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A NOVEL ALZHEIMER DISEASE LOCUS LOCATED NEAR THE GENE ENCODING TAU PROTEIN

Identifieur interne : 000B59 ( Pmc/Corpus ); précédent : 000B58; suivant : 000B60

A NOVEL ALZHEIMER DISEASE LOCUS LOCATED NEAR THE GENE ENCODING TAU PROTEIN

Auteurs : Gyungah Jun ; Carla A. Ibrahim-Verbaas ; Maria Vronskaya ; Jean-Charles Lambert ; Jaeyoon Chung ; Adam C. Naj ; Brian W. Kunkle ; Li-San Wang ; Joshua C. Bis ; Céline Bellenguez ; Denise Harold ; Kathryn L. Lunetta ; Anita L. Destefano ; Benjamin Grenier-Boley ; Rebecca Sims ; Gary W. Beecham ; Albert V. Smith ; Vincent Chouraki ; Kara L. Hamilton-Nelson ; M. Arfan Ikram ; Nathalie Fievet ; Nicola Denning ; Eden R. Martin ; Helena Schmidt ; Yochiro Kamatani ; Melanie L. Dunstan ; Otto Valladares ; Agustin Ruiz Laza ; Diana Zelenika ; Alfredo Ramirez ; Tatiana M. Foroud ; Seung-Hoan Choi ; Anne Boland ; Tim Becker ; Walter A. Kukull ; Sven J. Van Der Lee ; Florence Pasquier ; Carlos Cruchaga ; Duane Beekly ; Annette L. Fitzpatrick ; Oliver Hanon ; Michael Gill ; Robert Barber ; Vilmundur Gudnason ; Dominique Campion ; Seth Love ; David A. Bennett ; Najaf Amin ; Claudine Berr ; Magda Tsolaki ; Joseph D. Buxbaum ; Oscar L. Lopez ; Vincent Deramecourt ; Nick C. Fox ; Laura B. Cantwell ; Lluis Tárraga ; Carole Dufouil ; John Hardy ; Paul K. Crane ; Gudny Eiriksdottir ; Didier Hannequin ; Robert Clarke ; Denis Evans ; Thomas H. Mosley ; Luc Letenneur ; Carol Brayne ; Wolfgang Maier ; Philip De Jager ; Valur Emilsson ; Jean-François Dartigues ; Harald Hampel ; M. Ilyas Kamboh ; Renee F. A. G. De Bruijn ; Christophe Tzourio ; Pau Pastor ; Eric B. Larson ; Jerome I. Rotter ; Michael C. O Onovan ; Thomas J. Montine ; Michael A. Nalls ; Simon Mead ; Eric M. Reiman ; Palmi V. Jonsson ; Clive Holmes ; Peter H. St George-Hyslop ; Mercè Boada ; Peter Passmore ; Jens R. Wendland ; Reinhold Schmidt ; Kevin Morgan ; Ashley R. Winslow ; John F. Powell ; Minerva Carasquillo ; Steven G. Younkin ; J Hanna Jakobsd Ttir ; John Sk Kauwe ; Kirk C. Wilhelmsen ; Dan Rujescu ; Markus M. Nöthen ; Albert Hofman ; Lesley Jones ; Jonathan L. Haines ; Bruce M. Psaty ; Christine Van Broeckhoven ; Peter Holmans ; Lenore J. Launer ; Richard Mayeux ; Mark Lathrop ; Alison M. Goate ; Valentina Escott-Price ; Sudha Seshadri ; Margaret A. Pericak-Vance ; Philippe Amouyel ; Julie Williams ; Cornelia M. Van Duijn ; Gerard D. Schellenberg ; Lindsay A. Farrer

Source :

RBID : PMC:4573764

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+ (10,352 cases and 9,207 controls) and APOE ε4− (7,184 cases and 26,968 controls) subgroups as well as in the total sample testing for interaction between a SNP and APOE ε4 status. Suggestive associations (P<1x10−4) in stage 1 were evaluated in an independent sample (stage 2) containing 4,203 subjects (APOE ε4+: 1,250 cases and 536 controls; APOE ε4-: 718 cases and 1,699 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 datasets (best SNP, rs2732703, P=5·8x10−9). 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=1·6x10−7) 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≤1.3x10−8), frontal cortex (P≤1.3x10−9), and temporal cortex (P≤1.2x10−11). Rs113986870 is also strongly associated with a MAPT probe that targets transcription of alternatively spliced exon 3 in frontal cortex (P=9.2x10−6) and temporal cortex (P=2.6x10−6). 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 to 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.


Url:
DOI: 10.1038/mp.2015.23
PubMed: 25778476
PubMed Central: 4573764

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PMC:4573764

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<nlm:aff id="A1">Department of Medicine (Biomedical Genetics), Boston University School of Medicine, Boston, MA, USA</nlm:aff>
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<nlm:aff id="A2">Department of Ophthalmology, Boston University School of Medicine, Boston, MA, USA</nlm:aff>
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<nlm:aff id="A3">Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA</nlm:aff>
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<name sortKey="Ibrahim Verbaas, Carla A" sort="Ibrahim Verbaas, Carla A" uniqKey="Ibrahim Verbaas C" first="Carla A." last="Ibrahim-Verbaas">Carla A. Ibrahim-Verbaas</name>
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<nlm:aff id="A4">Department of Epidemiology, Erasmus University Medical Center, Erasmus, Rotterdam, The Netherlands</nlm:aff>
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<nlm:aff id="A5">Department of Neurology, Erasmus University Medical Center, Erasmus, Rotterdam, The Netherlands</nlm:aff>
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<name sortKey="Vronskaya, Maria" sort="Vronskaya, Maria" uniqKey="Vronskaya M" first="Maria" last="Vronskaya">Maria Vronskaya</name>
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<nlm:aff id="A6">Institute of Psychological Medicine and Clinical Neurosciences, Medical Research Council (MRC) Centre for Neuropsychiatric Genetics & Genomics, Cardiff University, Cardiff, UK</nlm:aff>
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<name sortKey="Lambert, Jean Charles" sort="Lambert, Jean Charles" uniqKey="Lambert J" first="Jean-Charles" last="Lambert">Jean-Charles Lambert</name>
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<nlm:aff id="A8">Université Lille 2, Lille, France</nlm:aff>
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<nlm:aff id="A9">Institut Pasteur de Lille, Lille, France</nlm:aff>
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<name sortKey="Chung, Jaeyoon" sort="Chung, Jaeyoon" uniqKey="Chung J" first="Jaeyoon" last="Chung">Jaeyoon Chung</name>
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<nlm:aff id="A1">Department of Medicine (Biomedical Genetics), Boston University School of Medicine, Boston, MA, USA</nlm:aff>
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<name sortKey="Naj, Adam C" sort="Naj, Adam C" uniqKey="Naj A" first="Adam C." last="Naj">Adam C. Naj</name>
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<nlm:aff id="A10">Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA</nlm:aff>
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<name sortKey="Kunkle, Brian W" sort="Kunkle, Brian W" uniqKey="Kunkle B" first="Brian W." last="Kunkle">Brian W. Kunkle</name>
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<nlm:aff id="A11">The John P. Hussman Institute for Human Genomics, University of Miami, Miami, FL, USA</nlm:aff>
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<name sortKey="Wang, Li San" sort="Wang, Li San" uniqKey="Wang L" first="Li-San" last="Wang">Li-San Wang</name>
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<nlm:aff id="A10">Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA</nlm:aff>
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<name sortKey="Bis, Joshua C" sort="Bis, Joshua C" uniqKey="Bis J" first="Joshua C." last="Bis">Joshua C. Bis</name>
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<nlm:aff id="A12">Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA</nlm:aff>
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<name sortKey="Bellenguez, Celine" sort="Bellenguez, Celine" uniqKey="Bellenguez C" first="Céline" last="Bellenguez">Céline Bellenguez</name>
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<nlm:aff id="A7">Inserm U744, Lille, France</nlm:aff>
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<affiliation>
<nlm:aff id="A8">Université Lille 2, Lille, France</nlm:aff>
</affiliation>
<affiliation>
<nlm:aff id="A9">Institut Pasteur de Lille, Lille, France</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Harold, Denise" sort="Harold, Denise" uniqKey="Harold D" first="Denise" last="Harold">Denise Harold</name>
<affiliation>
<nlm:aff id="A13">Trinity College, University of Dublin, Dublin, Ireland</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Lunetta, Kathryn L" sort="Lunetta, Kathryn L" uniqKey="Lunetta K" first="Kathryn L." last="Lunetta">Kathryn L. Lunetta</name>
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<nlm:aff id="A3">Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Destefano, Anita L" sort="Destefano, Anita L" uniqKey="Destefano A" first="Anita L." last="Destefano">Anita L. Destefano</name>
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<nlm:aff id="A3">Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Grenier Boley, Benjamin" sort="Grenier Boley, Benjamin" uniqKey="Grenier Boley B" first="Benjamin" last="Grenier-Boley">Benjamin Grenier-Boley</name>
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<nlm:aff id="A7">Inserm U744, Lille, France</nlm:aff>
</affiliation>
<affiliation>
<nlm:aff id="A8">Université Lille 2, Lille, France</nlm:aff>
</affiliation>
<affiliation>
<nlm:aff id="A9">Institut Pasteur de Lille, Lille, France</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Sims, Rebecca" sort="Sims, Rebecca" uniqKey="Sims R" first="Rebecca" last="Sims">Rebecca Sims</name>
<affiliation>
<nlm:aff id="A6">Institute of Psychological Medicine and Clinical Neurosciences, Medical Research Council (MRC) Centre for Neuropsychiatric Genetics & Genomics, Cardiff University, Cardiff, UK</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Beecham, Gary W" sort="Beecham, Gary W" uniqKey="Beecham G" first="Gary W." last="Beecham">Gary W. Beecham</name>
<affiliation>
<nlm:aff id="A11">The John P. Hussman Institute for Human Genomics, University of Miami, Miami, FL, USA</nlm:aff>
</affiliation>
<affiliation>
<nlm:aff id="A14">Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami, Miami, FL, USA</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Smith, Albert V" sort="Smith, Albert V" uniqKey="Smith A" first="Albert V." last="Smith">Albert V. Smith</name>
<affiliation>
<nlm:aff id="A15">University of Iceland, Faculty of Medicine, Reykjavik, Iceland</nlm:aff>
</affiliation>
<affiliation>
<nlm:aff id="A16">Icelandic Heart Association, Kopavogur, Iceland</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Chouraki, Vincent" sort="Chouraki, Vincent" uniqKey="Chouraki V" first="Vincent" last="Chouraki">Vincent Chouraki</name>
<affiliation>
<nlm:aff id="A17">Department of Neurology, Boston University School of Medicine, Boston, MA, USA</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Hamilton Nelson, Kara L" sort="Hamilton Nelson, Kara L" uniqKey="Hamilton Nelson K" first="Kara L." last="Hamilton-Nelson">Kara L. Hamilton-Nelson</name>
<affiliation>
<nlm:aff id="A11">The John P. Hussman Institute for Human Genomics, University of Miami, Miami, FL, USA</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Ikram, M Arfan" sort="Ikram, M Arfan" uniqKey="Ikram M" first="M. Arfan" last="Ikram">M. Arfan Ikram</name>
<affiliation>
<nlm:aff id="A4">Department of Epidemiology, Erasmus University Medical Center, Erasmus, Rotterdam, The Netherlands</nlm:aff>
</affiliation>
<affiliation>
<nlm:aff id="A18">Netherlands Consortium for Healthy Aging, Leiden, The Netherlands</nlm:aff>
</affiliation>
<affiliation>
<nlm:aff id="A19">Department of Radiology, Erasmus University Medical Center, Erasmus, Rotterdam, The Netherlands</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Fievet, Nathalie" sort="Fievet, Nathalie" uniqKey="Fievet N" first="Nathalie" last="Fievet">Nathalie Fievet</name>
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<nlm:aff id="A7">Inserm U744, Lille, France</nlm:aff>
</affiliation>
<affiliation>
<nlm:aff id="A8">Université Lille 2, Lille, France</nlm:aff>
</affiliation>
<affiliation>
<nlm:aff id="A9">Institut Pasteur de Lille, Lille, France</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Denning, Nicola" sort="Denning, Nicola" uniqKey="Denning N" first="Nicola" last="Denning">Nicola Denning</name>
<affiliation>
<nlm:aff id="A6">Institute of Psychological Medicine and Clinical Neurosciences, Medical Research Council (MRC) Centre for Neuropsychiatric Genetics & Genomics, Cardiff University, Cardiff, UK</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Martin, Eden R" sort="Martin, Eden R" uniqKey="Martin E" first="Eden R." last="Martin">Eden R. Martin</name>
<affiliation>
<nlm:aff id="A11">The John P. Hussman Institute for Human Genomics, University of Miami, Miami, FL, USA</nlm:aff>
</affiliation>
<affiliation>
<nlm:aff id="A14">Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami, Miami, FL, USA</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Schmidt, Helena" sort="Schmidt, Helena" uniqKey="Schmidt H" first="Helena" last="Schmidt">Helena Schmidt</name>
<affiliation>
<nlm:aff id="A20">Institute for Molecular Biology and Biochemistry, Medical University of Graz, Graz, Austria</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Kamatani, Yochiro" sort="Kamatani, Yochiro" uniqKey="Kamatani Y" first="Yochiro" last="Kamatani">Yochiro Kamatani</name>
<affiliation>
<nlm:aff id="A21">Laboratory for Statistical Analysis, Center for Integrative Medical Sciences, Riken, Kanagawa, Japan</nlm:aff>
</affiliation>
<affiliation>
<nlm:aff id="A22">Foundation Jean Dausset – CEPH, Paris, France</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Dunstan, Melanie L" sort="Dunstan, Melanie L" uniqKey="Dunstan M" first="Melanie L" last="Dunstan">Melanie L. Dunstan</name>
<affiliation>
<nlm:aff id="A6">Institute of Psychological Medicine and Clinical Neurosciences, Medical Research Council (MRC) Centre for Neuropsychiatric Genetics & Genomics, Cardiff University, Cardiff, UK</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Valladares, Otto" sort="Valladares, Otto" uniqKey="Valladares O" first="Otto" last="Valladares">Otto Valladares</name>
<affiliation>
<nlm:aff id="A10">Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Laza, Agustin Ruiz" sort="Laza, Agustin Ruiz" uniqKey="Laza A" first="Agustin Ruiz" last="Laza">Agustin Ruiz Laza</name>
<affiliation>
<nlm:aff id="A23">Memory Clinic of Fundació ACE. Institut Català de Neurociències Aplicades, Barcelona, Spain</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Zelenika, Diana" sort="Zelenika, Diana" uniqKey="Zelenika D" first="Diana" last="Zelenika">Diana Zelenika</name>
</author>
<author>
<name sortKey="Ramirez, Alfredo" sort="Ramirez, Alfredo" uniqKey="Ramirez A" first="Alfredo" last="Ramirez">Alfredo Ramirez</name>
<affiliation>
<nlm:aff id="A25">Department of Psychiatry and Psychotherapy, University of Bonn, Bonn, Germany</nlm:aff>
</affiliation>
<affiliation>
<nlm:aff id="A26">Institute of Human Genetics, University of Bonn, Bonn, Germany</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Foroud, Tatiana M" sort="Foroud, Tatiana M" uniqKey="Foroud T" first="Tatiana M." last="Foroud">Tatiana M. Foroud</name>
<affiliation>
<nlm:aff id="A27">Department of Medical and Molecular Genetics, Indiana University, Indianapolis, IN, USA</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Choi, Seung Hoan" sort="Choi, Seung Hoan" uniqKey="Choi S" first="Seung-Hoan" last="Choi">Seung-Hoan Choi</name>
<affiliation>
<nlm:aff id="A3">Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Boland, Anne" sort="Boland, Anne" uniqKey="Boland A" first="Anne" last="Boland">Anne Boland</name>
<affiliation>
<nlm:aff id="A24">Centre National de Genotypage, Institut Genomique, Commissariat a l’energie Atomique, Evry, France</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Becker, Tim" sort="Becker, Tim" uniqKey="Becker T" first="Tim" last="Becker">Tim Becker</name>
<affiliation>
<nlm:aff id="A28">German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany</nlm:aff>
</affiliation>
<affiliation>
<nlm:aff id="A29">Institute for Medical Biometry, Informatics and Epidemiology, University of Bonn, Bonn, Germany</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Kukull, Walter A" sort="Kukull, Walter A" uniqKey="Kukull W" first="Walter A." last="Kukull">Walter A. Kukull</name>
<affiliation>
<nlm:aff id="A30">Department of Epidemiology, University of Washington, Seattle, WA, USA</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Van Der Lee, Sven J" sort="Van Der Lee, Sven J" uniqKey="Van Der Lee S" first="Sven J." last="Van Der Lee">Sven J. Van Der Lee</name>
<affiliation>
<nlm:aff id="A4">Department of Epidemiology, Erasmus University Medical Center, Erasmus, Rotterdam, The Netherlands</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Pasquier, Florence" sort="Pasquier, Florence" uniqKey="Pasquier F" first="Florence" last="Pasquier">Florence Pasquier</name>
<affiliation>
<nlm:aff id="A8">Université Lille 2, Lille, France</nlm:aff>
</affiliation>
<affiliation>
<nlm:aff id="A31">Centre National de Reference pour les Malades Alzheimer Jeunes (CNR-MAJ), Centre Hospitalier Régional Universitaire de Lille, Lille, France</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Cruchaga, Carlos" sort="Cruchaga, Carlos" uniqKey="Cruchaga C" first="Carlos" last="Cruchaga">Carlos Cruchaga</name>
<affiliation>
<nlm:aff id="A32">Hope Center Program on Protein Aggregation and Neurodegeneration, Washington University School of Medicine, St. Louis, MO, USA</nlm:aff>
</affiliation>
<affiliation>
<nlm:aff id="A33">Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Beekly, Duane" sort="Beekly, Duane" uniqKey="Beekly D" first="Duane" last="Beekly">Duane Beekly</name>
<affiliation>
<nlm:aff id="A34">National Alzheimer’s Coordinating Center, University of Washington, Seattle, WA, USA</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Fitzpatrick, Annette L" sort="Fitzpatrick, Annette L" uniqKey="Fitzpatrick A" first="Annette L." last="Fitzpatrick">Annette L. Fitzpatrick</name>
<affiliation>
<nlm:aff id="A30">Department of Epidemiology, University of Washington, Seattle, WA, USA</nlm:aff>
</affiliation>
<affiliation>
<nlm:aff id="A35">Departments of Health Services, University of Washington, Seattle, WA, USA</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Hanon, Oliver" sort="Hanon, Oliver" uniqKey="Hanon O" first="Oliver" last="Hanon">Oliver Hanon</name>
<affiliation>
<nlm:aff id="A36">University Paris Descartes, Sorbonne Paris V, France</nlm:aff>
</affiliation>
<affiliation>
<nlm:aff id="A37">Broca Hospital, Geriatrics Department, Paris, France</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Gill, Michael" sort="Gill, Michael" uniqKey="Gill M" first="Michael" last="Gill">Michael Gill</name>
<affiliation>
<nlm:aff id="A38">Mercer’s Institute for Research on Aging, St. James Hospital and Trinity College, Dublin, Ireland</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Barber, Robert" sort="Barber, Robert" uniqKey="Barber R" first="Robert" last="Barber">Robert Barber</name>
<affiliation>
<nlm:aff id="A39">Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, Fort Worth, TX, USA</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Gudnason, Vilmundur" sort="Gudnason, Vilmundur" uniqKey="Gudnason V" first="Vilmundur" last="Gudnason">Vilmundur Gudnason</name>
<affiliation>
<nlm:aff id="A15">University of Iceland, Faculty of Medicine, Reykjavik, Iceland</nlm:aff>
</affiliation>
<affiliation>
<nlm:aff id="A16">Icelandic Heart Association, Kopavogur, Iceland</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Campion, Dominique" sort="Campion, Dominique" uniqKey="Campion D" first="Dominique" last="Campion">Dominique Campion</name>
<affiliation>
<nlm:aff id="A40">CNR-MAJ, Inserm U1079, Rouen, France</nlm:aff>
</affiliation>
<affiliation>
<nlm:aff id="A41">University Hospital, 76031 Rouen, France</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Love, Seth" sort="Love, Seth" uniqKey="Love S" first="Seth" last="Love">Seth Love</name>
<affiliation>
<nlm:aff id="A42">University of Bristol Institute of Clinical Neurosciences, School of Clinical Sciences, Frenchay Hospital, Bristol, UK</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Bennett, David A" sort="Bennett, David A" uniqKey="Bennett D" first="David A." last="Bennett">David A. Bennett</name>
<affiliation>
<nlm:aff id="A43">Department of Neurological Sciences, Rush University Medical Center, Chicago, IL, USA</nlm:aff>
</affiliation>
<affiliation>
<nlm:aff id="A44">Rush Alzheimer’s Disease Center, Rush University Medical Center, Chicago, IL, USA</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Amin, Najaf" sort="Amin, Najaf" uniqKey="Amin N" first="Najaf" last="Amin">Najaf Amin</name>
<affiliation>
<nlm:aff id="A4">Department of Epidemiology, Erasmus University Medical Center, Erasmus, Rotterdam, The Netherlands</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Berr, Claudine" sort="Berr, Claudine" uniqKey="Berr C" first="Claudine" last="Berr">Claudine Berr</name>
<affiliation>
<nlm:aff id="A45">Inserm U888, Hôpital La Colombière, Montpellier, France</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Tsolaki, Magda" sort="Tsolaki, Magda" uniqKey="Tsolaki M" first="Magda" last="Tsolaki">Magda Tsolaki</name>
<affiliation>
<nlm:aff id="A46">Department of Neurology, Aristotle University of Thessaloniki, Thessaloniki, Greece</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Buxbaum, Joseph D" sort="Buxbaum, Joseph D" uniqKey="Buxbaum J" first="Joseph D." last="Buxbaum">Joseph D. Buxbaum</name>
<affiliation>
<nlm:aff id="A47">Department of Neuroscience, Mount Sinai School of Medicine, New York, NY, USA</nlm:aff>
</affiliation>
<affiliation>
<nlm:aff id="A48">Department of Psychiatry, Mount Sinai School of Medicine, New York, NY, USA</nlm:aff>
</affiliation>
<affiliation>
<nlm:aff id="A49">Departments of Genetics and Genomic Sciences, Mount Sinai School of Medicine, New York, NY, USA</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Lopez, Oscar L" sort="Lopez, Oscar L" uniqKey="Lopez O" first="Oscar L." last="Lopez">Oscar L. Lopez</name>
<affiliation>
<nlm:aff id="A50">University of Pittsburgh Alzheimer’s Disease Research Center, Pittsburgh, PA, USA</nlm:aff>
</affiliation>
<affiliation>
<nlm:aff id="A51">Departments of Neurology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Deramecourt, Vincent" sort="Deramecourt, Vincent" uniqKey="Deramecourt V" first="Vincent" last="Deramecourt">Vincent Deramecourt</name>
<affiliation>
<nlm:aff id="A8">Université Lille 2, Lille, France</nlm:aff>
</affiliation>
<affiliation>
<nlm:aff id="A31">Centre National de Reference pour les Malades Alzheimer Jeunes (CNR-MAJ), Centre Hospitalier Régional Universitaire de Lille, Lille, France</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Fox, Nick C" sort="Fox, Nick C" uniqKey="Fox N" first="Nick C" last="Fox">Nick C. Fox</name>
<affiliation>
<nlm:aff id="A52">Dementia Research Centre, Department of Neurodegenerative Disease, University College London Institute of Neurology, London, UK</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Cantwell, Laura B" sort="Cantwell, Laura B" uniqKey="Cantwell L" first="Laura B." last="Cantwell">Laura B. Cantwell</name>
