseases Group, Department of Molecular Genetics, VIB, Antwerp, Belgium.
P HolmansInstitute of Psychological Medicine and Clinical Neurosciences, Medical Research Council (MRC) Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, UK.
L J LaunerLaboratory of Epidemiology, Demography, and Biometry, National Institute of Health, Bethesda, MD, USA.
R MayeuxTaub Institute on Alzheimer's Disease and the Aging Brain, Columbia University, New York, NY, USA.
M LathropFoundation Jean Dausset-CEPH, Paris, France.
A M GoateHope Center Program on Protein Aggregation and Neurodegeneration, Washington University School of Medicine, St Louis, MO, USA.
V Escott-PriceInstitute of Psychological Medicine and Clinical Neurosciences, Medical Research Council (MRC) Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, UK.
S SeshadriDepartment of Neurology, Boston University School of Medicine, Boston, MA, USA.
M A Pericak-VanceThe John P. Hussman Institute for Human Genomics, University of Miami, Miami, FL, USA.
P AmouyelInserm U744, Lille, France.ORCID http://orcid.org/0000-0001-9088-234X
J WilliamsInstitute of Psychological Medicine and Clinical Neurosciences, Medical Research Council (MRC) Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, UK.
C M van DuijnDepartment of Epidemiology, Erasmus University Medical Center, Erasmus, Rotterdam,The Netherlands.
G D SchellenbergDepartment of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
L A FarrerDepartment of Medicine (Biomedical Genetics), Boston University School of Medicine, Boston, MA, USA.
Cardiff University · GBInserm · FRUniversity of Miami · USBoston University · USErasmus MC · NLUniversity of Bonn · DEUniversity of Iceland · ISUniversity of Pennsylvania · USUniversity of Washington · USGroup Health Cooperative · USWashington University in St. Louis · USColumbia University · USFundació ACE · ESTrinity College Dublin · IEUniversity of Pittsburgh · USBrigham Young University · USBroad Institute · USCase Western Reserve University · USFondation Jean Dausset-CEPH · FRIcelandic Heart Association · IS