<affiliation>
<nlm:aff id="A10">Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Tarraga, Lluis" sort="Tarraga, Lluis" uniqKey="Tarraga L" first="Lluis" last="Tárraga">Lluis Tárraga</name>
<affiliation>
<nlm:aff id="A53">Memory Clinic of Fundació ACE. Institut Català de Neurociències Aplicades, Barcelona, Spain</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Dufouil, Carole" sort="Dufouil, Carole" uniqKey="Dufouil C" first="Carole" last="Dufouil">Carole Dufouil</name>
<affiliation>
<nlm:aff id="A54">Inserm U897, Victor Segalen University, F-33076, Bordeaux, France</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Hardy, John" sort="Hardy, John" uniqKey="Hardy J" first="John" last="Hardy">John Hardy</name>
<affiliation>
<nlm:aff id="A55">Department of Molecular Neuroscience, Institute of Neurology, London, UK</nlm:aff>
</affiliation>
<affiliation>
<nlm:aff id="A56">Reta Lilla Weston Laboratories, Institute of Neurology, London, UK</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Crane, Paul K" sort="Crane, Paul K" uniqKey="Crane P" first="Paul K." last="Crane">Paul K. Crane</name>
<affiliation>
<nlm:aff id="A57">Department of Medicine, University of Washington, Seattle, WA, USA</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Eiriksdottir, Gudny" sort="Eiriksdottir, Gudny" uniqKey="Eiriksdottir G" first="Gudny" last="Eiriksdottir">Gudny Eiriksdottir</name>
<affiliation>
<nlm:aff id="A16">Icelandic Heart Association, Kopavogur, Iceland</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Hannequin, Didier" sort="Hannequin, Didier" uniqKey="Hannequin D" first="Didier" last="Hannequin">Didier Hannequin</name>
<affiliation>
<nlm:aff id="A40">CNR-MAJ, Inserm U1079, Rouen, France</nlm:aff>
</affiliation>
<affiliation>
<nlm:aff id="A54">Inserm U897, Victor Segalen University, F-33076, Bordeaux, France</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Clarke, Robert" sort="Clarke, Robert" uniqKey="Clarke R" first="Robert" last="Clarke">Robert Clarke</name>
<affiliation>
<nlm:aff id="A58">Oxford Healthy Aging Project (OHAP), Clinical Trial Service Unit, University of Oxford, Oxford, UK</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Evans, Denis" sort="Evans, Denis" uniqKey="Evans D" first="Denis" last="Evans">Denis Evans</name>
<affiliation>
<nlm:aff id="A59">Rush Institute for Healthy Aging, Department of Internal Medicine, Rush University Medical Center, Chicago, IL, USA</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Mosley, Thomas H" sort="Mosley, Thomas H" uniqKey="Mosley T" first="Thomas H." last="Mosley">Thomas H. Mosley</name>
<affiliation>
<nlm:aff id="A60">Department of Medicine (Geriatrics), University of Mississippi Medical Center, Jackson, MS, USA</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Letenneur, Luc" sort="Letenneur, Luc" uniqKey="Letenneur L" first="Luc" last="Letenneur">Luc Letenneur</name>
<affiliation>
<nlm:aff id="A54">Inserm U897, Victor Segalen University, F-33076, Bordeaux, France</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Brayne, Carol" sort="Brayne, Carol" uniqKey="Brayne C" first="Carol" last="Brayne">Carol Brayne</name>
<affiliation>
<nlm:aff id="A61">Institute of Public Health, University of Cambridge, Cambridge, UK</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Maier, Wolfgang" sort="Maier, Wolfgang" uniqKey="Maier W" first="Wolfgang" last="Maier">Wolfgang Maier</name>
<affiliation>
<nlm:aff id="A25">Department of Psychiatry and Psychotherapy, University of Bonn, Bonn, Germany</nlm:aff>
</affiliation>
<affiliation>
<nlm:aff id="A28">German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="De Jager, Philip" sort="De Jager, Philip" uniqKey="De Jager P" first="Philip" last="De Jager">Philip De Jager</name>
<affiliation>
<nlm:aff id="A62">Program in Translational NeuroPsychiatric Genomics, Institute for the Neurosciences, Department of Neurology & Psychiatry, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA</nlm:aff>
</affiliation>
<affiliation>
<nlm:aff id="A5">Department of Neurology, Erasmus University Medical Center, Erasmus, Rotterdam, The Netherlands</nlm:aff>
</affiliation>
<affiliation>
<nlm:aff id="A63">Program in Medical and Population Genetics, Broad Institute, Cambridge, MA, USA</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Emilsson, Valur" sort="Emilsson, Valur" uniqKey="Emilsson V" first="Valur" last="Emilsson">Valur Emilsson</name>
<affiliation>
<nlm:aff id="A16">Icelandic Heart Association, Kopavogur, Iceland</nlm:aff>
</affiliation>
<affiliation>
<nlm:aff id="A64">Faculty of Pharmaceutical Sciences, University of Iceland, Reykjavik, Iceland</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Dartigues, Jean Francois" sort="Dartigues, Jean Francois" uniqKey="Dartigues J" first="Jean-François" last="Dartigues">Jean-François Dartigues</name>
<affiliation>
<nlm:aff id="A54">Inserm U897, Victor Segalen University, F-33076, Bordeaux, France</nlm:aff>
</affiliation>
<affiliation>
<nlm:aff id="A65">Centre de Mémoire de Ressources et de Recherche de Bordeaux, CHU de Bordeaux, Bordeaux, France</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Hampel, Harald" sort="Hampel, Harald" uniqKey="Hampel H" first="Harald" last="Hampel">Harald Hampel</name>
<affiliation>
<nlm:aff id="A66">Department of Psychiatry, University of Frankfurt, Frankfurt am Main, Germany</nlm:aff>
</affiliation>
<affiliation>
<nlm:aff id="A67">Department of Psychiatry, Ludwig Maximilians University, Munich, Germany</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Kamboh, M Ilyas" sort="Kamboh, M Ilyas" uniqKey="Kamboh M" first="M. Ilyas" last="Kamboh">M. Ilyas Kamboh</name>
<affiliation>
<nlm:aff id="A50">University of Pittsburgh Alzheimer’s Disease Research Center, Pittsburgh, PA, USA</nlm:aff>
</affiliation>
<affiliation>
<nlm:aff id="A68">Department of Human Genetics, University of Pittsburgh, Pittsburgh, PA, USA</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="De Bruijn, Renee F A G" sort="De Bruijn, Renee F A G" uniqKey="De Bruijn R" first="Renee F. A. G." last="De Bruijn">Renee F. A. G. De Bruijn</name>
<affiliation>
<nlm:aff id="A4">Department of Epidemiology, Erasmus University Medical Center, Erasmus, Rotterdam, The Netherlands</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Tzourio, Christophe" sort="Tzourio, Christophe" uniqKey="Tzourio C" first="Christophe" last="Tzourio">Christophe Tzourio</name>
<affiliation>
<nlm:aff id="A54">Inserm U897, Victor Segalen University, F-33076, Bordeaux, France</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Pastor, Pau" sort="Pastor, Pau" uniqKey="Pastor P" first="Pau" last="Pastor">Pau Pastor</name>
<affiliation>
<nlm:aff id="A69">Neurogenetics Laboratory, Division of Neurosciences, Center for Applied Medical Research, University of Navarra School of Medicine, Pamplona, Spain</nlm:aff>
</affiliation>
<affiliation>
<nlm:aff id="A70">CIBERNED, Instituto de Salud Carlos III, Madrid, Spain</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Larson, Eric B" sort="Larson, Eric B" uniqKey="Larson E" first="Eric B." last="Larson">Eric B. Larson</name>
<affiliation>
<nlm:aff id="A57">Department of Medicine, University of Washington, Seattle, WA, USA</nlm:aff>
</affiliation>
<affiliation>
<nlm:aff id="A71">Group Health, Group Health Research Institute, Seattle, WA, USA</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Rotter, Jerome I" sort="Rotter, Jerome I" uniqKey="Rotter J" first="Jerome I." last="Rotter">Jerome I. Rotter</name>
<affiliation>
<nlm:aff id="A72">Institute for Translational Genomics and Population Sciences. Los Angeles BioMedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA, USA</nlm:aff>
</affiliation>
<affiliation>
<nlm:aff id="A73">Division of Genetic Outcomes, Department of Pediatrics, Harbor-UCLA Medical Center, Torrance, CA, USA</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="O Onovan, Michael C" sort="O Onovan, Michael C" uniqKey="O Onovan M" first="Michael C" last="O Onovan">Michael C. O Onovan</name>
<affiliation>
<nlm:aff id="A6">Institute of Psychological Medicine and Clinical Neurosciences, Medical Research Council (MRC) Centre for Neuropsychiatric Genetics & Genomics, Cardiff University, Cardiff, UK</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Montine, Thomas J" sort="Montine, Thomas J" uniqKey="Montine T" first="Thomas J." last="Montine">Thomas J. Montine</name>
<affiliation>
<nlm:aff id="A74">Department of Pathology, University of Washington, Seattle, WA, USA</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Nalls, Michael A" sort="Nalls, Michael A" uniqKey="Nalls M" first="Michael A." last="Nalls">Michael A. Nalls</name>
<affiliation>
<nlm:aff id="A75">Laboratory of Neurogenetics, Intramural Research Program, National Institute on Aging, Bethesda, MD, USA</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Mead, Simon" sort="Mead, Simon" uniqKey="Mead S" first="Simon" last="Mead">Simon Mead</name>
<affiliation>
<nlm:aff id="A55">Department of Molecular Neuroscience, Institute of Neurology, London, UK</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Reiman, Eric M" sort="Reiman, Eric M" uniqKey="Reiman E" first="Eric M." last="Reiman">Eric M. Reiman</name>
<affiliation>
<nlm:aff id="A76">Arizona Alzheimer’s Consortium, Phoenix, AZ, USA</nlm:aff>
</affiliation>
<affiliation>
<nlm:aff id="A77">Department of Psychiatry, University of Arizona, Phoenix, AZ, USA</nlm:aff>
</affiliation>
<affiliation>
<nlm:aff id="A78">Banner Alzheimer’s Institute, Phoenix, AZ, USA</nlm:aff>
</affiliation>
<affiliation>
<nlm:aff id="A79">Neurogenomics Division, Translational Genomics Research Institute, Phoenix, Arizona</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Jonsson, Palmi V" sort="Jonsson, Palmi V" uniqKey="Jonsson P" first="Palmi V." last="Jonsson">Palmi V. Jonsson</name>
<affiliation>
<nlm:aff id="A15">University of Iceland, Faculty of Medicine, Reykjavik, Iceland</nlm:aff>
</affiliation>
<affiliation>
<nlm:aff id="A80">Department of Geriatrics, Landspitali National University Hospital, Reykjavik, Iceland</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Holmes, Clive" sort="Holmes, Clive" uniqKey="Holmes C" first="Clive" last="Holmes">Clive Holmes</name>
<affiliation>
<nlm:aff id="A81">Division of Clinical Neurosciences, School of Medicine, University of Southampton, Southampton, UK</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="St George Hyslop, Peter H" sort="St George Hyslop, Peter H" uniqKey="St George Hyslop P" first="Peter H." last="St George-Hyslop">Peter H. St George-Hyslop</name>
<affiliation>
<nlm:aff id="A82">Tanz Centre for Research in Neurodegenerative Disease, University of Toronto, Toronto, Canada</nlm:aff>
</affiliation>
<affiliation>
<nlm:aff id="A83">Cambridge Institute for Medical Research and Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Boada, Merce" sort="Boada, Merce" uniqKey="Boada M" first="Mercè" last="Boada">Mercè Boada</name>
<affiliation>
<nlm:aff id="A53">Memory Clinic of Fundació ACE. Institut Català de Neurociències Aplicades, Barcelona, Spain</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Passmore, Peter" sort="Passmore, Peter" uniqKey="Passmore P" first="Peter" last="Passmore">Peter Passmore</name>
<affiliation>
<nlm:aff id="A84">Ageing Group, Centre for Public Health, School of Medicine, Dentistry and Biomedical Sciences, Queen’s University, Belfast, UK</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Wendland, Jens R" sort="Wendland, Jens R" uniqKey="Wendland J" first="Jens R." last="Wendland">Jens R. Wendland</name>
<affiliation>
<nlm:aff id="A85">PharmaTherapeutics Clinical Research, Pfizer Worldwide Research and Development, Cambridge, MA, USA</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Schmidt, Reinhold" sort="Schmidt, Reinhold" uniqKey="Schmidt R" first="Reinhold" last="Schmidt">Reinhold Schmidt</name>
<affiliation>
<nlm:aff id="A86">Department of Neurology, Medical University of Graz, Graz, Austria</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Morgan, Kevin" sort="Morgan, Kevin" uniqKey="Morgan K" first="Kevin" last="Morgan">Kevin Morgan</name>
<affiliation>
<nlm:aff id="A87">Institute of Genetics, Queen’s Medical Centre, University of Nottingham, Nottingham, UK</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Winslow, Ashley R" sort="Winslow, Ashley R" uniqKey="Winslow A" first="Ashley R." last="Winslow">Ashley R. Winslow</name>
<affiliation>
<nlm:aff id="A85">PharmaTherapeutics Clinical Research, Pfizer Worldwide Research and Development, Cambridge, MA, USA</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Powell, John F" sort="Powell, John F" uniqKey="Powell J" first="John F" last="Powell">John F. Powell</name>
<affiliation>
<nlm:aff id="A88">King’s College London, Institute of Psychiatry, Department of Neuroscience, De Crespigny Park, Denmark Hill, London, UK</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Carasquillo, Minerva" sort="Carasquillo, Minerva" uniqKey="Carasquillo M" first="Minerva" last="Carasquillo">Minerva Carasquillo</name>
<affiliation>
<nlm:aff id="A89">Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Younkin, Steven G" sort="Younkin, Steven G" uniqKey="Younkin S" first="Steven G." last="Younkin">Steven G. Younkin</name>
<affiliation>
<nlm:aff id="A89">Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Jakobsd Ttir, J Hanna" sort="Jakobsd Ttir, J Hanna" uniqKey="Jakobsd Ttir J" first="J Hanna" last="Jakobsd Ttir">J Hanna Jakobsd Ttir</name>
<affiliation>
<nlm:aff id="A16">Icelandic Heart Association, Kopavogur, Iceland</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Kauwe, John Sk" sort="Kauwe, John Sk" uniqKey="Kauwe J" first="John Sk" last="Kauwe">John Sk Kauwe</name>
<affiliation>
<nlm:aff id="A90">Department of Biology, Brigham Young University, Provo, Utah, USA</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Wilhelmsen, Kirk C" sort="Wilhelmsen, Kirk C" uniqKey="Wilhelmsen K" first="Kirk C." last="Wilhelmsen">Kirk C. Wilhelmsen</name>
<affiliation>
<nlm:aff id="A91">Department of Genetics, University of North Carolina Chapel Hill, Chapel Hill, NC, USA</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Rujescu, Dan" sort="Rujescu, Dan" uniqKey="Rujescu D" first="Dan" last="Rujescu">Dan Rujescu</name>
<affiliation>
<nlm:aff id="A92">Department of Psychiatry, Psychotherapy and Psychosomatics Martin-Luther-University Halle-Wittenberg, Julius-Kühn-Str. 706112 Halle Germany</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Nothen, Markus M" sort="Nothen, Markus M" uniqKey="Nothen M" first="Markus M" last="Nöthen">Markus M. Nöthen</name>
<affiliation>
<nlm:aff id="A26">Institute of Human Genetics, University of Bonn, Bonn, Germany</nlm:aff>
</affiliation>
<affiliation>
<nlm:aff id="A93">Institute of Human Genetics, Department of Genomics, Life and Brain Center, University of Bonn, Bonn, Germany</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Hofman, Albert" sort="Hofman, Albert" uniqKey="Hofman A" first="Albert" last="Hofman">Albert Hofman</name>
<affiliation>
<nlm:aff id="A4">Department of Epidemiology, Erasmus University Medical Center, Erasmus, Rotterdam, The Netherlands</nlm:aff>
</affiliation>
<affiliation>
<nlm:aff id="A19">Department of Radiology, Erasmus University Medical Center, Erasmus, Rotterdam, The Netherlands</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Jones, Lesley" sort="Jones, Lesley" uniqKey="Jones L" first="Lesley" last="Jones">Lesley Jones</name>
<affiliation>
<nlm:aff id="A6">Institute of Psychological Medicine and Clinical Neurosciences, Medical Research Council (MRC) Centre for Neuropsychiatric Genetics & Genomics, Cardiff University, Cardiff, UK</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Haines, Jonathan L" sort="Haines, Jonathan L" uniqKey="Haines J" first="Jonathan L." last="Haines">Jonathan L. Haines</name>
<affiliation>
<nlm:aff id="A94">Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, OH, USA</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Psaty, Bruce M" sort="Psaty, Bruce M" uniqKey="Psaty B" first="Bruce M." last="Psaty">Bruce M. Psaty</name>
<affiliation>
<nlm:aff id="A12">Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA</nlm:aff>
</affiliation>
<affiliation>
<nlm:aff id="A30">Department of Epidemiology, University of Washington, Seattle, WA, USA</nlm:aff>
</affiliation>
<affiliation>
<nlm:aff id="A35">Departments of Health Services, University of Washington, Seattle, WA, USA</nlm:aff>
</affiliation>
<affiliation>
<nlm:aff id="A71">Group Health, Group Health Research Institute, Seattle, WA, USA</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Van Broeckhoven, Christine" sort="Van Broeckhoven, Christine" uniqKey="Van Broeckhoven C" first="Christine" last="Van Broeckhoven">Christine Van Broeckhoven</name>
<affiliation>
<nlm:aff id="A95">Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, VIB, Antwerp, Belgium</nlm:aff>
</affiliation>
<affiliation>
<nlm:aff id="A96">Institute Born-Bunge, University of Antwerp, Antwerp, Belgium</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Holmans, Peter" sort="Holmans, Peter" uniqKey="Holmans P" first="Peter" last="Holmans">Peter Holmans</name>
<affiliation>
<nlm:aff id="A6">Institute of Psychological Medicine and Clinical Neurosciences, Medical Research Council (MRC) Centre for Neuropsychiatric Genetics & Genomics, Cardiff University, Cardiff, UK</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Launer, Lenore J" sort="Launer, Lenore J" uniqKey="Launer L" first="Lenore J." last="Launer">Lenore J. Launer</name>
<affiliation>
<nlm:aff id="A97">Laboratory of Epidemiology, Demography, and Biometry, National Institute of Health, Bethesda, MD, USA</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Mayeux, Richard" sort="Mayeux, Richard" uniqKey="Mayeux R" first="Richard" last="Mayeux">Richard Mayeux</name>
<affiliation>
<nlm:aff id="A98">Taub Institute on Alzheimer’s Disease and the Aging Brain, Columbia University, New York, NY, USA</nlm:aff>
</affiliation>
<affiliation>
<nlm:aff id="A99">Gertrude H. Sergievsky Center, Columbia University, New York, NY, USA</nlm:aff>
</affiliation>
<affiliation>
<nlm:aff id="A100">Department of Neurology, Columbia University, New York, NY, USA</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Lathrop, Mark" sort="Lathrop, Mark" uniqKey="Lathrop M" first="Mark" last="Lathrop">Mark Lathrop</name>
<affiliation>
<nlm:aff id="A24">Centre National de Genotypage, Institut Genomique, Commissariat a l’energie Atomique, Evry, France</nlm:aff>
</affiliation>
<affiliation>
<nlm:aff id="A101">McGill University and Génome Québec Innovation Centre, Montreal, Canada</nlm:aff>
</affiliation>
<affiliation>
<nlm:aff id="A102">Fondation Jean Dausset- CEPH, Paris, France</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Goate, Alison M" sort="Goate, Alison M" uniqKey="Goate A" first="Alison M." last="Goate">Alison M. Goate</name>
<affiliation>
<nlm:aff id="A32">Hope Center Program on Protein Aggregation and Neurodegeneration, Washington University School of Medicine, St. Louis, MO, USA</nlm:aff>
</affiliation>
<affiliation>
<nlm:aff id="A33">Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Escott Price, Valentina" sort="Escott Price, Valentina" uniqKey="Escott Price V" first="Valentina" last="Escott-Price">Valentina Escott-Price</name>
<affiliation>
<nlm:aff id="A6">Institute of Psychological Medicine and Clinical Neurosciences, Medical Research Council (MRC) Centre for Neuropsychiatric Genetics & Genomics, Cardiff University, Cardiff, UK</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Seshadri, Sudha" sort="Seshadri, Sudha" uniqKey="Seshadri S" first="Sudha" last="Seshadri">Sudha Seshadri</name>
<affiliation>
<nlm:aff id="A17">Department of Neurology, Boston University School of Medicine, Boston, MA, USA</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Pericak Vance, Margaret A" sort="Pericak Vance, Margaret A" uniqKey="Pericak Vance M" first="Margaret A." last="Pericak-Vance">Margaret A. Pericak-Vance</name>
<affiliation>
<nlm:aff id="A11">The John P. Hussman Institute for Human Genomics, University of Miami, Miami, FL, USA</nlm:aff>
</affiliation>
<affiliation>
<nlm:aff id="A14">Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami, Miami, FL, USA</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Amouyel, Philippe" sort="Amouyel, Philippe" uniqKey="Amouyel P" first="Philippe" last="Amouyel">Philippe Amouyel</name>
<affiliation>
<nlm:aff id="A7">Inserm U744, Lille, France</nlm:aff>
</affiliation>
<affiliation>
<nlm:aff id="A8">Université Lille 2, Lille, France</nlm:aff>
</affiliation>
<affiliation>
<nlm:aff id="A9">Institut Pasteur de Lille, Lille, France</nlm:aff>
</affiliation>
<affiliation>
<nlm:aff id="A103">University Hospital, CHRU Lille, Lille, France</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Williams, Julie" sort="Williams, Julie" uniqKey="Williams J" first="Julie" last="Williams">Julie Williams</name>
<affiliation>
<nlm:aff id="A6">Institute of Psychological Medicine and Clinical Neurosciences, Medical Research Council (MRC) Centre for Neuropsychiatric Genetics & Genomics, Cardiff University, Cardiff, UK</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Van Duijn, Cornelia M" sort="Van Duijn, Cornelia M" uniqKey="Van Duijn C" first="Cornelia M." last="Van Duijn">Cornelia M. Van Duijn</name>
<affiliation>
<nlm:aff id="A4">Department of Epidemiology, Erasmus University Medical Center, Erasmus, Rotterdam, The Netherlands</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Schellenberg, Gerard D" sort="Schellenberg, Gerard D" uniqKey="Schellenberg G" first="Gerard D." last="Schellenberg">Gerard D. Schellenberg</name>
<affiliation>
<nlm:aff id="A10">Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Farrer, Lindsay A" sort="Farrer, Lindsay A" uniqKey="Farrer L" first="Lindsay A." last="Farrer">Lindsay A. Farrer</name>
<affiliation>
<nlm:aff id="A1">Department of Medicine (Biomedical Genetics), Boston University School of Medicine, Boston, MA, USA</nlm:aff>
</affiliation>
<affiliation>
<nlm:aff id="A2">Department of Ophthalmology, Boston University School of Medicine, Boston, MA, USA</nlm:aff>
</affiliation>
<affiliation>
<nlm:aff id="A3">Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA</nlm:aff>
</affiliation>
<affiliation>
<nlm:aff id="A17">Department of Neurology, Boston University School of Medicine, Boston, MA, USA</nlm:aff>
</affiliation>
<affiliation>
<nlm:aff id="A104">Department of Epidemiology, Boston University School of Public Health, Boston, MA, USA</nlm:aff>
</affiliation>
</author>
</titleStmt>
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<idno type="pmid">25778476</idno>
<idno type="pmc">4573764</idno>
<idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4573764</idno>
<idno type="RBID">PMC:4573764</idno>
<idno type="doi">10.1038/mp.2015.23</idno>
<date when="2015">2015</date>
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<analytic>
<title xml:lang="en" level="a" type="main">A NOVEL ALZHEIMER DISEASE LOCUS LOCATED NEAR THE GENE ENCODING TAU PROTEIN</title>
<author>
<name sortKey="Jun, Gyungah" sort="Jun, Gyungah" uniqKey="Jun G" first="Gyungah" last="Jun">Gyungah Jun</name>
<affiliation>
<nlm:aff id="A1">Department of Medicine (Biomedical Genetics), Boston University School of Medicine, Boston, MA, USA</nlm:aff>
</affiliation>
<affiliation>
<nlm:aff id="A2">Department of Ophthalmology, Boston University School of Medicine, Boston, MA, USA</nlm:aff>
</affiliation>
<affiliation>
<nlm:aff id="A3">Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Ibrahim Verbaas, Carla A" sort="Ibrahim Verbaas, Carla A" uniqKey="Ibrahim Verbaas C" first="Carla A." last="Ibrahim-Verbaas">Carla A. Ibrahim-Verbaas</name>
<affiliation>
<nlm:aff id="A4">Department of Epidemiology, Erasmus University Medical Center, Erasmus, Rotterdam, The Netherlands</nlm:aff>
</affiliation>
<affiliation>
<nlm:aff id="A5">Department of Neurology, Erasmus University Medical Center, Erasmus, Rotterdam, The Netherlands</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Vronskaya, Maria" sort="Vronskaya, Maria" uniqKey="Vronskaya M" first="Maria" last="Vronskaya">Maria Vronskaya</name>
<affiliation>
<nlm:aff id="A6">Institute of Psychological Medicine and Clinical Neurosciences, Medical Research Council (MRC) Centre for Neuropsychiatric Genetics & Genomics, Cardiff University, Cardiff, UK</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Lambert, Jean Charles" sort="Lambert, Jean Charles" uniqKey="Lambert J" first="Jean-Charles" last="Lambert">Jean-Charles Lambert</name>
<affiliation>
<nlm:aff id="A7">Inserm U744, Lille, France</nlm:aff>
</affiliation>
<affiliation>
<nlm:aff id="A8">Université Lille 2, Lille, France</nlm:aff>
</affiliation>
<affiliation>
<nlm:aff id="A9">Institut Pasteur de Lille, Lille, France</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Chung, Jaeyoon" sort="Chung, Jaeyoon" uniqKey="Chung J" first="Jaeyoon" last="Chung">Jaeyoon Chung</name>
<affiliation>
<nlm:aff id="A1">Department of Medicine (Biomedical Genetics), Boston University School of Medicine, Boston, MA, USA</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Naj, Adam C" sort="Naj, Adam C" uniqKey="Naj A" first="Adam C." last="Naj">Adam C. Naj</name>
<affiliation>
<nlm:aff id="A10">Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Kunkle, Brian W" sort="Kunkle, Brian W" uniqKey="Kunkle B" first="Brian W." last="Kunkle">Brian W. Kunkle</name>
<affiliation>
<nlm:aff id="A11">The John P. Hussman Institute for Human Genomics, University of Miami, Miami, FL, USA</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Wang, Li San" sort="Wang, Li San" uniqKey="Wang L" first="Li-San" last="Wang">Li-San Wang</name>
<affiliation>
<nlm:aff id="A10">Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Bis, Joshua C" sort="Bis, Joshua C" uniqKey="Bis J" first="Joshua C." last="Bis">Joshua C. Bis</name>
<affiliation>
<nlm:aff id="A12">Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Bellenguez, Celine" sort="Bellenguez, Celine" uniqKey="Bellenguez C" first="Céline" last="Bellenguez">Céline Bellenguez</name>
<affiliation>
<nlm:aff id="A7">Inserm U744, Lille, France</nlm:aff>
</affiliation>
<affiliation>
<nlm:aff id="A8">Université Lille 2, Lille, France</nlm:aff>
</affiliation>
<affiliation>
<nlm:aff id="A9">Institut Pasteur de Lille, Lille, France</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Harold, Denise" sort="Harold, Denise" uniqKey="Harold D" first="Denise" last="Harold">Denise Harold</name>
<affiliation>
<nlm:aff id="A13">Trinity College, University of Dublin, Dublin, Ireland</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Lunetta, Kathryn L" sort="Lunetta, Kathryn L" uniqKey="Lunetta K" first="Kathryn L." last="Lunetta">Kathryn L. Lunetta</name>
<affiliation>
<nlm:aff id="A3">Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Destefano, Anita L" sort="Destefano, Anita L" uniqKey="Destefano A" first="Anita L." last="Destefano">Anita L. Destefano</name>
<affiliation>
<nlm:aff id="A3">Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Grenier Boley, Benjamin" sort="Grenier Boley, Benjamin" uniqKey="Grenier Boley B" first="Benjamin" last="Grenier-Boley">Benjamin Grenier-Boley</name>
<affiliation>
<nlm:aff id="A7">Inserm U744, Lille, France</nlm:aff>
</affiliation>
<affiliation>
<nlm:aff id="A8">Université Lille 2, Lille, France</nlm:aff>
</affiliation>
<affiliation>
<nlm:aff id="A9">Institut Pasteur de Lille, Lille, France</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Sims, Rebecca" sort="Sims, Rebecca" uniqKey="Sims R" first="Rebecca" last="Sims">Rebecca Sims</name>
<affiliation>
<nlm:aff id="A6">Institute of Psychological Medicine and Clinical Neurosciences, Medical Research Council (MRC) Centre for Neuropsychiatric Genetics & Genomics, Cardiff University, Cardiff, UK</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Beecham, Gary W" sort="Beecham, Gary W" uniqKey="Beecham G" first="Gary W." last="Beecham">Gary W. Beecham</name>
<affiliation>
<nlm:aff id="A11">The John P. Hussman Institute for Human Genomics, University of Miami, Miami, FL, USA</nlm:aff>
</affiliation>
<affiliation>
<nlm:aff id="A14">Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami, Miami, FL, USA</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Smith, Albert V" sort="Smith, Albert V" uniqKey="Smith A" first="Albert V." last="Smith">Albert V. Smith</name>
<affiliation>
<nlm:aff id="A15">University of Iceland, Faculty of Medicine, Reykjavik, Iceland</nlm:aff>
</affiliation>
<affiliation>
<nlm:aff id="A16">Icelandic Heart Association, Kopavogur, Iceland</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Chouraki, Vincent" sort="Chouraki, Vincent" uniqKey="Chouraki V" first="Vincent" last="Chouraki">Vincent Chouraki</name>
<affiliation>
<nlm:aff id="A17">Department of Neurology, Boston University School of Medicine, Boston, MA, USA</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Hamilton Nelson, Kara L" sort="Hamilton Nelson, Kara L" uniqKey="Hamilton Nelson K" first="Kara L." last="Hamilton-Nelson">Kara L. Hamilton-Nelson</name>
<affiliation>
<nlm:aff id="A11">The John P. Hussman Institute for Human Genomics, University of Miami, Miami, FL, USA</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Ikram, M Arfan" sort="Ikram, M Arfan" uniqKey="Ikram M" first="M. Arfan" last="Ikram">M. Arfan Ikram</name>
<affiliation>
<nlm:aff id="A4">Department of Epidemiology, Erasmus University Medical Center, Erasmus, Rotterdam, The Netherlands</nlm:aff>
</affiliation>
<affiliation>
<nlm:aff id="A18">Netherlands Consortium for Healthy Aging, Leiden, The Netherlands</nlm:aff>
</affiliation>
<affiliation>
<nlm:aff id="A19">Department of Radiology, Erasmus University Medical Center, Erasmus, Rotterdam, The Netherlands</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Fievet, Nathalie" sort="Fievet, Nathalie" uniqKey="Fievet N" first="Nathalie" last="Fievet">Nathalie Fievet</name>
<affiliation>
<nlm:aff id="A7">Inserm U744, Lille, France</nlm:aff>
</affiliation>
<affiliation>
<nlm:aff id="A8">Université Lille 2, Lille, France</nlm:aff>
</affiliation>
<affiliation>
<nlm:aff id="A9">Institut Pasteur de Lille, Lille, France</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Denning, Nicola" sort="Denning, Nicola" uniqKey="Denning N" first="Nicola" last="Denning">Nicola Denning</name>
<affiliation>
<nlm:aff id="A6">Institute of Psychological Medicine and Clinical Neurosciences, Medical Research Council (MRC) Centre for Neuropsychiatric Genetics & Genomics, Cardiff University, Cardiff, UK</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Martin, Eden R" sort="Martin, Eden R" uniqKey="Martin E" first="Eden R." last="Martin">Eden R. Martin</name>
<affiliation>
<nlm:aff id="A11">The John P. Hussman Institute for Human Genomics, University of Miami, Miami, FL, USA</nlm:aff>
</affiliation>
<affiliation>
<nlm:aff id="A14">Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami, Miami, FL, USA</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Schmidt, Helena" sort="Schmidt, Helena" uniqKey="Schmidt H" first="Helena" last="Schmidt">Helena Schmidt</name>
<affiliation>
<nlm:aff id="A20">Institute for Molecular Biology and Biochemistry, Medical University of Graz, Graz, Austria</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Kamatani, Yochiro" sort="Kamatani, Yochiro" uniqKey="Kamatani Y" first="Yochiro" last="Kamatani">Yochiro Kamatani</name>
<affiliation>
<nlm:aff id="A21">Laboratory for Statistical Analysis, Center for Integrative Medical Sciences, Riken, Kanagawa, Japan</nlm:aff>
</affiliation>
<affiliation>
<nlm:aff id="A22">Foundation Jean Dausset – CEPH, Paris, France</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Dunstan, Melanie L" sort="Dunstan, Melanie L" uniqKey="Dunstan M" first="Melanie L" last="Dunstan">Melanie L. Dunstan</name>
<affiliation>
<nlm:aff id="A6">Institute of Psychological Medicine and Clinical Neurosciences, Medical Research Council (MRC) Centre for Neuropsychiatric Genetics & Genomics, Cardiff University, Cardiff, UK</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Valladares, Otto" sort="Valladares, Otto" uniqKey="Valladares O" first="Otto" last="Valladares">Otto Valladares</name>
<affiliation>
<nlm:aff id="A10">Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Laza, Agustin Ruiz" sort="Laza, Agustin Ruiz" uniqKey="Laza A" first="Agustin Ruiz" last="Laza">Agustin Ruiz Laza</name>
<affiliation>
<nlm:aff id="A23">Memory Clinic of Fundació ACE. Institut Català de Neurociències Aplicades, Barcelona, Spain</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Zelenika, Diana" sort="Zelenika, Diana" uniqKey="Zelenika D" first="Diana" last="Zelenika">Diana Zelenika</name>
</author>
<author>
<name sortKey="Ramirez, Alfredo" sort="Ramirez, Alfredo" uniqKey="Ramirez A" first="Alfredo" last="Ramirez">Alfredo Ramirez</name>
<affiliation>
<nlm:aff id="A25">Department of Psychiatry and Psychotherapy, University of Bonn, Bonn, Germany</nlm:aff>
</affiliation>
<affiliation>
<nlm:aff id="A26">Institute of Human Genetics, University of Bonn, Bonn, Germany</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Foroud, Tatiana M" sort="Foroud, Tatiana M" uniqKey="Foroud T" first="Tatiana M." last="Foroud">Tatiana M. Foroud</name>
<affiliation>
<nlm:aff id="A27">Department of Medical and Molecular Genetics, Indiana University, Indianapolis, IN, USA</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Choi, Seung Hoan" sort="Choi, Seung Hoan" uniqKey="Choi S" first="Seung-Hoan" last="Choi">Seung-Hoan Choi</name>
<affiliation>
<nlm:aff id="A3">Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Boland, Anne" sort="Boland, Anne" uniqKey="Boland A" first="Anne" last="Boland">Anne Boland</name>
<affiliation>
<nlm:aff id="A24">Centre National de Genotypage, Institut Genomique, Commissariat a l’energie Atomique, Evry, France</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Becker, Tim" sort="Becker, Tim" uniqKey="Becker T" first="Tim" last="Becker">Tim Becker</name>
<affiliation>
<nlm:aff id="A28">German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany</nlm:aff>
</affiliation>
<affiliation>
<nlm:aff id="A29">Institute for Medical Biometry, Informatics and Epidemiology, University of Bonn, Bonn, Germany</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Kukull, Walter A" sort="Kukull, Walter A" uniqKey="Kukull W" first="Walter A." last="Kukull">Walter A. Kukull</name>
<affiliation>
<nlm:aff id="A30">Department of Epidemiology, University of Washington, Seattle, WA, USA</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Van Der Lee, Sven J" sort="Van Der Lee, Sven J" uniqKey="Van Der Lee S" first="Sven J." last="Van Der Lee">Sven J. Van Der Lee</name>
<affiliation>
<nlm:aff id="A4">Department of Epidemiology, Erasmus University Medical Center, Erasmus, Rotterdam, The Netherlands</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Pasquier, Florence" sort="Pasquier, Florence" uniqKey="Pasquier F" first="Florence" last="Pasquier">Florence Pasquier</name>
<affiliation>
<nlm:aff id="A8">Université Lille 2, Lille, France</nlm:aff>
</affiliation>
<affiliation>
<nlm:aff id="A31">Centre National de Reference pour les Malades Alzheimer Jeunes (CNR-MAJ), Centre Hospitalier Régional Universitaire de Lille, Lille, France</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Cruchaga, Carlos" sort="Cruchaga, Carlos" uniqKey="Cruchaga C" first="Carlos" last="Cruchaga">Carlos Cruchaga</name>
<affiliation>
<nlm:aff id="A32">Hope Center Program on Protein Aggregation and Neurodegeneration, Washington University School of Medicine, St. Louis, MO, USA</nlm:aff>
</affiliation>
<affiliation>
<nlm:aff id="A33">Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Beekly, Duane" sort="Beekly, Duane" uniqKey="Beekly D" first="Duane" last="Beekly">Duane Beekly</name>
<affiliation>
<nlm:aff id="A34">National Alzheimer’s Coordinating Center, University of Washington, Seattle, WA, USA</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Fitzpatrick, Annette L" sort="Fitzpatrick, Annette L" uniqKey="Fitzpatrick A" first="Annette L." last="Fitzpatrick">Annette L. Fitzpatrick</name>
<affiliation>
<nlm:aff id="A30">Department of Epidemiology, University of Washington, Seattle, WA, USA</nlm:aff>
</affiliation>
<affiliation>
<nlm:aff id="A35">Departments of Health Services, University of Washington, Seattle, WA, USA</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Hanon, Oliver" sort="Hanon, Oliver" uniqKey="Hanon O" first="Oliver" last="Hanon">Oliver Hanon</name>
<affiliation>
<nlm:aff id="A36">University Paris Descartes, Sorbonne Paris V, France</nlm:aff>
</affiliation>
<affiliation>
<nlm:aff id="A37">Broca Hospital, Geriatrics Department, Paris, France</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Gill, Michael" sort="Gill, Michael" uniqKey="Gill M" first="Michael" last="Gill">Michael Gill</name>
<affiliation>
<nlm:aff id="A38">Mercer’s Institute for Research on Aging, St. James Hospital and Trinity College, Dublin, Ireland</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Barber, Robert" sort="Barber, Robert" uniqKey="Barber R" first="Robert" last="Barber">Robert Barber</name>
<affiliation>
<nlm:aff id="A39">Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, Fort Worth, TX, USA</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Gudnason, Vilmundur" sort="Gudnason, Vilmundur" uniqKey="Gudnason V" first="Vilmundur" last="Gudnason">Vilmundur Gudnason</name>
<affiliation>
<nlm:aff id="A15">University of Iceland, Faculty of Medicine, Reykjavik, Iceland</nlm:aff>
</affiliation>
<affiliation>
<nlm:aff id="A16">Icelandic Heart Association, Kopavogur, Iceland</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Campion, Dominique" sort="Campion, Dominique" uniqKey="Campion D" first="Dominique" last="Campion">Dominique Campion</name>
<affiliation>
<nlm:aff id="A40">CNR-MAJ, Inserm U1079, Rouen, France</nlm:aff>
</affiliation>
<affiliation>
<nlm:aff id="A41">University Hospital, 76031 Rouen, France</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Love, Seth" sort="Love, Seth" uniqKey="Love S" first="Seth" last="Love">Seth Love</name>
<affiliation>
<nlm:aff id="A42">University of Bristol Institute of Clinical Neurosciences, School of Clinical Sciences, Frenchay Hospital, Bristol, UK</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Bennett, David A" sort="Bennett, David A" uniqKey="Bennett D" first="David A." last="Bennett">David A. Bennett</name>
<affiliation>
<nlm:aff id="A43">Department of Neurological Sciences, Rush University Medical Center, Chicago, IL, USA</nlm:aff>
</affiliation>
<affiliation>
<nlm:aff id="A44">Rush Alzheimer’s Disease Center, Rush University Medical Center, Chicago, IL, USA</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Amin, Najaf" sort="Amin, Najaf" uniqKey="Amin N" first="Najaf" last="Amin">Najaf Amin</name>
<affiliation>
<nlm:aff id="A4">Department of Epidemiology, Erasmus University Medical Center, Erasmus, Rotterdam, The Netherlands</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Berr, Claudine" sort="Berr, Claudine" uniqKey="Berr C" first="Claudine" last="Berr">Claudine Berr</name>
<affiliation>
<nlm:aff id="A45">Inserm U888, Hôpital La Colombière, Montpellier, France</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Tsolaki, Magda" sort="Tsolaki, Magda" uniqKey="Tsolaki M" first="Magda" last="Tsolaki">Magda Tsolaki</name>
<affiliation>
<nlm:aff id="A46">Department of Neurology, Aristotle University of Thessaloniki, Thessaloniki, Greece</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Buxbaum, Joseph D" sort="Buxbaum, Joseph D" uniqKey="Buxbaum J" first="Joseph D." last="Buxbaum">Joseph D. Buxbaum</name>
<affiliation>
<nlm:aff id="A47">Department of Neuroscience, Mount Sinai School of Medicine, New York, NY, USA</nlm:aff>
</affiliation>
<affiliation>
<nlm:aff id="A48">Department of Psychiatry, Mount Sinai School of Medicine, New York, NY, USA</nlm:aff>
</affiliation>
<affiliation>
<nlm:aff id="A49">Departments of Genetics and Genomic Sciences, Mount Sinai School of Medicine, New York, NY, USA</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Lopez, Oscar L" sort="Lopez, Oscar L" uniqKey="Lopez O" first="Oscar L." last="Lopez">Oscar L. Lopez</name>
<affiliation>
<nlm:aff id="A50">University of Pittsburgh Alzheimer’s Disease Research Center, Pittsburgh, PA, USA</nlm:aff>
</affiliation>
<affiliation>
<nlm:aff id="A51">Departments of Neurology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Deramecourt, Vincent" sort="Deramecourt, Vincent" uniqKey="Deramecourt V" first="Vincent" last="Deramecourt">Vincent Deramecourt</name>
<affiliation>
<nlm:aff id="A8">Université Lille 2, Lille, France</nlm:aff>
</affiliation>
<affiliation>
<nlm:aff id="A31">Centre National de Reference pour les Malades Alzheimer Jeunes (CNR-MAJ), Centre Hospitalier Régional Universitaire de Lille, Lille, France</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Fox, Nick C" sort="Fox, Nick C" uniqKey="Fox N" first="Nick C" last="Fox">Nick C. Fox</name>
<affiliation>
<nlm:aff id="A52">Dementia Research Centre, Department of Neurodegenerative Disease, University College London Institute of Neurology, London, UK</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Cantwell, Laura B" sort="Cantwell, Laura B" uniqKey="Cantwell L" first="Laura B." last="Cantwell">Laura B. Cantwell</name>
<affiliation>
<nlm:aff id="A10">Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Tarraga, Lluis" sort="Tarraga, Lluis" uniqKey="Tarraga L" first="Lluis" last="Tárraga">Lluis Tárraga</name>
<affiliation>
<nlm:aff id="A53">Memory Clinic of Fundació ACE. Institut Català de Neurociències Aplicades, Barcelona, Spain</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Dufouil, Carole" sort="Dufouil, Carole" uniqKey="Dufouil C" first="Carole" last="Dufouil">Carole Dufouil</name>
<affiliation>
<nlm:aff id="A54">Inserm U897, Victor Segalen University, F-33076, Bordeaux, France</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Hardy, John" sort="Hardy, John" uniqKey="Hardy J" first="John" last="Hardy">John Hardy</name>
<affiliation>
<nlm:aff id="A55">Department of Molecular Neuroscience, Institute of Neurology, London, UK</nlm:aff>
</affiliation>
<affiliation>
<nlm:aff id="A56">Reta Lilla Weston Laboratories, Institute of Neurology, London, UK</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Crane, Paul K" sort="Crane, Paul K" uniqKey="Crane P" first="Paul K." last="Crane">Paul K. Crane</name>
<affiliation>
<nlm:aff id="A57">Department of Medicine, University of Washington, Seattle, WA, USA</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Eiriksdottir, Gudny" sort="Eiriksdottir, Gudny" uniqKey="Eiriksdottir G" first="Gudny" last="Eiriksdottir">Gudny Eiriksdottir</name>
<affiliation>
<nlm:aff id="A16">Icelandic Heart Association, Kopavogur, Iceland</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Hannequin, Didier" sort="Hannequin, Didier" uniqKey="Hannequin D" first="Didier" last="Hannequin">Didier Hannequin</name>
<affiliation>
<nlm:aff id="A40">CNR-MAJ, Inserm U1079, Rouen, France</nlm:aff>
</affiliation>
<affiliation>
<nlm:aff id="A54">Inserm U897, Victor Segalen University, F-33076, Bordeaux, France</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Clarke, Robert" sort="Clarke, Robert" uniqKey="Clarke R" first="Robert" last="Clarke">Robert Clarke</name>
<affiliation>
<nlm:aff id="A58">Oxford Healthy Aging Project (OHAP), Clinical Trial Service Unit, University of Oxford, Oxford, UK</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Evans, Denis" sort="Evans, Denis" uniqKey="Evans D" first="Denis" last="Evans">Denis Evans</name>
<affiliation>
<nlm:aff id="A59">Rush Institute for Healthy Aging, Department of Internal Medicine, Rush University Medical Center, Chicago, IL, USA</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Mosley, Thomas H" sort="Mosley, Thomas H" uniqKey="Mosley T" first="Thomas H." last="Mosley">Thomas H. Mosley</name>
<affiliation>
<nlm:aff id="A60">Department of Medicine (Geriatrics), University of Mississippi Medical Center, Jackson, MS, USA</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Letenneur, Luc" sort="Letenneur, Luc" uniqKey="Letenneur L" first="Luc" last="Letenneur">Luc Letenneur</name>
<affiliation>
<nlm:aff id="A54">Inserm U897, Victor Segalen University, F-33076, Bordeaux, France</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Brayne, Carol" sort="Brayne, Carol" uniqKey="Brayne C" first="Carol" last="Brayne">Carol Brayne</name>
<affiliation>
<nlm:aff id="A61">Institute of Public Health, University of Cambridge, Cambridge, UK</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Maier, Wolfgang" sort="Maier, Wolfgang" uniqKey="Maier W" first="Wolfgang" last="Maier">Wolfgang Maier</name>
<affiliation>
<nlm:aff id="A25">Department of Psychiatry and Psychotherapy, University of Bonn, Bonn, Germany</nlm:aff>
</affiliation>
<affiliation>
<nlm:aff id="A28">German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="De Jager, Philip" sort="De Jager, Philip" uniqKey="De Jager P" first="Philip" last="De Jager">Philip De Jager</name>
<affiliation>
<nlm:aff id="A62">Program in Translational NeuroPsychiatric Genomics, Institute for the Neurosciences, Department of Neurology & Psychiatry, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA</nlm:aff>
</affiliation>
<affiliation>