Funding

Alzheimer's Disease Neuroimaging Initiative - SupplementU01AG024904 · NIA · NORTHERN CALIFORNIA INSTITUTE RES &EDUC · PI WEINER, MICHAEL W · 2004 to 2015
$121.0M
National Centralized Repository for Alzheimer's Disease and Related Dementias (NCRAD)U24AG021886 · NIA · INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS · PI TATIANA M. FOROUD · 2002 to 2026
$119.8M
TRIAL OF VALPROATE TO ATTENUATE THE PROGRESSION OF ADU01AG010483 · NIA · UNIVERSITY OF ROCHESTER · PI AISEN, PAUL S. · 1991 to 2012
$116.2M
Institute for Clinical and Translational Research (UL1)UL1RR025005 · NCRR · JOHNS HOPKINS UNIVERSITY · PI FORD, DANIEL ERNEST · 2007 to 2011
$75.8M
NATIONAL ALZHEIMERS COORDINATING CENTER (NACC)U01AG016976 · NIA · UNIVERSITY OF WASHINGTON · PI KUKULL, WALTER ANTHONY · 1999 to 2020
$72.8M
Smartphone-Based "Burst" Cognitive AssessmentsP01AG003991 · NIA · WASHINGTON UNIVERSITY · PI Tammie Lee Smith Benzinger · 1985 to 2026
$69.5M
TDP-43 Loss-of-Function: Biology to BiomarkersP01AG019724 · NIA · UNIVERSITY OF PENNSYLVANIA · PI Jennifer Merrilees · 2002 to 2026
$67.2M
Alzheimer's Disease Genetics ConsortiumU01AG032984 · NIA · UNIVERSITY OF PENNSYLVANIA · PI SCHELLENBERG, GERARD DAVID · 2009 to 2024
$60.4M
THERAPEUTIC EFFECTS OF INTRA-NASAL INSULIN DETEMIRP50AG005136 · NIA · UNIVERSITY OF WASHINGTON · PI JAYADEY, SUMAN · 1985 to 2019
$57.2M
UCLA Clinical and Translational Science InstituteUL1TR000124 · NCATS · UNIVERSITY OF CALIFORNIA LOS ANGELES · PI DUBINETT, STEVEN M. · 2012 to 2015
$57.0M
VIRUS-INDUCED BRAIN PATHOLOGYP50AG005131 · NIA · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI BREWER, JAMES B · 1985 to 2018
$55.4M
WASHINGTON UNIVERSITY ALZHEIMERS DISEASE RESEARCH CENTERP50AG005681 · NIA · WASHINGTON UNIVERSITY · PI MORRIS, JOHN · 1985 to 2019
$52.1M
Alzheimer's Society 167Howard Hughes Medical InstituteMedical Research Council G0300429Medical Research Council G0902227Medical Research Council MC_G1000734Medical Research Council MC_PC_14095Medical Research Council MC_U123160651Medical Research Council MC_U123192748Medical Research Council MR/K006584/1Medical Research Council MR/K013041/1Medical Research Council MR/L010305/1Medical Research Council MR/L023784/1Medical Research Council MR/L023784/2Medical Research Council MR/L501517/1Medical Research Council MR/L501529/1NCATS NIH HHS UL1 TR000124NCATS NIH HHS UL1TR000124NCATS NIH HHS UL1 TR001108NCI NIH HHS R01 CA129769NCI NIH HHS U54 CA132378NCI NIH HHS U54 CA137788NCRR NIH HHS M01 RR000096NCRR NIH HHS MO1RR00096NCRR NIH HHS UL1 RR025005NCRR NIH HHS UL1RR025005NCRR NIH HHS UL1RR02777NCRR NIH HHS UL1 RR029893NHGRI NIH HHS U01 HG004402NHGRI NIH HHS U01-HG004402NHGRI NIH HHS U01 HG004610NHGRI NIH HHS U01 HG006375NHGRI NIH HHS UO1 HG004610NHLBI NIH HHS HHSN268200800007CNHLBI NIH HHS HHSN268201200036CNHLBI NIH HHS HL093029NHLBI NIH HHS K24HL038444NHLBI NIH HHS N01 HC025195NHLBI NIH HHS N01 HC055015NHLBI NIH HHS N01 HC055016NHLBI NIH HHS N01 HC055018NHLBI NIH HHS N01 HC055019NHLBI NIH HHS N01 HC055020NHLBI NIH HHS N01 HC055021NHLBI NIH HHS N01 HC055022NHLBI NIH HHS N01 HC055222NHLBI NIH HHS N01 HC085079NHLBI NIH HHS N01 HC085080NHLBI NIH HHS N01 HC085081NHLBI NIH HHS N01 HC085082NHLBI NIH HHS N01 HC085083NHLBI NIH HHS N01 HC085086NHLBI NIH HHS N01-HC-25195NHLBI NIH HHS N01-HC-55015NHLBI NIH HHS N01-HC-55016NHLBI NIH HHS N01-HC-55018NHLBI NIH HHS N01-HC-55019NHLBI NIH HHS N01-HC-55020NHLBI NIH HHS N01-HC-55021NHLBI NIH HHS N01-HC-55022NHLBI NIH HHS N02-HL-6-4278NHLBI NIH HHS R01 HL087641NHLBI NIH HHS R01-HL087641NHLBI NIH HHS R01 HL087652NHLBI NIH HHS R01HL087652NHLBI NIH HHS R01 HL093029NHLBI NIH HHS R01-HL093029NHLBI NIH HHS R01 HL103612NHLBI NIH HHS