<nlm:aff id="A5">Department of Neurology, Erasmus University Medical Center, Erasmus, Rotterdam, The Netherlands</nlm:aff>
</affiliation>
<affiliation>
<nlm:aff id="A63">Program in Medical and Population Genetics, Broad Institute, Cambridge, MA, USA</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Emilsson, Valur" sort="Emilsson, Valur" uniqKey="Emilsson V" first="Valur" last="Emilsson">Valur Emilsson</name>
<affiliation>
<nlm:aff id="A16">Icelandic Heart Association, Kopavogur, Iceland</nlm:aff>
</affiliation>
<affiliation>
<nlm:aff id="A64">Faculty of Pharmaceutical Sciences, University of Iceland, Reykjavik, Iceland</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Dartigues, Jean Francois" sort="Dartigues, Jean Francois" uniqKey="Dartigues J" first="Jean-François" last="Dartigues">Jean-François Dartigues</name>
<affiliation>
<nlm:aff id="A54">Inserm U897, Victor Segalen University, F-33076, Bordeaux, France</nlm:aff>
</affiliation>
<affiliation>
<nlm:aff id="A65">Centre de Mémoire de Ressources et de Recherche de Bordeaux, CHU de Bordeaux, Bordeaux, France</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Hampel, Harald" sort="Hampel, Harald" uniqKey="Hampel H" first="Harald" last="Hampel">Harald Hampel</name>
<affiliation>
<nlm:aff id="A66">Department of Psychiatry, University of Frankfurt, Frankfurt am Main, Germany</nlm:aff>
</affiliation>
<affiliation>
<nlm:aff id="A67">Department of Psychiatry, Ludwig Maximilians University, Munich, Germany</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Kamboh, M Ilyas" sort="Kamboh, M Ilyas" uniqKey="Kamboh M" first="M. Ilyas" last="Kamboh">M. Ilyas Kamboh</name>
<affiliation>
<nlm:aff id="A50">University of Pittsburgh Alzheimer’s Disease Research Center, Pittsburgh, PA, USA</nlm:aff>
</affiliation>
<affiliation>
<nlm:aff id="A68">Department of Human Genetics, University of Pittsburgh, Pittsburgh, PA, USA</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="De Bruijn, Renee F A G" sort="De Bruijn, Renee F A G" uniqKey="De Bruijn R" first="Renee F. A. G." last="De Bruijn">Renee F. A. G. De Bruijn</name>
<affiliation>
<nlm:aff id="A4">Department of Epidemiology, Erasmus University Medical Center, Erasmus, Rotterdam, The Netherlands</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Tzourio, Christophe" sort="Tzourio, Christophe" uniqKey="Tzourio C" first="Christophe" last="Tzourio">Christophe Tzourio</name>
<affiliation>
<nlm:aff id="A54">Inserm U897, Victor Segalen University, F-33076, Bordeaux, France</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Pastor, Pau" sort="Pastor, Pau" uniqKey="Pastor P" first="Pau" last="Pastor">Pau Pastor</name>
<affiliation>
<nlm:aff id="A69">Neurogenetics Laboratory, Division of Neurosciences, Center for Applied Medical Research, University of Navarra School of Medicine, Pamplona, Spain</nlm:aff>
</affiliation>
<affiliation>
<nlm:aff id="A70">CIBERNED, Instituto de Salud Carlos III, Madrid, Spain</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Larson, Eric B" sort="Larson, Eric B" uniqKey="Larson E" first="Eric B." last="Larson">Eric B. Larson</name>
<affiliation>
<nlm:aff id="A57">Department of Medicine, University of Washington, Seattle, WA, USA</nlm:aff>
</affiliation>
<affiliation>
<nlm:aff id="A71">Group Health, Group Health Research Institute, Seattle, WA, USA</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Rotter, Jerome I" sort="Rotter, Jerome I" uniqKey="Rotter J" first="Jerome I." last="Rotter">Jerome I. Rotter</name>
<affiliation>
<nlm:aff id="A72">Institute for Translational Genomics and Population Sciences. Los Angeles BioMedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA, USA</nlm:aff>
</affiliation>
<affiliation>
<nlm:aff id="A73">Division of Genetic Outcomes, Department of Pediatrics, Harbor-UCLA Medical Center, Torrance, CA, USA</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="O Onovan, Michael C" sort="O Onovan, Michael C" uniqKey="O Onovan M" first="Michael C" last="O Onovan">Michael C. O Onovan</name>
<affiliation>
<nlm:aff id="A6">Institute of Psychological Medicine and Clinical Neurosciences, Medical Research Council (MRC) Centre for Neuropsychiatric Genetics & Genomics, Cardiff University, Cardiff, UK</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Montine, Thomas J" sort="Montine, Thomas J" uniqKey="Montine T" first="Thomas J." last="Montine">Thomas J. Montine</name>
<affiliation>
<nlm:aff id="A74">Department of Pathology, University of Washington, Seattle, WA, USA</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Nalls, Michael A" sort="Nalls, Michael A" uniqKey="Nalls M" first="Michael A." last="Nalls">Michael A. Nalls</name>
<affiliation>
<nlm:aff id="A75">Laboratory of Neurogenetics, Intramural Research Program, National Institute on Aging, Bethesda, MD, USA</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Mead, Simon" sort="Mead, Simon" uniqKey="Mead S" first="Simon" last="Mead">Simon Mead</name>
<affiliation>
<nlm:aff id="A55">Department of Molecular Neuroscience, Institute of Neurology, London, UK</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Reiman, Eric M" sort="Reiman, Eric M" uniqKey="Reiman E" first="Eric M." last="Reiman">Eric M. Reiman</name>
<affiliation>
<nlm:aff id="A76">Arizona Alzheimer’s Consortium, Phoenix, AZ, USA</nlm:aff>
</affiliation>
<affiliation>
<nlm:aff id="A77">Department of Psychiatry, University of Arizona, Phoenix, AZ, USA</nlm:aff>
</affiliation>
<affiliation>
<nlm:aff id="A78">Banner Alzheimer’s Institute, Phoenix, AZ, USA</nlm:aff>
</affiliation>
<affiliation>
<nlm:aff id="A79">Neurogenomics Division, Translational Genomics Research Institute, Phoenix, Arizona</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Jonsson, Palmi V" sort="Jonsson, Palmi V" uniqKey="Jonsson P" first="Palmi V." last="Jonsson">Palmi V. Jonsson</name>
<affiliation>
<nlm:aff id="A15">University of Iceland, Faculty of Medicine, Reykjavik, Iceland</nlm:aff>
</affiliation>
<affiliation>
<nlm:aff id="A80">Department of Geriatrics, Landspitali National University Hospital, Reykjavik, Iceland</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Holmes, Clive" sort="Holmes, Clive" uniqKey="Holmes C" first="Clive" last="Holmes">Clive Holmes</name>
<affiliation>
<nlm:aff id="A81">Division of Clinical Neurosciences, School of Medicine, University of Southampton, Southampton, UK</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="St George Hyslop, Peter H" sort="St George Hyslop, Peter H" uniqKey="St George Hyslop P" first="Peter H." last="St George-Hyslop">Peter H. St George-Hyslop</name>
<affiliation>
<nlm:aff id="A82">Tanz Centre for Research in Neurodegenerative Disease, University of Toronto, Toronto, Canada</nlm:aff>
</affiliation>
<affiliation>
<nlm:aff id="A83">Cambridge Institute for Medical Research and Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Boada, Merce" sort="Boada, Merce" uniqKey="Boada M" first="Mercè" last="Boada">Mercè Boada</name>
<affiliation>
<nlm:aff id="A53">Memory Clinic of Fundació ACE. Institut Català de Neurociències Aplicades, Barcelona, Spain</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Passmore, Peter" sort="Passmore, Peter" uniqKey="Passmore P" first="Peter" last="Passmore">Peter Passmore</name>
<affiliation>
<nlm:aff id="A84">Ageing Group, Centre for Public Health, School of Medicine, Dentistry and Biomedical Sciences, Queen’s University, Belfast, UK</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Wendland, Jens R" sort="Wendland, Jens R" uniqKey="Wendland J" first="Jens R." last="Wendland">Jens R. Wendland</name>
<affiliation>
<nlm:aff id="A85">PharmaTherapeutics Clinical Research, Pfizer Worldwide Research and Development, Cambridge, MA, USA</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Schmidt, Reinhold" sort="Schmidt, Reinhold" uniqKey="Schmidt R" first="Reinhold" last="Schmidt">Reinhold Schmidt</name>
<affiliation>
<nlm:aff id="A86">Department of Neurology, Medical University of Graz, Graz, Austria</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Morgan, Kevin" sort="Morgan, Kevin" uniqKey="Morgan K" first="Kevin" last="Morgan">Kevin Morgan</name>
<affiliation>
<nlm:aff id="A87">Institute of Genetics, Queen’s Medical Centre, University of Nottingham, Nottingham, UK</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Winslow, Ashley R" sort="Winslow, Ashley R" uniqKey="Winslow A" first="Ashley R." last="Winslow">Ashley R. Winslow</name>
<affiliation>
<nlm:aff id="A85">PharmaTherapeutics Clinical Research, Pfizer Worldwide Research and Development, Cambridge, MA, USA</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Powell, John F" sort="Powell, John F" uniqKey="Powell J" first="John F" last="Powell">John F. Powell</name>
<affiliation>
<nlm:aff id="A88">King’s College London, Institute of Psychiatry, Department of Neuroscience, De Crespigny Park, Denmark Hill, London, UK</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Carasquillo, Minerva" sort="Carasquillo, Minerva" uniqKey="Carasquillo M" first="Minerva" last="Carasquillo">Minerva Carasquillo</name>
<affiliation>
<nlm:aff id="A89">Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Younkin, Steven G" sort="Younkin, Steven G" uniqKey="Younkin S" first="Steven G." last="Younkin">Steven G. Younkin</name>
<affiliation>
<nlm:aff id="A89">Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Jakobsd Ttir, J Hanna" sort="Jakobsd Ttir, J Hanna" uniqKey="Jakobsd Ttir J" first="J Hanna" last="Jakobsd Ttir">J Hanna Jakobsd Ttir</name>
<affiliation>
<nlm:aff id="A16">Icelandic Heart Association, Kopavogur, Iceland</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Kauwe, John Sk" sort="Kauwe, John Sk" uniqKey="Kauwe J" first="John Sk" last="Kauwe">John Sk Kauwe</name>
<affiliation>
<nlm:aff id="A90">Department of Biology, Brigham Young University, Provo, Utah, USA</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Wilhelmsen, Kirk C" sort="Wilhelmsen, Kirk C" uniqKey="Wilhelmsen K" first="Kirk C." last="Wilhelmsen">Kirk C. Wilhelmsen</name>
<affiliation>
<nlm:aff id="A91">Department of Genetics, University of North Carolina Chapel Hill, Chapel Hill, NC, USA</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Rujescu, Dan" sort="Rujescu, Dan" uniqKey="Rujescu D" first="Dan" last="Rujescu">Dan Rujescu</name>
<affiliation>
<nlm:aff id="A92">Department of Psychiatry, Psychotherapy and Psychosomatics Martin-Luther-University Halle-Wittenberg, Julius-Kühn-Str. 706112 Halle Germany</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Nothen, Markus M" sort="Nothen, Markus M" uniqKey="Nothen M" first="Markus M" last="Nöthen">Markus M. Nöthen</name>
<affiliation>
<nlm:aff id="A26">Institute of Human Genetics, University of Bonn, Bonn, Germany</nlm:aff>
</affiliation>
<affiliation>
<nlm:aff id="A93">Institute of Human Genetics, Department of Genomics, Life and Brain Center, University of Bonn, Bonn, Germany</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Hofman, Albert" sort="Hofman, Albert" uniqKey="Hofman A" first="Albert" last="Hofman">Albert Hofman</name>
<affiliation>
<nlm:aff id="A4">Department of Epidemiology, Erasmus University Medical Center, Erasmus, Rotterdam, The Netherlands</nlm:aff>
</affiliation>
<affiliation>
<nlm:aff id="A19">Department of Radiology, Erasmus University Medical Center, Erasmus, Rotterdam, The Netherlands</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Jones, Lesley" sort="Jones, Lesley" uniqKey="Jones L" first="Lesley" last="Jones">Lesley Jones</name>
<affiliation>
<nlm:aff id="A6">Institute of Psychological Medicine and Clinical Neurosciences, Medical Research Council (MRC) Centre for Neuropsychiatric Genetics & Genomics, Cardiff University, Cardiff, UK</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Haines, Jonathan L" sort="Haines, Jonathan L" uniqKey="Haines J" first="Jonathan L." last="Haines">Jonathan L. Haines</name>
<affiliation>
<nlm:aff id="A94">Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, OH, USA</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Psaty, Bruce M" sort="Psaty, Bruce M" uniqKey="Psaty B" first="Bruce M." last="Psaty">Bruce M. Psaty</name>
<affiliation>
<nlm:aff id="A12">Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA</nlm:aff>
</affiliation>
<affiliation>
<nlm:aff id="A30">Department of Epidemiology, University of Washington, Seattle, WA, USA</nlm:aff>
</affiliation>
<affiliation>
<nlm:aff id="A35">Departments of Health Services, University of Washington, Seattle, WA, USA</nlm:aff>
</affiliation>
<affiliation>
<nlm:aff id="A71">Group Health, Group Health Research Institute, Seattle, WA, USA</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Van Broeckhoven, Christine" sort="Van Broeckhoven, Christine" uniqKey="Van Broeckhoven C" first="Christine" last="Van Broeckhoven">Christine Van Broeckhoven</name>
<affiliation>
<nlm:aff id="A95">Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, VIB, Antwerp, Belgium</nlm:aff>
</affiliation>
<affiliation>
<nlm:aff id="A96">Institute Born-Bunge, University of Antwerp, Antwerp, Belgium</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Holmans, Peter" sort="Holmans, Peter" uniqKey="Holmans P" first="Peter" last="Holmans">Peter Holmans</name>
<affiliation>
<nlm:aff id="A6">Institute of Psychological Medicine and Clinical Neurosciences, Medical Research Council (MRC) Centre for Neuropsychiatric Genetics & Genomics, Cardiff University, Cardiff, UK</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Launer, Lenore J" sort="Launer, Lenore J" uniqKey="Launer L" first="Lenore J." last="Launer">Lenore J. Launer</name>
<affiliation>
<nlm:aff id="A97">Laboratory of Epidemiology, Demography, and Biometry, National Institute of Health, Bethesda, MD, USA</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Mayeux, Richard" sort="Mayeux, Richard" uniqKey="Mayeux R" first="Richard" last="Mayeux">Richard Mayeux</name>
<affiliation>
<nlm:aff id="A98">Taub Institute on Alzheimer’s Disease and the Aging Brain, Columbia University, New York, NY, USA</nlm:aff>
</affiliation>
<affiliation>
<nlm:aff id="A99">Gertrude H. Sergievsky Center, Columbia University, New York, NY, USA</nlm:aff>
</affiliation>
<affiliation>
<nlm:aff id="A100">Department of Neurology, Columbia University, New York, NY, USA</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Lathrop, Mark" sort="Lathrop, Mark" uniqKey="Lathrop M" first="Mark" last="Lathrop">Mark Lathrop</name>
<affiliation>
<nlm:aff id="A24">Centre National de Genotypage, Institut Genomique, Commissariat a l’energie Atomique, Evry, France</nlm:aff>
</affiliation>
<affiliation>
<nlm:aff id="A101">McGill University and Génome Québec Innovation Centre, Montreal, Canada</nlm:aff>
</affiliation>
<affiliation>
<nlm:aff id="A102">Fondation Jean Dausset- CEPH, Paris, France</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Goate, Alison M" sort="Goate, Alison M" uniqKey="Goate A" first="Alison M." last="Goate">Alison M. Goate</name>
<affiliation>
<nlm:aff id="A32">Hope Center Program on Protein Aggregation and Neurodegeneration, Washington University School of Medicine, St. Louis, MO, USA</nlm:aff>
</affiliation>
<affiliation>
<nlm:aff id="A33">Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Escott Price, Valentina" sort="Escott Price, Valentina" uniqKey="Escott Price V" first="Valentina" last="Escott-Price">Valentina Escott-Price</name>
<affiliation>
<nlm:aff id="A6">Institute of Psychological Medicine and Clinical Neurosciences, Medical Research Council (MRC) Centre for Neuropsychiatric Genetics & Genomics, Cardiff University, Cardiff, UK</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Seshadri, Sudha" sort="Seshadri, Sudha" uniqKey="Seshadri S" first="Sudha" last="Seshadri">Sudha Seshadri</name>
<affiliation>
<nlm:aff id="A17">Department of Neurology, Boston University School of Medicine, Boston, MA, USA</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Pericak Vance, Margaret A" sort="Pericak Vance, Margaret A" uniqKey="Pericak Vance M" first="Margaret A." last="Pericak-Vance">Margaret A. Pericak-Vance</name>
<affiliation>
<nlm:aff id="A11">The John P. Hussman Institute for Human Genomics, University of Miami, Miami, FL, USA</nlm:aff>
</affiliation>
<affiliation>
<nlm:aff id="A14">Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami, Miami, FL, USA</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Amouyel, Philippe" sort="Amouyel, Philippe" uniqKey="Amouyel P" first="Philippe" last="Amouyel">Philippe Amouyel</name>
<affiliation>
<nlm:aff id="A7">Inserm U744, Lille, France</nlm:aff>
</affiliation>
<affiliation>
<nlm:aff id="A8">Université Lille 2, Lille, France</nlm:aff>
</affiliation>
<affiliation>
<nlm:aff id="A9">Institut Pasteur de Lille, Lille, France</nlm:aff>
</affiliation>
<affiliation>
<nlm:aff id="A103">University Hospital, CHRU Lille, Lille, France</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Williams, Julie" sort="Williams, Julie" uniqKey="Williams J" first="Julie" last="Williams">Julie Williams</name>
<affiliation>
<nlm:aff id="A6">Institute of Psychological Medicine and Clinical Neurosciences, Medical Research Council (MRC) Centre for Neuropsychiatric Genetics & Genomics, Cardiff University, Cardiff, UK</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Van Duijn, Cornelia M" sort="Van Duijn, Cornelia M" uniqKey="Van Duijn C" first="Cornelia M." last="Van Duijn">Cornelia M. Van Duijn</name>
<affiliation>
<nlm:aff id="A4">Department of Epidemiology, Erasmus University Medical Center, Erasmus, Rotterdam, The Netherlands</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Schellenberg, Gerard D" sort="Schellenberg, Gerard D" uniqKey="Schellenberg G" first="Gerard D." last="Schellenberg">Gerard D. Schellenberg</name>
<affiliation>
<nlm:aff id="A10">Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Farrer, Lindsay A" sort="Farrer, Lindsay A" uniqKey="Farrer L" first="Lindsay A." last="Farrer">Lindsay A. Farrer</name>
<affiliation>
<nlm:aff id="A1">Department of Medicine (Biomedical Genetics), Boston University School of Medicine, Boston, MA, USA</nlm:aff>
</affiliation>
<affiliation>
<nlm:aff id="A2">Department of Ophthalmology, Boston University School of Medicine, Boston, MA, USA</nlm:aff>
</affiliation>
<affiliation>
<nlm:aff id="A3">Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA</nlm:aff>
</affiliation>
<affiliation>
<nlm:aff id="A17">Department of Neurology, Boston University School of Medicine, Boston, MA, USA</nlm:aff>
</affiliation>
<affiliation>
<nlm:aff id="A104">Department of Epidemiology, Boston University School of Public Health, Boston, MA, USA</nlm:aff>
</affiliation>
</author>
</analytic>
<series>
<title level="j">Molecular psychiatry</title>
<idno type="ISSN">1359-4184</idno>
<idno type="eISSN">1476-5578</idno>
<imprint>
<date when="2015">2015</date>
</imprint>
</series>
</biblStruct>
</sourceDesc>
</fileDesc>
<profileDesc>
<textClass></textClass>
</profileDesc>
</teiHeader>
<front>
<div type="abstract" xml:lang="en">
<p id="P1">
<italic>APOE</italic>
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
<italic>APOE</italic>
ε4+ (10,352 cases and 9,207 controls) and
<italic>APOE</italic>
ε4− (7,184 cases and 26,968 controls) subgroups as well as in the total sample testing for interaction between a SNP and
<italic>APOE</italic>
ε4 status. Suggestive associations (P<1x10
<sup>−4</sup>
) in stage 1 were evaluated in an independent sample (stage 2) containing 4,203 subjects (
<italic>APOE</italic>
ε4+: 1,250 cases and 536 controls;
<italic>APOE</italic>
ε4-: 718 cases and 1,699 controls). Among
<italic>APOE</italic>
ε4− subjects, novel genome-wide significant (GWS) association was observed with 17 SNPs (all between
<italic>KANSL1</italic>
and
<italic>LRRC37A</italic>
on chromosome 17 near
<italic>MAPT</italic>
) in a meta-analysis of the stage 1 and stage 2 datasets (best SNP, rs2732703, P=5·8x10
<sup>−9</sup>
). Conditional analysis revealed that rs2732703 accounted for association signals in the entire 100 kilobase region that includes
<italic>MAPT</italic>
. Except for previously identified AD loci showing stronger association in
<italic>APOE</italic>
ε4+ subjects (
<italic>CR1</italic>
and
<italic>CLU</italic>
) or
<italic>APOE</italic>
ε4− subjects (
<italic>MS4A6A/MS4A4A/ MS4A6E</italic>
), no other SNPs were significantly associated with AD in a specific
<italic>APOE</italic>
genotype subgroup. In addition, the finding in the stage 1 sample that AD risk is significantly influenced by the interaction of
<italic>APOE</italic>
with rs1595014 in
<italic>TMEM106B</italic>
(P=1·6x10
<sup>−7</sup>
) is noteworthy because
<italic>TMEM106B</italic>
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
<italic>KANSL1</italic>
probes that target transcription of the first translated exon and an untranslated exon in hippocampus (P≤1.3x10
<sup>−8</sup>
), frontal cortex (P≤1.3x10
<sup>−9</sup>
), and temporal cortex (P≤1.2x10
<sup>−11</sup>
). Rs113986870 is also strongly associated with a
<italic>MAPT</italic>
probe that targets transcription of alternatively spliced exon 3 in frontal cortex (P=9.2x10
<sup>−6</sup>
) and temporal cortex (P=2.6x10
<sup>−6</sup>
). Our
<italic>APOE</italic>
-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
<italic>APOE</italic>
ε4 compared to 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.</p>
</div>
</front>
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<journal-meta>
<journal-id journal-id-type="nlm-journal-id">9607835</journal-id>
<journal-id journal-id-type="pubmed-jr-id">20545</journal-id>
<journal-id journal-id-type="nlm-ta">Mol Psychiatry</journal-id>
<journal-id journal-id-type="iso-abbrev">Mol. Psychiatry</journal-id>
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<journal-title>Molecular psychiatry</journal-title>
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<issn pub-type="ppub">1359-4184</issn>
<issn pub-type="epub">1476-5578</issn>
</journal-meta>
<article-meta>
<article-id pub-id-type="pmid">25778476</article-id>
<article-id pub-id-type="pmc">4573764</article-id>
<article-id pub-id-type="doi">10.1038/mp.2015.23</article-id>
<article-id pub-id-type="manuscript">NIHMS654371</article-id>
<article-categories>
<subj-group subj-group-type="heading">
<subject>Article</subject>
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<article-title>A NOVEL ALZHEIMER DISEASE LOCUS LOCATED NEAR THE GENE ENCODING TAU PROTEIN</article-title>
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<contrib contrib-type="author">
<name>
<surname>Nalls</surname>
<given-names>Michael A.</given-names>
</name>
<xref ref-type="aff" rid="A75">75</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Mead</surname>
<given-names>Simon</given-names>
</name>
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</contrib>
<contrib contrib-type="author">
<name>
<surname>Reiman</surname>
<given-names>Eric M.</given-names>
</name>
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<contrib contrib-type="author">
<name>
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<given-names>Palmi V.</given-names>
</name>
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<contrib contrib-type="author">
<name>
<surname>Holmes</surname>
<given-names>Clive</given-names>
</name>
<xref ref-type="aff" rid="A81">81</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>St George-Hyslop</surname>
<given-names>Peter H.</given-names>
</name>
<xref ref-type="aff" rid="A82">82</xref>
<xref ref-type="aff" rid="A83">83</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Boada</surname>
<given-names>Mercè</given-names>
</name>
<xref ref-type="aff" rid="A53">53</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Passmore</surname>
<given-names>Peter</given-names>
</name>
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</contrib>
<contrib contrib-type="author">
<name>
<surname>Wendland</surname>
<given-names>Jens R.</given-names>
</name>
<xref ref-type="aff" rid="A85">85</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Schmidt</surname>
<given-names>Reinhold</given-names>
</name>
<xref ref-type="aff" rid="A86">86</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Morgan</surname>
<given-names>Kevin</given-names>
</name>
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</contrib>
<contrib contrib-type="author">
<name>
<surname>Winslow</surname>
<given-names>Ashley R.</given-names>
</name>
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</contrib>
<contrib contrib-type="author">
<name>
<surname>Powell</surname>
<given-names>John F</given-names>
</name>
<xref ref-type="aff" rid="A88">88</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Carasquillo</surname>
<given-names>Minerva</given-names>
</name>
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</contrib>
<contrib contrib-type="author">
<name>
<surname>Younkin</surname>
<given-names>Steven G.</given-names>
</name>
<xref ref-type="aff" rid="A89">89</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Jakobsdóttir</surname>
<given-names>Jóhanna</given-names>
</name>
<xref ref-type="aff" rid="A16">16</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Kauwe</surname>
<given-names>John SK</given-names>
</name>
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</contrib>
<contrib contrib-type="author">
<name>
<surname>Wilhelmsen</surname>
<given-names>Kirk C.</given-names>
</name>
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</contrib>
<contrib contrib-type="author">
<name>
<surname>Rujescu</surname>
<given-names>Dan</given-names>
</name>
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</contrib>
<contrib contrib-type="author">
<name>
<surname>Nöthen</surname>
<given-names>Markus M</given-names>
</name>
<xref ref-type="aff" rid="A26">26</xref>
<xref ref-type="aff" rid="A93">93</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Hofman</surname>
<given-names>Albert</given-names>
</name>
<xref ref-type="aff" rid="A4">4</xref>
<xref ref-type="aff" rid="A19">19</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Jones</surname>
<given-names>Lesley</given-names>
</name>
<xref ref-type="aff" rid="A6">6</xref>
</contrib>
<contrib contrib-type="author">
<collab>IGAP Consortium</collab>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Haines</surname>
<given-names>Jonathan L.</given-names>
</name>
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<contrib contrib-type="author">
<name>
<surname>Psaty</surname>
<given-names>Bruce M.</given-names>
</name>
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<xref ref-type="aff" rid="A71">71</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Van Broeckhoven</surname>
<given-names>Christine</given-names>
</name>
<xref ref-type="aff" rid="A95">95</xref>
<xref ref-type="aff" rid="A96">96</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Holmans</surname>
<given-names>Peter</given-names>
</name>
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</contrib>
<contrib contrib-type="author">
<name>
<surname>Launer</surname>
<given-names>Lenore J.</given-names>
</name>
<xref ref-type="aff" rid="A97">97</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Mayeux</surname>
<given-names>Richard</given-names>
</name>
<xref ref-type="aff" rid="A98">98</xref>
<xref ref-type="aff" rid="A99">99</xref>
<xref ref-type="aff" rid="A100">100</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Lathrop</surname>
<given-names>Mark</given-names>
</name>
<xref ref-type="aff" rid="A24">24</xref>
<xref ref-type="aff" rid="A101">101</xref>
<xref ref-type="aff" rid="A102">102</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Goate</surname>
<given-names>Alison M.</given-names>
</name>
<xref ref-type="aff" rid="A32">32</xref>
<xref ref-type="aff" rid="A33">33</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Escott-Price</surname>
<given-names>Valentina</given-names>
</name>
<xref ref-type="aff" rid="A6">6</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Seshadri</surname>
<given-names>Sudha</given-names>
</name>
<xref ref-type="aff" rid="A17">17</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Pericak-Vance</surname>
<given-names>Margaret A.</given-names>
</name>
<xref ref-type="aff" rid="A11">11</xref>
<xref ref-type="aff" rid="A14">14</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Amouyel</surname>
<given-names>Philippe</given-names>
</name>
<xref ref-type="aff" rid="A7">7</xref>
<xref ref-type="aff" rid="A8">8</xref>
<xref ref-type="aff" rid="A9">9</xref>
<xref ref-type="aff" rid="A103">103</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Williams</surname>
<given-names>Julie</given-names>
</name>
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</contrib>
<contrib contrib-type="author">
<name>
<surname>van Duijn</surname>
<given-names>Cornelia M.</given-names>
</name>
<xref ref-type="aff" rid="A4">4</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Schellenberg</surname>
<given-names>Gerard D.</given-names>
</name>
<xref ref-type="aff" rid="A10">10</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Farrer</surname>
<given-names>Lindsay A.</given-names>
</name>
<xref ref-type="aff" rid="A1">1</xref>
<xref ref-type="aff" rid="A2">2</xref>
<xref ref-type="aff" rid="A3">3</xref>
<xref ref-type="aff" rid="A17">17</xref>
<xref ref-type="aff" rid="A104">104</xref>
<xref rid="FN1" ref-type="author-notes">†</xref>
</contrib>
</contrib-group>
<aff id="A1">
<label>1</label>
Department of Medicine (Biomedical Genetics), Boston University School of Medicine, Boston, MA, USA</aff>
<aff id="A2">
<label>2</label>
Department of Ophthalmology, Boston University School of Medicine, Boston, MA, USA</aff>
<aff id="A3">
<label>3</label>
Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA</aff>
<aff id="A4">
<label>4</label>
Department of Epidemiology, Erasmus University Medical Center, Erasmus, Rotterdam, The Netherlands</aff>
<aff id="A5">
<label>5</label>
Department of Neurology, Erasmus University Medical Center, Erasmus, Rotterdam, The Netherlands</aff>
<aff id="A6">
<label>6</label>
Institute of Psychological Medicine and Clinical Neurosciences, Medical Research Council (MRC) Centre for Neuropsychiatric Genetics & Genomics, Cardiff University, Cardiff, UK</aff>
<aff id="A7">
<label>7</label>
Inserm U744, Lille, France</aff>
<aff id="A8">
<label>8</label>
Université Lille 2, Lille, France</aff>
<aff id="A9">
<label>9</label>
Institut Pasteur de Lille, Lille, France</aff>
<aff id="A10">
<label>10</label>
Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA</aff>
<aff id="A11">
<label>11</label>
The John P. Hussman Institute for Human Genomics, University of Miami, Miami, FL, USA</aff>
<aff id="A12">
<label>12</label>
Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA</aff>
<aff id="A13">
<label>13</label>
Trinity College, University of Dublin, Dublin, Ireland</aff>
<aff id="A14">
<label>14</label>
Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami, Miami, FL, USA</aff>
<aff id="A15">
<label>15</label>
University of Iceland, Faculty of Medicine, Reykjavik, Iceland</aff>
<aff id="A16">
<label>16</label>
Icelandic Heart Association, Kopavogur, Iceland</aff>
<aff id="A17">
<label>17</label>
Department of Neurology, Boston University School of Medicine, Boston, MA, USA</aff>
<aff id="A18">
<label>18</label>
Netherlands Consortium for Healthy Aging, Leiden, The Netherlands</aff>
<aff id="A19">
<label>19</label>
Department of Radiology, Erasmus University Medical Center, Erasmus, Rotterdam, The Netherlands</aff>
<aff id="A20">
<label>20</label>
Institute for Molecular Biology and Biochemistry, Medical University of Graz, Graz, Austria</aff>
<aff id="A21">
<label>21</label>
Laboratory for Statistical Analysis, Center for Integrative Medical Sciences, Riken, Kanagawa, Japan</aff>
<aff id="A22">
<label>22</label>
Foundation Jean Dausset – CEPH, Paris, France</aff>
<aff id="A23">
<label>23</label>
Memory Clinic of Fundació ACE. Institut Català de Neurociències Aplicades, Barcelona, Spain</aff>
<aff id="A24">
<label>24</label>
Centre National de Genotypage, Institut Genomique, Commissariat a l’energie Atomique, Evry, France</aff>
<aff id="A25">
<label>25</label>
Department of Psychiatry and Psychotherapy, University of Bonn, Bonn, Germany</aff>
<aff id="A26">
<label>26</label>
Institute of Human Genetics, University of Bonn, Bonn, Germany</aff>
<aff id="A27">
<label>27</label>
Department of Medical and Molecular Genetics, Indiana University, Indianapolis, IN, USA</aff>
<aff id="A28">
<label>28</label>
German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany</aff>
<aff id="A29">
<label>29</label>
Institute for Medical Biometry, Informatics and Epidemiology, University of Bonn, Bonn, Germany</aff>
<aff id="A30">
<label>30</label>
Department of Epidemiology, University of Washington, Seattle, WA, USA</aff>
<aff id="A31">
<label>31</label>
Centre National de Reference pour les Malades Alzheimer Jeunes (CNR-MAJ), Centre Hospitalier Régional Universitaire de Lille, Lille, France</aff>
<aff id="A32">
<label>32</label>
Hope Center Program on Protein Aggregation and Neurodegeneration, Washington University School of Medicine, St. Louis, MO, USA</aff>
<aff id="A33">
<label>33</label>
Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA</aff>
<aff id="A34">
<label>34</label>
National Alzheimer’s Coordinating Center, University of Washington, Seattle, WA, USA</aff>
<aff id="A35">
<label>35</label>
Departments of Health Services, University of Washington, Seattle, WA, USA</aff>
<aff id="A36">
<label>36</label>
University Paris Descartes, Sorbonne Paris V, France</aff>
<aff id="A37">
<label>37</label>
Broca Hospital, Geriatrics Department, Paris, France</aff>
<aff id="A38">
<label>38</label>
Mercer’s Institute for Research on Aging, St. James Hospital and Trinity College, Dublin, Ireland</aff>
<aff id="A39">
<label>39</label>
Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, Fort Worth, TX, USA</aff>
<aff id="A40">
<label>40</label>
CNR-MAJ, Inserm U1079, Rouen, France</aff>
<aff id="A41">
<label>41</label>
University Hospital, 76031 Rouen, France</aff>
<aff id="A42">
<label>42</label>
University of Bristol Institute of Clinical Neurosciences, School of Clinical Sciences, Frenchay Hospital, Bristol, UK</aff>
<aff id="A43">
<label>43</label>
Department of Neurological Sciences, Rush University Medical Center, Chicago, IL, USA</aff>
<aff id="A44">
<label>44</label>
Rush Alzheimer’s Disease Center, Rush University Medical Center, Chicago, IL, USA</aff>
<aff id="A45">
<label>45</label>
Inserm U888, Hôpital La Colombière, Montpellier, France</aff>
<aff id="A46">
<label>46</label>
Department of Neurology, Aristotle University of Thessaloniki, Thessaloniki, Greece</aff>
<aff id="A47">
<label>47</label>
Department of Neuroscience, Mount Sinai School of Medicine, New York, NY, USA</aff>
<aff id="A48">
<label>48</label>
Department of Psychiatry, Mount Sinai School of Medicine, New York, NY, USA</aff>
<aff id="A49">
<label>49</label>
Departments of Genetics and Genomic Sciences, Mount Sinai School of Medicine, New York, NY, USA</aff>
<aff id="A50">
<label>50</label>
University of Pittsburgh Alzheimer’s Disease Research Center, Pittsburgh, PA, USA</aff>
<aff id="A51">
<label>51</label>
Departments of Neurology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA</aff>
<aff id="A52">
<label>52</label>
Dementia Research Centre, Department of Neurodegenerative Disease, University College London Institute of Neurology, London, UK</aff>
<aff id="A53">
<label>53</label>
Memory Clinic of Fundació ACE. Institut Català de Neurociències Aplicades, Barcelona, Spain</aff>
<aff id="A54">
<label>54</label>
Inserm U897, Victor Segalen University, F-33076, Bordeaux, France</aff>
<aff id="A55">
<label>55</label>
Department of Molecular Neuroscience, Institute of Neurology, London, UK</aff>
<aff id="A56">
<label>56</label>
Reta Lilla Weston Laboratories, Institute of Neurology, London, UK</aff>
<aff id="A57">
<label>57</label>
Department of Medicine, University of Washington, Seattle, WA, USA</aff>
<aff id="A58">
<label>58</label>
Oxford Healthy Aging Project (OHAP), Clinical Trial Service Unit, University of Oxford, Oxford, UK</aff>
<aff id="A59">
<label>59</label>
Rush Institute for Healthy Aging, Department of Internal Medicine, Rush University Medical Center, Chicago, IL, USA</aff>
<aff id="A60">
<label>60</label>
Department of Medicine (Geriatrics), University of Mississippi Medical Center, Jackson, MS, USA</aff>
<aff id="A61">
<label>61</label>
Institute of Public Health, University of Cambridge, Cambridge, UK</aff>
<aff id="A62">
<label>62</label>
Program in Translational NeuroPsychiatric Genomics, Institute for the Neurosciences, Department of Neurology & Psychiatry, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA</aff>
<aff id="A63">
<label>63</label>
Program in Medical and Population Genetics, Broad Institute, Cambridge, MA, USA</aff>
<aff id="A64">
<label>64</label>
Faculty of Pharmaceutical Sciences, University of Iceland, Reykjavik, Iceland</aff>
<aff id="A65">
<label>65</label>
Centre de Mémoire de Ressources et de Recherche de Bordeaux, CHU de Bordeaux, Bordeaux, France</aff>
<aff id="A66">
<label>66</label>
Department of Psychiatry, University of Frankfurt, Frankfurt am Main, Germany</aff>
<aff id="A67">
<label>67</label>
Department of Psychiatry, Ludwig Maximilians University, Munich, Germany</aff>
<aff id="A68">
<label>68</label>
Department of Human Genetics, University of Pittsburgh, Pittsburgh, PA, USA</aff>
<aff id="A69">
<label>69</label>
Neurogenetics Laboratory, Division of Neurosciences, Center for Applied Medical Research, University of Navarra School of Medicine, Pamplona, Spain</aff>
<aff id="A70">
<label>70</label>
CIBERNED, Instituto de Salud Carlos III, Madrid, Spain</aff>
<aff id="A71">
<label>71</label>
Group Health, Group Health Research Institute, Seattle, WA, USA</aff>
<aff id="A72">
<label>72</label>
Institute for Translational Genomics and Population Sciences. Los Angeles BioMedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA, USA</aff>
<aff id="A73">
<label>73</label>
Division of Genetic Outcomes, Department of Pediatrics, Harbor-UCLA Medical Center, Torrance, CA, USA</aff>
<aff id="A74">
<label>74</label>
Department of Pathology, University of Washington, Seattle, WA, USA</aff>
<aff id="A75">
<label>75</label>
Laboratory of Neurogenetics, Intramural Research Program, National Institute on Aging, Bethesda, MD, USA</aff>
<aff id="A76">
<label>76</label>
Arizona Alzheimer’s Consortium, Phoenix, AZ, USA</aff>
<aff id="A77">
<label>77</label>
Department of Psychiatry, University of Arizona, Phoenix, AZ, USA</aff>
<aff id="A78">
<label>78</label>
Banner Alzheimer’s Institute, Phoenix, AZ, USA</aff>
<aff id="A79">
<label>79</label>
Neurogenomics Division, Translational Genomics Research Institute, Phoenix, Arizona</aff>
<aff id="A80">
<label>80</label>
Department of Geriatrics, Landspitali National University Hospital, Reykjavik, Iceland</aff>
<aff id="A81">
<label>81</label>
Division of Clinical Neurosciences, School of Medicine, University of Southampton, Southampton, UK</aff>
<aff id="A82">
<label>82</label>
Tanz Centre for Research in Neurodegenerative Disease, University of Toronto, Toronto, Canada</aff>
<aff id="A83">
<label>83</label>
Cambridge Institute for Medical Research and Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK</aff>
<aff id="A84">
<label>84</label>
Ageing Group, Centre for Public Health, School of Medicine, Dentistry and Biomedical Sciences, Queen’s University, Belfast, UK</aff>
<aff id="A85">
<label>85</label>
PharmaTherapeutics Clinical Research, Pfizer Worldwide Research and Development, Cambridge, MA, USA</aff>
<aff id="A86">
<label>86</label>
Department of Neurology, Medical University of Graz, Graz, Austria</aff>
<aff id="A87">
<label>87</label>
Institute of Genetics, Queen’s Medical Centre, University of Nottingham, Nottingham, UK</aff>
<aff id="A88">
<label>88</label>
King’s College London, Institute of Psychiatry, Department of Neuroscience, De Crespigny Park, Denmark Hill, London, UK</aff>
<aff id="A89">
<label>89</label>
Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA</aff>
<aff id="A90">
<label>90</label>
Department of Biology, Brigham Young University, Provo, Utah, USA</aff>
<aff id="A91">
<label>91</label>
Department of Genetics, University of North Carolina Chapel Hill, Chapel Hill, NC, USA</aff>
<aff id="A92">
<label>92</label>
Department of Psychiatry, Psychotherapy and Psychosomatics Martin-Luther-University Halle-Wittenberg, Julius-Kühn-Str. 706112 Halle Germany</aff>
<aff id="A93">
<label>93</label>
Institute of Human Genetics, Department of Genomics, Life and Brain Center, University of Bonn, Bonn, Germany</aff>
<aff id="A94">
<label>94</label>
Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, OH, USA</aff>
<aff id="A95">
<label>95</label>
Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, VIB, Antwerp, Belgium</aff>
<aff id="A96">
<label>96</label>
Institute Born-Bunge, University of Antwerp, Antwerp, Belgium</aff>
<aff id="A97">
<label>97</label>
Laboratory of Epidemiology, Demography, and Biometry, National Institute of Health, Bethesda, MD, USA</aff>
<aff id="A98">
<label>98</label>
Taub Institute on Alzheimer’s Disease and the Aging Brain, Columbia University, New York, NY, USA</aff>
<aff id="A99">
<label>99</label>
Gertrude H. Sergievsky Center, Columbia University, New York, NY, USA</aff>
<aff id="A100">
<label>100</label>
Department of Neurology, Columbia University, New York, NY, USA</aff>
<aff id="A101">
<label>101</label>
McGill University and Génome Québec Innovation Centre, Montreal, Canada</aff>
<aff id="A102">
<label>102</label>
Fondation Jean Dausset- CEPH, Paris, France</aff>
<aff id="A103">
<label>103</label>
University Hospital, CHRU Lille, Lille, France</aff>
<aff id="A104">
<label>104</label>
Department of Epidemiology, Boston University School of Public Health, Boston, MA, USA</aff>
<author-notes>
<corresp id="FN1">
<label>†</label>
Corresponding author: Lindsay A. Farrer, Ph.D., Biomedical Genetics E200, Boston University School of Medicine, 72 East Concord Street, Boston, MA. Phone: (617) 638-5393; FAX: (617) 638-4275;
<email>farrer@bu.edu</email>
</corresp>
</author-notes>
<pub-date pub-type="nihms-submitted">
<day>11</day>
<month>1</month>
<year>2015</year>
</pub-date>
<pub-date pub-type="epub">
<day>17</day>
<month>3</month>
<year>2015</year>
</pub-date>
<pub-date pub-type="ppub">
<month>1</month>
<year>2016</year>
</pub-date>
<pub-date pub-type="pmc-release">
<day>18</day>
<month>5</month>
<year>2016</year>
</pub-date>
<volume>21</volume>
<issue>1</issue>
<fpage>108</fpage>
<lpage>117</lpage>
<pmc-comment>elocation-id from pubmed: 10.1038/mp.2015.23</pmc-comment>
<permissions>
<license xlink:href="http://www.nature.com/authors/editorial_policies/license.html#terms">
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<abstract>
<p id="P1">
<italic>APOE</italic>
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
<italic>APOE</italic>
ε4+ (10,352 cases and 9,207 controls) and
<italic>APOE</italic>
ε4− (7,184 cases and 26,968 controls) subgroups as well as in the total sample testing for interaction between a SNP and
<italic>APOE</italic>
ε4 status. Suggestive associations (P<1x10
<sup>−4</sup>
) in stage 1 were evaluated in an independent sample (stage 2) containing 4,203 subjects (
<italic>APOE</italic>
ε4+: 1,250 cases and 536 controls;
<italic>APOE</italic>
ε4-: 718 cases and 1,699 controls). Among
<italic>APOE</italic>
ε4− subjects, novel genome-wide significant (GWS) association was observed with 17 SNPs (all between
<italic>KANSL1</italic>
and
<italic>LRRC37A</italic>
on chromosome 17 near
<italic>MAPT</italic>
) in a meta-analysis of the stage 1 and stage 2 datasets (best SNP, rs2732703, P=5·8x10
<sup>−9</sup>
). Conditional analysis revealed that rs2732703 accounted for association signals in the entire 100 kilobase region that includes
<italic>MAPT</italic>
. Except for previously identified AD loci showing stronger association in
<italic>APOE</italic>
ε4+ subjects (
<italic>CR1</italic>
and
<italic>CLU</italic>
) or
<italic>APOE</italic>
ε4− subjects (
<italic>MS4A6A/MS4A4A/ MS4A6E</italic>
), no other SNPs were significantly associated with AD in a specific
<italic>APOE</italic>
genotype subgroup. In addition, the finding in the stage 1 sample that AD risk is significantly influenced by the interaction of
<italic>APOE</italic>
with rs1595014 in
<italic>TMEM106B</italic>
(P=1·6x10
<sup>−7</sup>
) is noteworthy because
<italic>TMEM106B</italic>
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
<italic>KANSL1</italic>
probes that target transcription of the first translated exon and an untranslated exon in hippocampus (P≤1.3x10
<sup>−8</sup>
), frontal cortex (P≤1.3x10
<sup>−9</sup>
), and temporal cortex (P≤1.2x10
<sup>−11</sup>
). Rs113986870 is also strongly associated with a
<italic>MAPT</italic>
probe that targets transcription of alternatively spliced exon 3 in frontal cortex (P=9.2x10
<sup>−6</sup>
) and temporal cortex (P=2.6x10
<sup>−6</sup>
). Our
<italic>APOE</italic>
-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
<italic>APOE</italic>
ε4 compared to 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.</p>
</abstract>
</article-meta>
</front>
<body>
<sec sec-type="intro" id="S2">
<title>INTRODUCTION</title>
<p id="P2">The common late-onset form of Alzheimer disease (AD) has a strong genetic component,
<sup>
<xref rid="R1" ref-type="bibr">1</xref>
</sup>
a portion of which is explained by
<italic>APOE</italic>
and several other genes identified by positional mapping, targeted gene analysis and genome-wide association studies (GWAS).