R01HL103612NHLBI NIH HHS R01 HL105756NHLBI NIH HHS R01HL105756NHLBI NIH HHS R01 HL120393NHLBI NIH HHS R01HL120393NHLBI NIH HHS RC2 HL102419NHLBI NIH HHS RC2-HL102419NHLBI NIH HHS U01 HL080295NHLBI NIH HHS U01HL080295NHLBI NIH HHS U01 HL096917NHLBI NIH HHS UC2 HL103010NIA NIH HHS AG010491NIA NIH HHS AG019757NIA NIH HHS AG021547NIA NIH HHS AG025688NIA NIH HHS AG027944NIA NIH HHS AG030653NIA NIH HHS AG031287NIA NIH HHS AG033040NIA NIH HHS AG033193NIA NIH HHS AG034504NIA NIH HHS AG041718NIA NIH HHS AG05128NIA NIH HHS AG08122NIA NIH HHS K01 AG030514NIA NIH HHS N01 AG012100NIA NIH HHS P01 AG002219NIA NIH HHS P01 AG003991NIA NIH HHS P01 AG010491NIA NIH HHS P01 AG019724NIA NIH HHS P01 AG03991NIA NIH HHS P30 AG008017NIA NIH HHS P30 AG008051NIA NIH HHS P30 AG010124NIA NIH HHS P30 AG010129NIA NIH HHS P30 AG010133NIA NIH HHS P30 AG010161NIA NIH HHS P30 AG012300NIA NIH HHS P30 AG013846NIA NIH HHS P30 AG013854NIA NIH HHS P30 AG019610NIA NIH HHS P30 AG028377NIA NIH HHS P30 AG028383NIA NIH HHS P30 AG08051NIA NIH HHS P30 AG10133NIA NIH HHS P50 AG005128NIA NIH HHS P50 AG005131NIA NIH HHS P50 AG005133NIA NIH HHS P50 AG005134NIA NIH HHS P50 AG005136NIA NIH HHS P50 AG005138NIA NIH HHS P50 AG005142NIA NIH HHS P50 AG005146NIA NIH HHS P50 AG005681NIA NIH HHS P50 AG008671NIA NIH HHS P50 AG008702NIA NIH HHS P50 AG016570NIA NIH HHS P50 AG016573NIA NIH HHS P50 AG016574NIA NIH HHS P50 AG016575NIA NIH HHS P50 AG016576NIA NIH HHS P50 AG016577NIA NIH HHS P50 AG016582NIA NIH HHS P50 AG023501NIA NIH HHS P50 AG025688NIA NIH HHS R01 AG008122NIA NIH HHS R01 AG015819NIA NIH HHS R01 AG015928NIA NIH HHS R01 AG016495NIA NIH HHS R01 AG017173NIA NIH HHS R01 AG017917NIA NIH HHS R01 AG019085NIA NIH HHS R01 AG019757NIA NIH HHS R01 AG020098NIA NIH HHS R01 AG020688NIA NIH HHS R01 AG021547NIA NIH HHS R01 AG023629NIA NIH HHS R01AG023629NIA NIH HHS R01 AG025259NIA NIH HHS R01 AG026390NIA NIH HHS R01 AG026916NIA NIH HHS R01 AG027058NIA NIH HHS R01AG027058NIA NIH HHS R01 AG027944NIA NIH HHS R01 AG030146NIA NIH HHS R01 AG030653NIA NIH HHS R01 AG031287NIA NIH HHS R01 AG031581NIA NIH HHS R01 AG033040NIA NIH HHS R01 AG033193NIA NIH HHS R01AG033193NIA NIH HHS R01 AG034504NIA NIH HHS R01 AG041232NIA NIH HHS R01 AG041797NIA NIH HHS R01 AG048927NIA NIH HHS R01 AG054076NIA NIH HHS R01 AG15819NIA NIH HHS R01AG15928NIA NIH HHS R01 AG16495NIA NIH HHS R01 AG17917NIA NIH HHS R01AG20098NIA NIH HHS R01 AG30146NIA NIH HHS R01AG33193NIA NIH HHS R37 AG015473NIA NIH HHS RC2 AG036528NIA NIH HHS RC2 AG036535NIA NIH HHS RF1 AG015473NIA NIH HHS RF1 AG015819NIA NIH HHS RF1 AG054023NIA NIH HHS RF1 AG055477NIA NIH HHS U01 AG006781NIA NIH HHS U01 AG010483NIA NIH HHS U01 AG016976NIA NIH HHS U01 AG024904NIA NIH HHS U01 AG032984NIA NIH HHS U01 AG046139NIA NIH HHS U01 AG049505NIA NIH HHS U01 AG10483NIA NIH HHS U24 AG021886NIA NIH HHS U24 AG026390NIA NIH HHS U24 AG026395NIA NIH HHS U24AG026395NIA NIH HHS U24-AG041689NIA NIH HHS U24 AG056270NIA NIH HHS UO1 AG06781NIDDK NIH HHS DK063491NIDDK NIH HHS P30 DK063491NIEHS NIH HHS P30 ES013508NIMH NIH HHS P50 MH060451NIMH NIH HHS R01 MH080295NINDS NIH HHS NS39764NINDS NIH HHS P50 NS039764NINDS NIH HHS R01 NS017950NINDS NIH HHS R01 NS059873NINDS NIH HHS R01 NS080820NINDS NIH HHS R01 NS17950NINDS NIH HHS U54 NS100693Wellcome Trust 081864Wellcome Trust 089701Wellcome Trust 089703
6 · The paper itself

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.

Indexed as

Polymorphism, Single NucleotideAlzheimer DiseaseApolipoprotein E4Chromosomes, Human, Pair 17Genome-Wide Association StudyHumanstau ProteinsApolipoprotein E4MAPT protein, humantau Proteins

Identifiers

PMID25778476
PMCPMC4573764
OpenAlexW2028546773

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