<sup>
<xref rid="R2" ref-type="bibr">2</xref>
–
<xref rid="R4" ref-type="bibr">4</xref>
</sup>
Together, these loci account for less than one-half of the heritable component in AD susceptibility, of which 20%–25% is due to
<italic>APOE</italic>
.
<sup>
<xref rid="R4" ref-type="bibr">4</xref>
,
<xref rid="R5" ref-type="bibr">5</xref>
</sup>
Because many of the known AD loci cluster in biological pathways, including those involved in inflammation, lipid metabolism and processing, and intracellular trafficking of Aβ, there are likely more AD risk loci that are difficult to detect because of very weak effect size, allelic heterogeneity, or rare variants. To examine yet another hypothesis, namely, that associations for some loci may be obscured by confounding or interaction with other loci, we conducted a two-stage GWAS in
<italic>APOE</italic>
genotype subgroups using the large resources of the International Genomics of Alzheimer’s Project (IGAP).</p>
</sec>
<sec sec-type="methods" id="S3">
<title>METHODS</title>
<sec id="S4">
<title>Study Population</title>
<p id="P3">Details of the stage 1 sample from the International Genomics of Alzheimer’s Project (IGAP) Consortium including subject recruitment, genotyping, imputation, quality control, population substructure, and statistical methods for association analyses were previously described.
<sup>
<xref rid="R4" ref-type="bibr">4</xref>
</sup>
In brief, phenotype and genotype data, including
<italic>APOE</italic>
genotypes, for a total of 53,711 subjects were assembled by IGAP from the Alzheimer’s Disease Genetic Consortium (ADGC), the Cohorts for Heart and Ageing Research in Genomic Epidemiology (CHARGE) consortium, the European Alzheimer’s Disease Initiative (EADI), and the Genetic and Environmental Risk in Alzheimer’s Disease (GERAD) consortium. Characteristics of this sample are in
<xref rid="SD2" ref-type="supplementary-material">Supplementary Table S1</xref>
.</p>
<p id="P4">The stage 2 dataset included GWAS and
<italic>APOE</italic>
genotype data for 4,203 subjects of European ancestry from the ADC4, ADC5, ADC6, MTV, Pfizer, and TARCC datasets in the ADGC. These individuals were recruited under protocols approved by the appropriate Institutional Review Boards. Details of the individual datasets are provided in the
<xref rid="SD1" ref-type="supplementary-material">Supplementary Materials</xref>
and summarized in
<xref rid="SD2" ref-type="supplementary-material">Supplementary Table S1</xref>
.</p>
</sec>
<sec id="S5">
<title>Procedures</title>
<sec id="S6">
<title>QC, Imputation, and Population Substructure in Stage 2 Datasets</title>
<p id="P5">Quality control of the clinical and genotype data in these cohorts was performed using procedures described elsewhere.
<sup>
<xref rid="R4" ref-type="bibr">4</xref>
</sup>
SNP genotypes in each stage 2 dataset were imputed with IMPUTE2 using reference haplotypes from the March 2012 release of 1000 Genomes. We compared imputation results for selected variants in the stage 1 datasets using the March 2012 release of 1000 Genomes and prior imputation on the December 2010 release, and found no significant difference in the distribution of genotype probabilities between old and new imputations for the same samples among the original ADGC datasets. We used actual
<italic>APOE</italic>
genotypes when available because previously we observed that imputation in this region using the 1000 Genomes reference panel is unreliable.
<sup>
<xref rid="R5" ref-type="bibr">5</xref>
</sup>
Population substructure was evaluated within each dataset by principal components (PC) analysis using EIGENSTRAT (
<ext-link ext-link-type="uri" xlink:href="http://www.hsph.harvard.edu/alkes-price/software/">http://www.hsph.harvard.edu/alkes-price/software/</ext-link>
) and a subset of 21,109 SNPs common to all genotyping platforms.</p>
</sec>
</sec>
<sec id="S7">
<title>Statistical Analysis</title>
<sec id="S8">
<title>Genome-wide Association Study</title>
<p id="P6">Within each stage 1 dataset, genome-wide association analyses were conducted separately in subgroups of subjects with and without the
<italic>APOE</italic>
ε4 allele using a logistic generalized linear model (GLM) in case-control datasets and a logistic generalized estimating equation (GEE) in family-based datasets. The potential independent effect of the
<italic>APOE</italic>
ε2 allele was not examined because of the paucity of carriers of this allele, thus rendering very small cell sizes particularly among AD cases and in smaller datasets. Cox-proportional hazards models were used to evaluate association with incident AD in three CHARGE cohorts. A quantitative estimate between 0 and 2 for the dose of the reference allele for a SNP was used to incorporate the uncertainty of the imputation estimates. Interaction between a SNP and
<italic>APOE</italic>
genotype was evaluated in the
<italic>APOE</italic>
genotype subgroups combined within each dataset using regression models including age, sex, the first three PCs, and terms for the SNP,
<italic>APOE</italic>
ε4 status, and interaction between the SNP and
<italic>APOE</italic>
ε4 status. Results for each model across datasets were combined by meta-analysis using the inverse variance method implemented in the software package METAL (
<ext-link ext-link-type="uri" xlink:href="http://www.sph.umich.edu/csg/abecasis/Metal/">http://www.sph.umich.edu/csg/abecasis/Metal/</ext-link>
). Effect sizes were weighted by their inverse variance and a combined estimate was calculated by summing the weighted estimates and dividing by the summed weights. SNPs with a minor allele frequency >5% that were available in at least 50% of the datasets were included in the meta-analysis. The meta-analysis
<italic>P-</italic>
value for association was estimated by the summarized test statistic, after applying genomic control within each individual study.</p>
</sec>
<sec id="S9">
<title>Follow-up Analysis in Stage 2 Datasets</title>
<p id="P7">SNPs attaining a P-value <10
<sup>−4</sup>
in the stage 1 GWAS were evaluated in each of the stage 2 GWAS datasets, containing a total of 1,786
<italic>APOE</italic>
ε4+ and 2,417
<italic>APOE</italic>
ε4− subjects (
<xref rid="SD2" ref-type="supplementary-material">Supplementary Table S1</xref>
), using the same approach described above.</p>
</sec>
</sec>
<sec id="S10">
<title>Gene Expression Analysis</title>
<p id="P8">The effect of top-ranked SNPs on gene expression was evaluated using an open access database of control brain microarray data (BRAINEAC) made publically available by the UK Human Brain Expression Consortium (
<ext-link ext-link-type="uri" xlink:href="http://caprica.genetics.kcl.ac.uk/BRAINEAC">http://caprica.genetics.kcl.ac.uk/BRAINEAC</ext-link>
). This dataset contains information generated by analysis of tissue samples obtained from 12 different central nervous system regions in 134 individuals. Details of the expression quantitative trait locus (eQTL) analysis are reported elsewhere.
<sup>
<xref rid="R6" ref-type="bibr">6</xref>
</sup>
In this study, the experiment-wise significance threshold for association of a genetic marker with expression was determined to be 1.6x10
<sup>−7</sup>
at the gene level and 1.8x10
<sup>−6</sup>
for individual exons. Potential for functionality of the top-ranked SNPs was assessed using the Regulome database (
<ext-link ext-link-type="uri" xlink:href="http://www.regulomedb.org">http://www.regulomedb.org</ext-link>
).</p>
</sec>
</sec>
<sec sec-type="results" id="S11">
<title>RESULTS</title>
<p id="P9">We conducted a genome-wide association study for AD using datasets stratified by
<italic>APOE</italic>
genotype assembled by IGAP which were from the ADGC, CHARGE consortium, EADI, and GERAD consortium. Meta-analyses were performed separately in
<italic>APOE</italic>
ε4+ (10,246 cases and 11,924 controls) and
<italic>APOE</italic>
ε4− (7,231 cases and 19,603 controls) subgroups, as well as the total sample using a model including a term for the interaction of the SNP with the
<italic>APOE</italic>
ε4 status. There was limited genomic inflation in the GWAS results in the
<italic>APOE</italic>
ε4+ (λ=1.05) and
<italic>APOE</italic>
ε4− (λ=1.06) groups, but not in the total sample (λ=0.98) testing the ε4 * SNP interaction (
<xref rid="SD1" ref-type="supplementary-material">Supplementary Figure S1</xref>
). Genome-wide significant (GWS) association (P<5x10
<sup>−8</sup>
) for AD was found in five distinct regions (
<italic>CR1, BIN1, CLU, PICALM</italic>
and
<italic>APOE</italic>
) in the
<italic>APOE</italic>
ε4+ subgroup (
<xref rid="SD1" ref-type="supplementary-material">Supplementary Figure S2A</xref>
,
<xref rid="SD2" ref-type="supplementary-material">Supplementary Table S2</xref>
) and four distinct regions (
<italic>BIN1</italic>
,
<italic>HBEGF</italic>
,
<italic>MS4A6A/MS4A4A</italic>
,
<italic>SLC24A4</italic>
, and
<italic>APOE</italic>
) in the
<italic>APOE</italic>
ε4− subgroup (
<xref rid="SD1" ref-type="supplementary-material">Supplementary Figure S2B</xref>
,
<xref rid="SD2" ref-type="supplementary-material">Supplementary Table S2</xref>
). No significant SNP*
<italic>APOE</italic>
interactions were found in the total group (
<xref rid="SD1" ref-type="supplementary-material">Supplementary Figure S2C</xref>
). Suggestive association (P<10
<sup>−6</sup>
) was observed with SNPs in five novel loci in the
<italic>APOE</italic>
ε4− subgroup (
<italic>SOX14/CLDN18</italic>
,
<italic>ACSL6</italic>
,
<italic>FAM20C</italic>
,
<italic>MAPT</italic>
region, and
<italic>CDR2L</italic>
;
<xref rid="SD1" ref-type="supplementary-material">Supplementary Figure S2B</xref>
,
<xref rid="SD2" ref-type="supplementary-material">Supplementary Table S3</xref>
) and with 21
<italic>TMEM106B</italic>
SNPs (top result: rs1595014, P=1.6x10
<sup>−7</sup>
) (
<xref rid="SD1" ref-type="supplementary-material">Supplementary Figure S2C</xref>
,
<xref rid="SD2" ref-type="supplementary-material">Supplementary Table S3</xref>
).</p>
<p id="P10">Approximately 1,130 SNPs from 38 regions (including seven previously established AD loci) were tested in Stage 2 (
<xref rid="SD2" ref-type="supplementary-material">Supplementary Table S3</xref>
). Follow-up analyses of the novel loci confirmed association with SNPs in
<italic>CDC42SE2-ACSL6, KANSL1/LRRC37A</italic>
, and
<italic>CDR2L</italic>
in the stage 2 sample (
<xref rid="T1" ref-type="table">Table 1</xref>
,
<xref rid="SD2" ref-type="supplementary-material">Supplementary Table S2</xref>
), but only SNPs near
<italic>MAPT</italic>
and between
<italic>KANSL1</italic>
and
<italic>LRRC37A</italic>
(
<xref rid="F1" ref-type="fig">Figure 1A</xref>
) were genome-wide significant after combining results from the stage 1 and stage 2 samples (best SNP: rs2732703, meta-analysis: P=5.8x10
<sup>−9</sup>
). The association was consistent in nearly all datasets which contained rs2732703 information (
<xref rid="F1" ref-type="fig">Figure 1B</xref>
). To verify the reliability of the association with rs2732703, an imputed SNP, we compared rs2732703 allele dosages obtained directly by genotyping using a Taqman assay with those derived from imputation among 1,010 subjects from the ACT, ADC4, ADC5 and ADC6 datasets. The correlation of these values, 0.813 in the entire sample and 0.834 among
<italic>APOE</italic>
ε4− subjects, as well as a genotype misclassification rate of only 3.5% among subjects with imputed probability scores > 0.8 for a particular genotype, suggest that our association findings were not influenced substantially by imputation quality.</p>
<p id="P11">Further examination of this region in the total sample revealed an association peak spanning more than 1.25 Mb that contains 15 genes (
<xref rid="F1" ref-type="fig">Figure 1A</xref>
). Within this region, 17 SNPs were GWS, have MAFs ranging from 0.13 to 0.17, and are located in a 10.2 kb segment upstream of both
<italic>KANSL1</italic>
and
<italic>LRRC37A</italic>
(
<xref rid="SD2" ref-type="supplementary-material">Supplementary Table S4</xref>
). Nominally significant association was observed with only one of these SNPs among ε4+ subjects (rs2732703, P=0.02) (
<xref rid="SD2" ref-type="supplementary-material">Supplementary Table S3</xref>
). Although the odds ratios (OR) for effect of the effect of minor allele on AD risk were substantially lower for all of the GWS SNPs in the ε4− group (0.54< OR <0.86) than in the ε4+ group (0.76< β <1.04), there was no evidence of interaction with
<italic>APOE</italic>
genotype (
<xref rid="SD2" ref-type="supplementary-material">Supplementary Table S3</xref>
). The minor alleles of these SNPs reduced AD risk by 20%–37% in the ε4− group. The 350 kb gap in the broad association signal is punctuated at one end by a “cliff” adjacent to the
<italic>MAPT-KANSL1-LRRC37A</italic>
association peak (
<xref rid="F1" ref-type="fig">Figure 1</xref>
). This gap is populated by relatively few SNPs and contains several copy number variation (CNV) polymorphisms.
<sup>
<xref rid="R7" ref-type="bibr">7</xref>
,
<xref rid="R8" ref-type="bibr">8</xref>
</sup>
To explore the possibility that the association observed in the present analysis is explained by previously identified haplotypes H1/H2 in the
<italic>MAPT</italic>
region,
<sup>
<xref rid="R8" ref-type="bibr">8</xref>
</sup>
we evaluated six models in the entire dataset conditioning on rs8070723 (an H1/H2 tagging SNP), rs2732703, or rs199533. Rs2732703 remained significant in models conditioning on rs8070723 (P=0.013) or rs199533 (P=0.0020), and rs8070723 was marginally significant in the model conditioning on rs199533 (P=0.043) (
<xref rid="SD2" ref-type="supplementary-material">Supplementary Table S5</xref>
,
<xref rid="SD1" ref-type="supplementary-material">Supplementary Figure S3</xref>
). These results suggest that
<italic>KANSL1/LRRC37A</italic>
is the only AD risk locus in this region.</p>
<p id="P12">We also examined the effect of
<italic>APOE</italic>
ε4 status on previously established AD loci (
<xref rid="SD2" ref-type="supplementary-material">Supplementary Table S2</xref>
). Four of these loci attained genome-wide significance in at least one of the
<italic>APOE</italic>
subgroups (
<xref rid="T2" ref-type="table">Table 2</xref>
), and the association signal in the
<italic>MS4A</italic>
cluster region was evident primarily in the
<italic>APOE</italic>
ε4− subgroup (
<xref rid="SD1" ref-type="supplementary-material">Supplementary Figure S4</xref>
). The association of AD with
<italic>CR1, BIN1,</italic>
and
<italic>CLU</italic>
was supported in both
<italic>APOE</italic>
subgroups.</p>
<p id="P13">Next, we interrogated the BRAINEAC database to determine whether any of the 17 GWS SNPs located between
<italic>KANSL1</italic>
and
<italic>LRRC37A</italic>
are cis-eQTLs. Data were available for only one of these SNPs (rs113986870) which is in high LD with and 2,461 base pairs away from rs2732703 (r
<sup>2</sup>
and D′>0.9). Ten exon probes from four genes (
<italic>KANSL1, LRRC37A4P, MAPT,</italic>
and
<italic>C17orf69</italic>
) were significantly associated with rs113986870 when averaged across all brain regions (
<xref rid="T3" ref-type="table">Table 3</xref>
). Rs113986870 was significantly associated with gene-level expression (
<xref rid="F2" ref-type="fig">Figure 2A</xref>
) as well as with exon-level expression (
<xref rid="F2" ref-type="fig">Figure 2B</xref>
) in hippocampus, temporal cortex, and cerebellum. In these brain regions, rs113986870 was significantly associated with
<italic>KANSL1</italic>
probes 3762011, 3762012 and 3762013 that measure expression of the first translated exon. Additionally, we observed that expression of probe 3760518 (
<xref rid="SD1" ref-type="supplementary-material">Supplementary Figure S5A</xref>
) present in all three transcripts (NM_001193466, NM_015443, and NM_001193465) and 3760219 in transcript variant 2 (NM_015443) was significantly associated with rs113986870 (
<xref rid="SD1" ref-type="supplementary-material">Supplementary Figure S5B</xref>
), while expression of probe 3760217 in transcript variant 1 ((NM_001193466) was not significant (
<xref rid="SD1" ref-type="supplementary-material">Supplementary Figure S5C</xref>
), indicating that alternative splicing may be a crucial mechanism for regulating
<italic>KANSL1</italic>
expression. Rs113986870 was also strongly associated with
<italic>MAPT</italic>
transcription (
<xref rid="SD1" ref-type="supplementary-material">Supplementary Figure S6A</xref>
) and in particular with probe 3723712 that targets transcription of alternatively spliced exon 3 in frontal cortex (P≤9.2x10
<sup>−6</sup>
) and temporal cortex (P≤2.6x10
<sup>−6</sup>
) (
<xref rid="SD1" ref-type="supplementary-material">Supplementary Figure S6B</xref>
). The rs113986870 minor allele (
<italic>A</italic>
), which is associated with reduced risk of AD (
<xref rid="SD2" ref-type="supplementary-material">Supplementary Table S4</xref>
), increased expression of the target exons in
<italic>KANSL1</italic>
and
<italic>MAPT</italic>
(
<xref rid="F2" ref-type="fig">Figure 2</xref>
,
<xref rid="SD1" ref-type="supplementary-material">Supplementary Figure S6</xref>
,
<xref rid="SD1" ref-type="supplementary-material">Supplementary Figure S7</xref>
). The association with
<italic>LRRC37A4P</italic>
exon probe 3759898 was significant in all three AD-related brain regions (P≤3.6x10
<sup>−9</sup>
). The association of rs113986870 with exon probe 3723594 for
<italic>C17orf69</italic>
was significant in hippocampus only (P=1.6x10
<sup>−7</sup>
). Five of the GWS SNPs including rs2732703 and rs113986870 are located within a transcription factor binding site or a DNase sensitivity peak and two of these five SNPs, including rs2668626 which is only 47 bp from rs2732703, have also been identified within an eQTL (
<xref rid="SD2" ref-type="supplementary-material">Supplementary Table S4</xref>
).</p>
</sec>
<sec sec-type="discussion" id="S12">
<title>DISCUSSION</title>
<p id="P14">This study was undertaken to identify loci whose effect on AD risk may be obscured by confounding or interaction with
<italic>APOE</italic>
genotype. Our
<italic>APOE</italic>
-stratified GWAS is the first to show GWS association for AD with SNPs in the chromosome 17q21.31 region including
<italic>MAPT, KANSL1</italic>
and
<italic>LRRC37A</italic>
. Among the genes expected to emerge from GWAS but never seen before is
<italic>MAPT</italic>
which encodes the microtubule-associated protein tau (
<italic>MAPT</italic>
) found in AD neurofibrillary tangles. The association peak is located between
<italic>KANSL1</italic>
and
<italic>LRRC37A</italic>
, approximately 200 kb downstream of
<italic>MAPT</italic>
, in a subset of subjects that do not possess the
<italic>APOE</italic>
ε4 allele. Although the association signal includes
<italic>MAPT</italic>
, conditional analysis suggests that the causal variant(s) are more likely located in a DNA segment between the 5′ end of
<italic>KANSL1</italic>
and 5′ end of
<italic>LRRC37A</italic>
and not within
<italic>MAPT</italic>
or another gene distal to
<italic>LRRC37A</italic>
.</p>
<p id="P15">The nature of the AD-related functional variant could not be discerned from our genetic association findings. None of the GWS SNPs are within 42.1 kb of the
<italic>KANSL1</italic>
start site or 16.8 kb of the
<italic>LRRC37A</italic>
start site, suggesting that the functional variant is not within the promoter region of either gene.
<italic>KANSL1</italic>
is a widely expressed gene encoding a member of the nonspecific lethal (NSL) complex. The KANSL1 protein is an evolutionarily conserved regulator of the chromatin modifier KAT8, which influences gene expression through histone H4 lysine 16 (H4K16) acetylation.
<sup>
<xref rid="R9" ref-type="bibr">9</xref>
</sup>
Notably, mutations in
<italic>KANSL1</italic>
cause the 17q21.31 microdeletion syndrome which is associated with a wide range of abnormalities including intellectual disability and developmental delay, and is therefore thought to be involved in neuronal development.
<sup>
<xref rid="R10" ref-type="bibr">10</xref>
,
<xref rid="R11" ref-type="bibr">11</xref>
</sup>
<italic>LRRC37A</italic>
encodes a member of the leucine-rich repeat containing 37 family. Leucine-rich repeats (LRRs) are protein-ligand interaction motifs found in a large number of proteins with different structure, localization, and function.
<sup>
<xref rid="R12" ref-type="bibr">12</xref>
</sup>
LRR motifs are important for intermolecular or intercellular interactions with exogenous factors in the immune system and/or with different cell types in the developing nervous system.
<sup>
<xref rid="R12" ref-type="bibr">12</xref>
</sup>
</p>
<p id="P16">However, expression analysis of exon array data in control brain tissue revealed that rs113986870, which is in high LD with the top-ranked SNP (rs2732703) in the GWAS, is an eQTL for expression of the first translated exon in
<italic>KANSL1</italic>
and the alternatively spliced exon 3 in
<italic>MAPT</italic>
. Previous studies suggest that splicing of
<italic>MAPT</italic>
may be a crucial regulatory mechanism in the brain and tauopathies in particular,
<sup>
<xref rid="R13" ref-type="bibr">13</xref>
</sup>
and that increased expression of exon 3 protects against neurodegeneration.
<sup>
<xref rid="R14" ref-type="bibr">14</xref>
</sup>
Although rs113986870 is apparently not an eQTL for its adjacent gene
<italic>LRRC37A</italic>
, it was significantly associated with a closely related gene,
<italic>LRRC37A4P</italic>
, in all three AD-related brain regions. These results suggest that rs113986870 may have a potential function as a cis-acting regulatory element for multiple genes in this region. Another confounding feature of this region are copy number variations that in part overlap with the 5′ end of
<italic>KANSL1</italic>
and possibly influence expression.
<sup>
<xref rid="R7" ref-type="bibr">7</xref>
,
<xref rid="R8" ref-type="bibr">8</xref>
</sup>
Thus, it is possible that the exon probes targeting the first translated in
<italic>KANSL1</italic>
may be tagging this duplication. In addition, interrogation of a database curating information about DNA features and regulatory regions revealed that five of the GWS SNPs, including rs2732703 and rs113986870, may have strong regulatory potential.</p>
<p id="P17">The association peak for AD on chromosome 17q21.31 is located in a well-recognized and perplexing genomic region containing a 900 kb inversion.
<sup>
<xref rid="R8" ref-type="bibr">8</xref>
</sup>
Previous GWAS identified associations of variants within and at the edges of this inversion with Parkinson disease (PD)
<sup>
<xref rid="R15" ref-type="bibr">15</xref>
</sup>
and progressive supranuclear palsy (PSP),
<sup>
<xref rid="R16" ref-type="bibr">16</xref>
</sup>
but the most significant associations were not with SNPs between
<italic>KANSL1</italic>
and
<italic>LRRC37A</italic>
(
<xref rid="SD2" ref-type="supplementary-material">Supplementary Table S6</xref>
). Multiple studies have identified more than 40
<italic>MAPT</italic>
deletions, missense mutations, and splice site mutations that cause frontotemporal dementia (FTD).
<sup>
<xref rid="R17" ref-type="bibr">17</xref>
</sup>
Although AD is only nominally associated with common variants in
<italic>MAPT</italic>
, previously we observed association of a rare
<italic>MAPT</italic>
variant (A152T) with increased risk for FTD and AD in a large sample,
<sup>
<xref rid="R18" ref-type="bibr">18</xref>
</sup>
a finding which was supported by a subsequent smaller study.
<sup>
<xref rid="R19" ref-type="bibr">19</xref>
</sup>
Ikram et al identified a GWS association peak with a
<italic>KANSL1</italic>
SNP approximately 166 kb away from our most significant AD SNP (rs2732703) for a continuous measure of intracranial volume in a sample of nearly 10,000 community-dwelling elders (
<xref rid="SD2" ref-type="supplementary-material">Supplementary Table S6</xref>
).
<sup>
<xref rid="R20" ref-type="bibr">20</xref>
</sup>
These two SNPs are moderately correlated (r
<sup>2</sup>
=0.71) which indicates that they may tag the same functional variant.</p>
<p id="P18">Other studies have focused on two divergent extended
<italic>MAPT</italic>
haplotypes, H1 and H2, which are in near complete LD with status of the inversion and contain independently derived partial duplications of
<italic>KANSL1</italic>
.
<sup>
<xref rid="R8" ref-type="bibr">8</xref>
,
<xref rid="R16" ref-type="bibr">16</xref>
</sup>
The common H1 haplotype is associated with increased risk of FTD,
<sup>
<xref rid="R21" ref-type="bibr">21</xref>
</sup>
PD,
<sup>
<xref rid="R22" ref-type="bibr">22</xref>
</sup>
PSP,
<sup>
<xref rid="R23" ref-type="bibr">23</xref>
</sup>
and corticobasal degeneration (CBD),
<sup>
<xref rid="R23" ref-type="bibr">23</xref>
</sup>
while H2 is linked to recurrent deletion events associated with the 17q21.31 microdeletion syndrome.
<sup>
<xref rid="R10" ref-type="bibr">10</xref>
</sup>
Among these non-AD forms of dementia, it is possible for FTD to masquerade clinically as AD and thereby cases of FTD could be present in our study group; however, any inadvertent inclusion of FTD cases is expected to be very small since the minimum age of dementia onset in our study group was 60 years and onset of dementia from FTD after age 69 years is relatively rare compared to AD that in most cases occurs after age 69.
<sup>
<xref rid="R24" ref-type="bibr">24</xref>
</sup>
Furthermore, a recent review of almost 5000 autopsy brains from a subset of cases in the ADGC cohort failed to identify any case of FTD.
<sup>
<xref rid="R25" ref-type="bibr">25</xref>
</sup>
Myers et al. reported association of AD with H1 and with common
<italic>MAPT</italic>
SNPs,
<sup>
<xref rid="R26" ref-type="bibr">26</xref>
</sup>
but this association is controversial
<sup>
<xref rid="R27" ref-type="bibr">27</xref>
</sup>
and did not reach genomewide significance in our study or previous GWAS. Another recent study showed that carriers of at least one H2 allele had a 5.4-fold increased risk of worsening hallucinations, but this result was marginally significant.
<sup>
<xref rid="R28" ref-type="bibr">28</xref>
</sup>
Previously, we observed in a subset of the sample studied here that the H2-haplotype tagging rs8070723-G allele was associated with reduced risk of AD.
<sup>
<xref rid="R29" ref-type="bibr">29</xref>
</sup>
However, this variant is no longer associated after conditioning on rs2732703 (
<xref rid="SD2" ref-type="supplementary-material">Supplementary Table S5</xref>
). In carriers of H2, the ancestral haplotype in both humans and chimpanzees,
<sup>
<xref rid="R30" ref-type="bibr">30</xref>
</sup>
increased expression of exon 3 in
<italic>MAPT</italic>
has been associated with an eQTL located approximately 1,500 bp from rs113986870 which decreases aggregation of microtubules.
<sup>
<xref rid="R31" ref-type="bibr">31</xref>
,
<xref rid="R32" ref-type="bibr">32</xref>
</sup>
These observations are consistent with our results showing that the rs113986870 minor allele is protective for AD and associated with elevated exon3 expression.</p>
<p id="P19">There is a large body of experimental evidence linking tau protein to AD pathogenesis,
<sup>
<xref rid="R33" ref-type="bibr">33</xref>
</sup>
and some studies show evidence of association of AD with common
<italic>MAPT</italic>
SNPs.
<sup>
<xref rid="R29" ref-type="bibr">29</xref>
,
<xref rid="R34" ref-type="bibr">34</xref>
</sup>
However, analysis of the
<italic>MAPT</italic>
coding sequence did not reveal disease-causing variants for early-onset AD
<sup>
<xref rid="R35" ref-type="bibr">35</xref>
</sup>
and other studies examining association of
<italic>MAPT</italic>
SNPs with late-onset AD were negative.
<sup>
<xref rid="R27" ref-type="bibr">27</xref>
,
<xref rid="R36" ref-type="bibr">36</xref>
</sup>
Recently, Allen et al. reported that the rs8070723-G allele was associated with reduced
<italic>MAPT</italic>
expression in the cerebellum and temporal cortex of AD subjects.
<sup>
<xref rid="R29" ref-type="bibr">29</xref>
</sup>
Robust genetic associations have also been identified for AD with several genes in cytoskeletal and axonal transport pathways including tau or leading to neurofibrillary tangles, most notably
<italic>BIN1, EPHA1, RIN3, CASS4,</italic>
and
<italic>FERMT2</italic>
.
<sup>
<xref rid="R4" ref-type="bibr">4</xref>
</sup>
</p>
<p id="P20">Based on the observation that overexpression of human ApoE4 in transgenic mouse neurons results in hyperphosphorylation of tau,
<sup>
<xref rid="R37" ref-type="bibr">37</xref>
</sup>
it is possible that associations with AD-related loci in the chromosome 17q21.31 region are obscured by the much stronger effect of
<italic>APOE</italic>
ε4 on
<italic>MAPT</italic>
expression or function.
<sup>
<xref rid="R38" ref-type="bibr">38</xref>
</sup>
This idea is consistent with lack of GWS association with 17q21.31 SNPs in the same dataset without stratification by
<italic>APOE</italic>
genotype,
<sup>
<xref rid="R4" ref-type="bibr">4</xref>
</sup>
and no evidence for interaction between
<italic>APOE</italic>
and any SNPs in the
<italic>MAPT-KANSL1-LRRC37A</italic>
region in the current study. Another possible explanation for the significant association of 17q21.31 SNPs with AD only among subjects lacking
<italic>APOE</italic>
ε4 is genetic heterogeneity suggesting that variation at the chromosome 17q21.31 locus is associated with a distinct etiological subtype of AD where tau is the primary disease activator.
<sup>
<xref rid="R39" ref-type="bibr">39</xref>
</sup>
Finally, the diagnosis of AD for most subjects in this dataset was established clinically suggesting the possibility of misdiagnosis or AD accompanied by other processes associated with other dementing illnesses. Further studies are needed to determine whether this subtype can be distinguished clinically or neuropathologically.</p>
<p id="P21">Our study also showed that the previously established association with the
<italic>MS4A</italic>
gene cluster is derived almost completely from subjects lacking
<italic>APOE</italic>
ε4, suggesting the contribution of the
<italic>MS4A</italic>
locus to AD may be mechanistically different than AD-related processes that are associated with
<italic>APOE</italic>
ε4. Members of the MS4A gene family encode membrane proteins, some of which have known roles in immune cell function,
<sup>
<xref rid="R40" ref-type="bibr">40</xref>
</sup>
however, little is known about the function of
<italic>MS4A6A, MS4A4A</italic>
or
<italic>MS4A6E</italic>
in humans. Karch et al. showed that expression of
<italic>MS4A6A</italic>
was upregulated in AD brains of AD patients compared to brains of controls, and significantly correlated with AD status, AIF1 expression (a marker for microglia which is the immune cell of the brain), cognitive dementia rating score, and extent of AD neuropathologic change.
<sup>
<xref rid="R41" ref-type="bibr">41</xref>
</sup>
</p>
<p id="P22">The observed statistical interaction of genotypes for
<italic>TMEM106B</italic>
with
<italic>APOE</italic>
on AD risk in the stage 1 GWAS is noteworthy (rs1595014, P=1.6x10
<sup>−7</sup>
) even though it is not supported by results in the comparatively small stage 2 sample. TMEM106B is a glycoprotein predominantly localized at the lysosomal membrane where it might interact with intracellular progranulin (GRN).
<sup>
<xref rid="R42" ref-type="bibr">42</xref>
,
<xref rid="R43" ref-type="bibr">43</xref>
</sup>
<italic>TMEM106B</italic>
variants, particularly the p. T185S (rs3173615) mutation, are risk factors for FTD, especially among persons carrying a
<italic>GRN</italic>
mutation.
<sup>
<xref rid="R44" ref-type="bibr">44</xref>
</sup>
<italic>TMEM106B</italic>
variants are also associated with development of cognitive impairment in amyotrophic lateral sclerosis
<sup>
<xref rid="R45" ref-type="bibr">45</xref>
</sup>
and implicated in the pathologic presentation of AD.
<sup>
<xref rid="R46" ref-type="bibr">46</xref>
</sup>
Cruchaga et al observed association of the
<italic>TMEM106B</italic>
SNP rs1990622 risk allele with younger onset of the FTLD subtype with TAR DNA-binding protein inclusions (FTLD-TDP),
<sup>
<xref rid="R47" ref-type="bibr">47</xref>
</sup>
a pattern reminiscent of the association of
<italic>APOE</italic>
ε4 with increased risk and younger onset of AD. The biological underpinning of the interaction of
<italic>TMEM106B</italic>
with
<italic>APOE</italic>
affecting AD risk is unclear.</p>
<p id="P23">Our top findings, including those that are genome-wide significant, should be confirmed in independent samples. Functional studies will be needed to understand the relationship between
<italic>APOE</italic>
and the causative variant(s) in 17q21.31 once they are identified, as well as with other loci showing much stronger association with AD in particular
<italic>APOE</italic>
genotype strata (e.g.,
<italic>MS4A6A/MS4A4A/ MS4A6E</italic>
) or through interaction with
<italic>APOE</italic>
(e.g.,
<italic>TMEM106B</italic>
). Our study provides a firm genetic connection of AD to several other pathologically distinct disorders in which dementia is a cardinal or common characteristic.</p>
</sec>
<sec sec-type="supplementary-material" id="S13">
<title>Supplementary Material</title>
<supplementary-material content-type="local-data" id="SD1">
<label>1</label>
<media xlink:href="NIHMS654371-supplement-1.docx" orientation="portrait" xlink:type="simple" id="d37e2653" position="anchor"></media>
</supplementary-material>
<supplementary-material content-type="local-data" id="SD2">
<label>2</label>
<media xlink:href="NIHMS654371-supplement-2.xlsx" orientation="portrait" xlink:type="simple" id="d37e2657" position="anchor"></media>
</supplementary-material>
</sec>
</body>
<back>
<ack id="S14">
<p>
<bold>ADGC</bold>
</p>
<p>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; 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; 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 # 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 and Co., Medpace, Inc., Merck and Co., Inc., Novartis AG, Pfizer Inc, F. Homan-La Roche, Schering-Plough, Synarc, Inc., 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 Drs. D. Stephen Snyder and 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</p>
<p>
<bold>CHARGE</bold>
</p>
<p>
<underline>AGES:</underline>
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).</p>
<p>
<underline>ASPS/PRODEM:</underline>
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.</p>
<p>
<underline>Cardiovascular Health Study (CHS):</underline>
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.</p>
<p>
<underline>Framingham Heart Study (FHS):</underline>
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). Drs. Seshadri and 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.</p>
<p>
<underline>Fundació ACE</underline>
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 to Ms. Trinitat Port-Carbó and her family for their generous support of Fundació ACE research programs.</p>
<p>
<underline>Erasmus Rucphen Family Study:</underline>
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 Organisation 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).</p>
<p>
<underline>The Rotterdam Study:</underline>
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, the Netherlands Organization for Health Research and Development (ZonMW Veni-grant no. 916.13.054).</p>
<p>
<underline>ARIC:</underline>
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.</p>
<p>
<bold>EADI</bold>
</p>
<p>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.</p>
<p>
<underline>Belgium sample collection:</underline>
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.</p>
<p>
<underline>Finish sample collection:</underline>
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.</p>
<p>
<underline>Italian sample collections:</underline>
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.</p>
<p>
<underline>Spanish sample collection:</underline>
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 Drs. P. Gil and 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.</p>
<p>
<bold>GERAD</bold>
</p>
<p>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 Department of Neurodegenerative Disease collection was supported by the UCLH/UCL 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.</p>
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<sec id="S19">
<title>Genetic and Environmental Risk in Alzheimer’s Disease (GERAD) Consortium</title>
<p id="P27">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</p>
</sec>
</app>
</app-group>
</back>
<floats-group>
<fig id="F1" orientation="portrait" position="float">
<label>Figure 1</label>
<caption>
<p>Association of AD with SNPs in chromosome 17q21.31 in the combined stage 1 and stage 2 samples.
<bold>(A)</bold>
Regional Manhattan plot in the
<italic>APOE</italic>
ε4+ (upper panel) and the
<italic>APOE</italic>
ε4− (lower panel) subgroups. SNPs with the lowest
<italic>P</italic>
-value are indicated with a purple diamond. Computed estimates of linkage disequilibrium (r
<sup>2</sup>
) of SNPs in this region with the most significant SNP are shown as red circles for r
<sup>2</sup>
≥ 0.8, orange circles for 0.6 ≤ r
<sup>2</sup>
< 0.8, green circles for 0.4 ≤ r
<sup>2</sup>
< 0.6, light blue circles for 0.2 ≤ r
<sup>2</sup>
< 0.4, and blue circles for r
<sup>2</sup>
< 0.2. Unannotated SNPs are shown as grey circles.
<bold>(B)</bold>
Forest plot of association results for rs2732703 in the Stage 1, Stage 2 and total samples among
<italic>APOE</italic>
ε4− subjects.</p>
</caption>
<graphic xlink:href="nihms654371f1"></graphic>
</fig>
<fig id="F2" orientation="portrait" position="float">
<label>Figure 2</label>
<caption>
<p>Genotype specific effect of the eQTL rs113986870 on expression of
<italic>KANSL1</italic>
.
<bold>(A)</bold>
Gene-level expression of
<italic>KANSL1</italic>
transcript t3760137. Transcript-level expression represents the average across all
<italic>KANSL1</italic>
exon probe sets.
<bold>(B)</bold>
Expression of exon probe 3760212. Probes 3760211, 3760212, and 3760213 measure expression of the first translated exon, are present in all three transcript variants, and were significantly associated with the eQTL. Expression profiles for probes 3760211 and 3760213 showed similar to those for probe 3760212 (
<xref rid="T3" ref-type="table">Table 3</xref>
). The distance from 3760212 to rs113986870 is 85,431 base pairs. Log2 scale of expression (Y-axis) is shown for 10 regions of cognitively normal human brains (X-axis) ordered by mean expression level. Rs113986870 genotype counts: AA=0, AG=56, and GG=76. Rs113986870 allele frequencies are 0.21 (A) and 0.79 (G).
<bold>CRBL =</bold>
cerebellum,
<bold>FCTX</bold>
= frontal cortex,
<bold>HIPP</bold>
= hippocampus,
<bold>MEDU</bold>
= medulla (specifically inferior olivary nucleus),
<bold>OCTX</bold>
= occipital cortex (specifically primary visual cortex),
<bold>PUTM</bold>
= putamen,
<bold>SNIG</bold>
= substantia nigra (SNIG),
<bold>THAL</bold>
= thalamus,
<bold>TCTX</bold>
= temporal cortex),
<bold>WHMT</bold>
= intralobular white matter.</p>
</caption>
<graphic xlink:href="nihms654371f2"></graphic>
</fig>
<table-wrap id="T1" position="float" orientation="landscape">
<label>Table 1</label>
<caption>
<p>Association results (P<10
<sup>−6</sup>
) in novel AD loci among APOE ε4− subjects in the combined stage 1 and stage 2 samples.</p>
</caption>
<table frame="hsides" rules="groups">
<thead>
<tr>
<th valign="middle" rowspan="2" align="center" colspan="1">SNP</th>
<th valign="middle" rowspan="2" align="center" colspan="1">CH</th>
<th valign="middle" rowspan="2" align="center" colspan="1">Region or Closest Gene</th>
<th valign="middle" rowspan="2" align="center" colspan="1">MA</th>
<th valign="middle" rowspan="2" align="center" colspan="1">MAF</th>
<th colspan="2" valign="bottom" align="center" rowspan="1">Stage 1
<hr></hr>
</th>
<th colspan="2" valign="bottom" align="center" rowspan="1">Stage 2
<hr></hr>
</th>
<th colspan="2" valign="bottom" align="center" rowspan="1">Stages 1 + 2
<hr></hr>
</th>
</tr>
<tr>
<th valign="middle" align="center" rowspan="1" colspan="1">OR (95% CI)</th>
<th valign="middle" align="center" rowspan="1" colspan="1">P</th>
<th valign="middle" align="center" rowspan="1" colspan="1">OR (95% CI)</th>
<th valign="middle" align="center" rowspan="1" colspan="1">P</th>
<th valign="middle" align="center" rowspan="1" colspan="1">OR (95% CI)</th>
<th valign="middle" align="center" rowspan="1" colspan="1">P</th>
</tr>
</thead>
<tbody>
<tr>
<td align="center" valign="top" rowspan="1" colspan="1">rs16847609</td>
<td align="center" valign="top" rowspan="1" colspan="1">3</td>
<td align="center" valign="top" rowspan="1" colspan="1">SOX14/CLDN18</td>
<td align="center" valign="top" rowspan="1" colspan="1">A</td>
<td align="center" valign="top" rowspan="1" colspan="1">0.09</td>
<td align="center" valign="top" rowspan="1" colspan="1">1.21 (1.12–1.29)</td>
<td align="center" valign="top" rowspan="1" colspan="1">2.3x10
<sup>−7</sup>
</td>
<td align="center" valign="top" rowspan="1" colspan="1">1.09 (0.87–1.37)</td>
<td align="center" valign="top" rowspan="1" colspan="1">0.47</td>
<td align="center" valign="top" rowspan="1" colspan="1">1.19 (1.11–1.28)</td>
<td align="center" valign="top" rowspan="1" colspan="1">5.3x10
<sup>−7</sup>
</td>
</tr>
<tr>
<td align="center" valign="top" rowspan="1" colspan="1">rs382216</td>
<td align="center" valign="top" rowspan="1" colspan="1">5</td>
<td align="center" valign="top" rowspan="1" colspan="1">CDC42SE2-ACSL6</td>
<td align="center" valign="top" rowspan="1" colspan="1">T</td>
<td align="center" valign="top" rowspan="1" colspan="1">0.36</td>
<td align="center" valign="top" rowspan="1" colspan="1">0.88 (0.83–0.93)</td>
<td align="center" valign="top" rowspan="1" colspan="1">6.5x10
<sup>−6</sup>
</td>
<td align="center" valign="top" rowspan="1" colspan="1">0.78 (0.67–0.91)</td>
<td align="center" valign="top" rowspan="1" colspan="1">0.002</td>
<td align="center" valign="top" rowspan="1" colspan="1">0.87 (0.82–0.92)</td>
<td align="center" valign="top" rowspan="1" colspan="1">2.0x10
<sup>−7</sup>
</td>
</tr>
<tr>
<td align="center" valign="top" rowspan="1" colspan="1">rs11168036</td>
<td align="center" valign="top" rowspan="1" colspan="1">5</td>
<td align="center" valign="top" rowspan="1" colspan="1">PFDN1/HBEGF</td>
<td align="center" valign="top" rowspan="1" colspan="1">T</td>
<td align="center" valign="top" rowspan="1" colspan="1">0.50</td>
<td align="center" valign="top" rowspan="1" colspan="1">1.14 (1.09–1.19)</td>
<td align="center" valign="top" rowspan="1" colspan="1">9.3x10
<sup>−9</sup>
</td>
<td align="center" valign="top" rowspan="1" colspan="1">0.97 (0.85–1.11)</td>
<td align="center" valign="top" rowspan="1" colspan="1">0.64</td>
<td align="center" valign="top" rowspan="1" colspan="1">1.12 (1.07–1.17)</td>
<td align="center" valign="top" rowspan="1" colspan="1">3.2x10
<sup>−7</sup>
</td>
</tr>
<tr>
<td align="center" valign="top" rowspan="1" colspan="1">rs2732703</td>
<td align="center" valign="top" rowspan="1" colspan="1">17</td>
<td align="center" valign="top" rowspan="1" colspan="1">KANSL1/LRRC37A</td>
<td align="center" valign="top" rowspan="1" colspan="1">G</td>
<td align="center" valign="top" rowspan="1" colspan="1">0.13</td>
<td align="center" valign="top" rowspan="1" colspan="1">0.73 (0.65–0.83)</td>
<td align="center" valign="top" rowspan="1" colspan="1">6.4x10
<sup>−7</sup>
</td>
<td align="center" valign="top" rowspan="1" colspan="1">0.71 (0.58–0.88)</td>
<td align="center" valign="top" rowspan="1" colspan="1">0.001</td>
<td align="center" valign="top" rowspan="1" colspan="1">0.73 (0.65–0.81)</td>
<td align="center" valign="top" rowspan="1" colspan="1">5.8x10
<sup>−9</sup>
</td>
</tr>
<tr>
<td align="center" valign="top" rowspan="1" colspan="1">rs71380849</td>
<td align="center" valign="top" rowspan="1" colspan="1">17</td>
<td align="center" valign="top" rowspan="1" colspan="1">CDR2L</td>
<td align="center" valign="top" rowspan="1" colspan="1">A</td>
<td align="center" valign="top" rowspan="1" colspan="1">0.06</td>
<td align="center" valign="top" rowspan="1" colspan="1">1.45 (1.24–1.70)</td>
<td align="center" valign="top" rowspan="1" colspan="1">3.8x10
<sup>−6</sup>
</td>
<td align="center" valign="top" rowspan="1" colspan="1">1.59 (1.01–2.50)</td>
<td align="center" valign="top" rowspan="1" colspan="1">0.04</td>
<td align="center" valign="top" rowspan="1" colspan="1">1.47 (1.26–1.71)</td>
<td align="center" valign="top" rowspan="1" colspan="1">9.1x10
<sup>−7</sup>
</td>
</tr>
</tbody>
</table>
</table-wrap>
<table-wrap id="T2" position="float" orientation="landscape">
<label>Table 2</label>
<caption>
<p>Results (P<10
<sup>−6</sup>
) in previously known AD loci showing different pattern of association among APOE ε4+ and ε4− subjects in the combined datasets.</p>
</caption>
<table frame="hsides" rules="groups">
<thead>
<tr>
<th valign="middle" rowspan="2" align="center" colspan="1">SNP</th>
<th valign="middle" rowspan="2" align="center" colspan="1">CH</th>
<th valign="middle" rowspan="2" align="center" colspan="1">Region or Closest Gene</th>
<th valign="middle" rowspan="2" align="center" colspan="1">MA</th>
<th valign="middle" rowspan="2" align="center" colspan="1">MAF</th>
<th colspan="2" valign="bottom" align="center" rowspan="1">
<italic>APOE</italic>
ε
<italic>4(+)</italic>
<hr></hr>
</th>
<th colspan="2" valign="bottom" align="center" rowspan="1">
<italic>APOE</italic>
ε
<italic>4(−)</italic>
<hr></hr>
</th>
</tr>
<tr>
<th valign="middle" align="center" rowspan="1" colspan="1">OR (95% CI)</th>
<th valign="middle" align="center" rowspan="1" colspan="1">P</th>
<th valign="middle" align="center" rowspan="1" colspan="1">OR (95% CI)</th>
<th valign="middle" align="center" rowspan="1" colspan="1">P</th>
</tr>
</thead>
<tbody>
<tr>
<td align="center" valign="top" rowspan="1" colspan="1">rs679515</td>
<td align="center" valign="top" rowspan="1" colspan="1">1</td>
<td align="center" valign="top" rowspan="1" colspan="1">CR1</td>
<td align="center" valign="top" rowspan="1" colspan="1">T</td>
<td align="center" valign="top" rowspan="1" colspan="1">0.21</td>
<td align="center" valign="top" rowspan="1" colspan="1">1.22 (1.14 –1.30)</td>
<td align="center" valign="top" rowspan="1" colspan="1">3.6x10
<sup>−9</sup>
</td>
<td align="center" valign="top" rowspan="1" colspan="1">1.13 (1.07 – 1.19)</td>
<td align="center" valign="top" rowspan="1" colspan="1">1.6x10
<sup>−5</sup>
</td>
</tr>
<tr>
<td align="center" valign="top" rowspan="1" colspan="1">rs4663105</td>
<td align="center" valign="top" rowspan="1" colspan="1">2</td>
<td align="center" valign="top" rowspan="1" colspan="1">BIN1</td>
<td align="center" valign="top" rowspan="1" colspan="1">C</td>
<td align="center" valign="top" rowspan="1" colspan="1">0.43</td>
<td align="center" valign="top" rowspan="1" colspan="1">1.19 (1.12 – 1.25)</td>
<td align="center" valign="top" rowspan="1" colspan="1">2.5x10
<sup>−9</sup>
</td>
<td align="center" valign="top" rowspan="1" colspan="1">1.19 (1.13 – 1.24)</td>
<td align="center" valign="top" rowspan="1" colspan="1">1.8x10
<sup>−12</sup>
</td>
</tr>
<tr>
<td align="center" valign="top" rowspan="1" colspan="1">rs9331896</td>
<td align="center" valign="top" rowspan="1" colspan="1">8</td>
<td align="center" valign="top" rowspan="1" colspan="1">CLU</td>
<td align="center" valign="top" rowspan="1" colspan="1">C</td>
<td align="center" valign="top" rowspan="1" colspan="1">0.38</td>
<td align="center" valign="top" rowspan="1" colspan="1">0.84 (0.80 – 0.89)</td>
<td align="center" valign="top" rowspan="1" colspan="1">2.8x10
<sup>−9</sup>
</td>
<td align="center" valign="top" rowspan="1" colspan="1">0.90 (0.86 – 0.94)</td>
<td align="center" valign="top" rowspan="1" colspan="1">9.6x10
<sup>−6</sup>
</td>
</tr>
<tr>
<td align="center" valign="top" rowspan="1" colspan="1">rs1582763</td>
<td align="center" valign="top" rowspan="1" colspan="1">11</td>
<td align="center" valign="top" rowspan="1" colspan="1">MS4 region</td>
<td align="center" valign="top" rowspan="1" colspan="1">A</td>
<td align="center" valign="top" rowspan="1" colspan="1">0.37</td>
<td align="center" valign="top" rowspan="1" colspan="1">0.92 (0.87 – 0.97)</td>
<td align="center" valign="top" rowspan="1" colspan="1">0.003</td>
<td align="center" valign="top" rowspan="1" colspan="1">0.87 (0.83 – 0.91)</td>
<td align="center" valign="top" rowspan="1" colspan="1">2.2x10
<sup>−9</sup>
</td>
</tr>
</tbody>
</table>
<table-wrap-foot>
<fn id="TFN1">
<p>CH = chromosome; MA = minor allele; MAF = minor allele frequency.</p>
</fn>
</table-wrap-foot>
</table-wrap>
<table-wrap id="T3" position="float" orientation="landscape">
<label>Table 3</label>
<caption>
<p>Exon probes covering the region between 43.5 and 45.0 Mb on chromosome 17 that reveal significant rs113986870 allelic expression differences averaged over of 10 brain areas</p>
</caption>
<table frame="hsides" rules="groups">
<thead>
<tr>
<th valign="bottom" align="center" rowspan="1" colspan="1">Gene</th>
<th valign="bottom" align="center" rowspan="1" colspan="1">ExprID</th>
<th valign="bottom" align="center" rowspan="1" colspan="1">Start</th>
<th valign="bottom" align="center" rowspan="1" colspan="1">End</th>
<th valign="bottom" align="center" rowspan="1" colspan="1">AVGALL</th>
<th valign="bottom" align="center" rowspan="1" colspan="1">FCTX</th>
<th valign="bottom" align="center" rowspan="1" colspan="1">HIPP</th>
<th valign="bottom" align="center" rowspan="1" colspan="1">TCTX</th>
</tr>
</thead>
<tbody>
<tr>
<td align="center" valign="top" rowspan="1" colspan="1">LRRC37A4P</td>
<td align="center" valign="top" rowspan="1" colspan="1">3759896</td>
<td align="center" valign="top" rowspan="1" colspan="1">43583231</td>
<td align="center" valign="top" rowspan="1" colspan="1">43583802</td>
<td align="center" valign="top" rowspan="1" colspan="1">1.4x10
<sup>−15</sup>
</td>
<td align="center" valign="top" rowspan="1" colspan="1">6.4x10
<sup>−4</sup>
</td>
<td align="center" valign="top" rowspan="1" colspan="1">4.0x10
<sup>−6</sup>
</td>
<td align="center" valign="top" rowspan="1" colspan="1">2.4x10
<sup>−5</sup>
</td>
</tr>
<tr>
<td align="center" valign="top" rowspan="1" colspan="1">LRRC37A4P</td>
<td align="center" valign="top" rowspan="1" colspan="1">3759898</td>
<td align="center" valign="top" rowspan="1" colspan="1">43584264</td>
<td align="center" valign="top" rowspan="1" colspan="1">43584884</td>
<td align="center" valign="top" rowspan="1" colspan="1">1.7x10
<sup>−20</sup>
</td>
<td align="center" valign="top" rowspan="1" colspan="1">8.0x10
<sup>−11</sup>
</td>
<td align="center" valign="top" rowspan="1" colspan="1">5.3x10
<sup>−10</sup>
</td>
<td align="center" valign="top" rowspan="1" colspan="1">3.6x10
<sup>−9</sup>
</td>
</tr>
<tr>
<td align="center" valign="top" rowspan="1" colspan="1">C17orf69</td>
<td align="center" valign="top" rowspan="1" colspan="1">3723594</td>
<td align="center" valign="top" rowspan="1" colspan="1">43716765</td>
<td align="center" valign="top" rowspan="1" colspan="1">43716853</td>
<td align="center" valign="top" rowspan="1" colspan="1">3.3x10
<sup>−13</sup>
</td>
<td align="center" valign="top" rowspan="1" colspan="1">2.0x10
<sup>−5</sup>
</td>
<td align="center" valign="top" rowspan="1" colspan="1">1.6x10
<sup>−7</sup>
</td>
<td align="center" valign="top" rowspan="1" colspan="1">8.3x10
<sup>−5</sup>
</td>
</tr>
<tr>
<td align="center" valign="top" rowspan="1" colspan="1">C17orf69</td>
<td align="center" valign="top" rowspan="1" colspan="1">3723604</td>
<td align="center" valign="top" rowspan="1" colspan="1">43723359</td>
<td align="center" valign="top" rowspan="1" colspan="1">43723556</td>
<td align="center" valign="top" rowspan="1" colspan="1">4.9x10
<sup>−10</sup>
</td>
<td align="center" valign="top" rowspan="1" colspan="1">0.004</td>
<td align="center" valign="top" rowspan="1" colspan="1">9.8x10
<sup>−4</sup>
</td>
<td align="center" valign="top" rowspan="1" colspan="1">1.3x10
<sup>−5</sup>
</td>
</tr>
<tr>
<td align="center" valign="top" rowspan="1" colspan="1">MAPT</td>
<td align="center" valign="top" rowspan="1" colspan="1">3723712</td>
<td align="center" valign="top" rowspan="1" colspan="1">44051752</td>
<td align="center" valign="top" rowspan="1" colspan="1">44051833</td>
<td align="center" valign="top" rowspan="1" colspan="1">3.6x10
<sup>−14</sup>
</td>
<td align="center" valign="top" rowspan="1" colspan="1">9.2x10
<sup>−6</sup>
</td>
<td align="center" valign="top" rowspan="1" colspan="1">7.6x10
<sup>−4</sup>
</td>
<td align="center" valign="top" rowspan="1" colspan="1">2.6x10
<sup>−6</sup>
</td>
</tr>
<tr>
<td align="center" valign="top" rowspan="1" colspan="1">KANSL1</td>
<td align="center" valign="top" rowspan="1" colspan="1">3760158</td>
<td align="center" valign="top" rowspan="1" colspan="1">44117069</td>
<td align="center" valign="top" rowspan="1" colspan="1">44117161</td>
<td align="center" valign="top" rowspan="1" colspan="1">9.8x10
<sup>−14</sup>
</td>
<td align="center" valign="top" rowspan="1" colspan="1">2.8x10
<sup>−5</sup>
</td>
<td align="center" valign="top" rowspan="1" colspan="1">0.008</td>
<td align="center" valign="top" rowspan="1" colspan="1">6.2x10
<sup>−5</sup>
</td>
</tr>
<tr>
<td align="center" valign="top" rowspan="1" colspan="1">KANSL1</td>
<td align="center" valign="top" rowspan="1" colspan="1">3760211</td>
<td align="center" valign="top" rowspan="1" colspan="1">44247654</td>
<td align="center" valign="top" rowspan="1" colspan="1">44247852</td>
<td align="center" valign="top" rowspan="1" colspan="1">4.0x10
<sup>−23</sup>
</td>
<td align="center" valign="top" rowspan="1" colspan="1">8.0x10
<sup>−13</sup>
</td>
<td align="center" valign="top" rowspan="1" colspan="1">3.0x10
<sup>−17</sup>
</td>
<td align="center" valign="top" rowspan="1" colspan="1">1.6x10
<sup>−15</sup>
</td>
</tr>
<tr>
<td align="center" valign="top" rowspan="1" colspan="1">KANSL1</td>
<td align="center" valign="top" rowspan="1" colspan="1">3760212</td>
<td align="center" valign="top" rowspan="1" colspan="1">44248224</td>
<td align="center" valign="top" rowspan="1" colspan="1">44248977</td>
<td align="center" valign="top" rowspan="1" colspan="1">1.4x10
<sup>−24</sup>
</td>
<td align="center" valign="top" rowspan="1" colspan="1">2.6x10
<sup>−18</sup>
</td>
<td align="center" valign="top" rowspan="1" colspan="1">7.8x10
<sup>−20</sup>
</td>
<td align="center" valign="top" rowspan="1" colspan="1">2.5x10
<sup>−21</sup>
</td>
</tr>
<tr>
<td align="center" valign="top" rowspan="1" colspan="1">KANSL1</td>
<td align="center" valign="top" rowspan="1" colspan="1">3760213</td>
<td align="center" valign="top" rowspan="1" colspan="1">44249529</td>
<td align="center" valign="top" rowspan="1" colspan="1">44249592</td>
<td align="center" valign="top" rowspan="1" colspan="1">7.7x10
<sup>−16</sup>
</td>
<td align="center" valign="top" rowspan="1" colspan="1">3.0x10
<sup>−11</sup>
</td>
<td align="center" valign="top" rowspan="1" colspan="1">1.1x10
<sup>−13</sup>
</td>
<td align="center" valign="top" rowspan="1" colspan="1">1.2x10
<sup>−11</sup>
</td>
</tr>
<tr>
<td align="center" valign="top" rowspan="1" colspan="1">KANSL1</td>
<td align="center" valign="top" rowspan="1" colspan="1">3760219</td>
<td align="center" valign="top" rowspan="1" colspan="1">44270189</td>
<td align="center" valign="top" rowspan="1" colspan="1">44270252</td>
<td align="center" valign="top" rowspan="1" colspan="1">4.3x10
<sup>−13</sup>
</td>
<td align="center" valign="top" rowspan="1" colspan="1">1.3x10
<sup>−9</sup>
</td>
<td align="center" valign="top" rowspan="1" colspan="1">1.3x10
<sup>−8</sup>
</td>
<td align="center" valign="top" rowspan="1" colspan="1">1.3x10
<sup>−11</sup>
</td>
</tr>
</tbody>
</table>
<table-wrap-foot>
<fn id="TFN2">
<p>Map position is based on 1000 Genomes database release GRCh37/hg19 assembly, February 2009. Significance threshold after multiple testing determined as 0.05/292,000 exon probes = 1.7x10
<sup>−7</sup>
; ExprID: exon-specific probeset ID. AVEALL: average expression levels across 10 regions including cerebellum (CRBL), frontal cortex (FCTX), hippocampus (HIPP), medulla (specifically inferior olivary nucleus, MEDU), occipital cortex (specifically primary visual cortex, OCTX), putamen (PUTM), substantia nigra (SNIG), thalamus (THAL), temporal cortex (TCTX), and intralobular white matter (WHMT).</p>
</fn>
</table-wrap-foot>
</table-wrap>
</floats-group>
</pmc>
</record>

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