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

G. Jun, C. A. Ibrahim-Verbaas, M. Vronskaya, J. C. Lambert, J. Chung, A. C. Naj, B. W. Kunkle, L. S. Wang, J. C. Bis, C. Bellenguez, D. Harold, K. L. Lunetta, A. L. Destefano, B. Grenier-Boley, R. Sims, G. W. Beecham, A. V. Smith, V. Chouraki, K. L. Hamilton-Nelson, M. A. IkramN. Fievet, N. Denning, E. R. Martin, H. Schmidt, Y. Kamatani, M. L. Dunstan, O. Valladares, A. R. Laza, D. Zelenika, A. Ramirez, T. M. Foroud, S. H. Choi, A. Boland, T. Becker, W. A. Kukull, S. J. Van Der Lee, F. Pasquier, C. Cruchaga, D. Beekly, A. L. Fitzpatrick, O. Hanon, M. Gill, R. Barber, V. Gudnason, D. Campion, S. Love, D. A. Bennett, N. Amin, C. Berr, Magda Tsolaki, J. D. Buxbaum, O. L. Lopez, V. Deramecourt, N. C. Fox, L. B. Cantwell, L. Tárraga, C. Dufouil, J. Hardy, P. K. Crane, G. Eiriksdottir, D. Hannequin, R. Clarke, D. Evans, T. H. Mosley, L. Letenneur, C. Brayne, W. Maier, P. De Jager, V. Emilsson, J. F. Dartigues, H. Hampel, M. I. Kamboh, R. F.A.G. De Bruijn, C. Tzourio, P. Pastor, E. B. Larson, J. I. Rotter, M. C. O'Donovan, T. J. Montine, M. A. Nalls, S. Mead, E. M. Reiman, P. V. Jonsson, C. Holmes, P. H. St George-Hyslop, M. Boada, P. Passmore, J. R. Wendland, R. Schmidt, K. Morgan, A. R. Winslow, J. F. Powell, M. Carasquillo, S. G. Younkin, J. Jakobsdóttir, J. S.K. Kauwe, K. C. Wilhelmsen, D. Rujescu, M. M. Nöthen, A. Hofman, L. Jones, J. L. Haines, B. M. Psaty, C. Van Broeckhoven, P. Holmans, L. J. Launer, R. Mayeux, M. Lathrop, A. M. Goate, V. Escott-Price, S. Seshadri, M. A. Pericak-Vance, P. Amouyel, J. Williams, C. M. Van Duijn, G. D. Schellenberg, L. A. Farrer, Perrie M. Adams, Marilyn S. Albert, Roger L. Albin, Liana G. Apostolova, Steven E. Arnold, Sanjay Asthana, Craig S. Atwood, Clinton T. Baldwin, Michjael M. Barmada, Lisa L. Barnes, Thomas G. Beach, Eileen H. Bigio, Thomas D. Bird, Deborah Blacker, Bradley F. Boeve, James D. Bowen, Adam Boxer, James R. Burke, Nigel J. Cairns, Chuanhai Cao, Chris S. Carlson, Cynthia M. Carlsson, Regina M. Carney, Minerva M. Carrasquillo, Steven L. Carroll, Helena C. Chui, David G. Clark, Jason Corneveaux, David H. Cribbs, Elizabeth A. Crocco, Charles DeCarli, Steven T. DeKosky, F. Yesim Demirci, Malcolm Dick, Dennis W. Dickson, Rachelle S. Doody, Ranjan Duara, Nilufer Ertekin-Taner, Kelley M. Faber, Thomas J. Fairchild, Kenneth B. Fallon, Martin R. Farlow, Steven Ferris, Matthew P. Frosch, Douglas R. Galasko, Marla Gearing, Daniel H. Geschwind, Bernardino Ghetti, John R. Gilbert, Jonathan D. Glass, Neill R. Graff-Radford, Robert C. Green, John H. Growdon, Hakon Hakonarson, Ronald L. Hamilton, Lindy E. Harrell, Elizabeth Head, Lawrence S. Honig, Ryan M. Huebinger, Matthew J. Huentelman, Christine M. Hulette, Bradley T. Hyman, Gail P. Jarvik, Gregory A. Jicha, Lee Way Jin, Anna Karydas, Jeffrey A. Kaye, Ronald Kim, Edward H. Koo, Neil W. Kowall, Joel H. Kramer, Frank M. LaFerla, James J. Lah, James B. Leverenz, Allan I. Levey, Ge Li, Andrew P. Lieberman, Chiao Feng Lin, Constantine G. Lyketsos, Wendy J. Mack, Daniel C. Marson, Frank Martiniuk, Deborah C. Mash, Eliezer Masliah, Wayne C. McCormick, Susan M. McCurry, Andrew N. McDavid, Ann C. McKee, Marsel Mesulam, Bruce L. Miller, Carol A. Miller, Joshua W. Miller, John C. Morris, Shubhabrata Mukherjee, Jill R. Murrell, Amanda J. Myers, Sid O'Bryant, John M. Olichney, Vernon S. Pankratz, Joseph E. Parisi, Amanda Partch, Henry L. Paulson, William Perry, Elaine Peskind, Ronald C. Petersen, Aimee Pierce, Wayne W. Poon, Huntington Potter, Joseph F. Quinn, Ashok Raj, Murray Raskind, Barry Reisberg, Joan S. Reisch, Christiane Reitz, John M. Ringman, Erik D. Roberson, Ekaterina Rogaeva, Howard J. Rosen, Roger N. Rosenberg, Donald R. Royall, Mark A. Sager, Mary Sano, Andrew J. Saykin, Julie A. Schneider, Lon S. Schneider, William W. Seeley, Amanda G. Smith, Joshua A. Sonnen, Salvatore Spina, Robert A. Stern, Rudolph E. Tanzi, Tricia A. Thornton-Wells, John Q. Trojanowski, Juan C. Troncoso, Debby W. Tsuang, Vivianna M. Van Deerlin, Linda J. Van Eldik, Badri N. Vardarajan, Harry V. Vinters, Jean Paul Vonsattel, Sandra Weintraub, Kathleen A. Welsh-Bohmer, Jennifer Williamson, Sarah Wishnek, Randall L. Woltjer, Clinton B. Wright, Chuang Kuo Wu, Chang En Yu, Lei Yu, Charlene Thomas, Amy Gerrish, Jade Chapman, Alexandra Stretton, Angharad Morgan, Harriet Oldham, Michael J. Owen, Patrick G. Kehoe, Christopher Medway, Kristelle Brown, Jenny Lord, James Turton, Nigel M. Hooper, Emma Vardy, Jason D. Warren, Jonathan M. Schott, James Uphill, Paul Hollingworth, Natalie Ryan, Martin Rossor, John Collinge, Yoav Ben-Shlomo, Daniilidou Makrina, Olymbia Gkatzima, Michelle Lupton, Maria Koutroumani, Despoina Avramidou, Antonia Germanou, Frank Jessen, Steffi Riedel-Heller, Martin Dichgans, Reiner Heun, Heike Kölsch, Britta Schürmann, Christine Herold, André Lacour, Dmitriy Drichel, Per Hoffmann, Johannes Kornhuber, Wei Gu, Thomas Feulner, Manuel Mayhaus, Sabrina Pichler, Matthias Riemenschneider, Hendrik van den Bussche, Brian Lawlor, Aoibhinn Lynch, David Mann, A. David Smith, Donald Warden, Gordon Wilcock, Isabella Heuser, Jens Wiltfang, Lutz Frölich, Michael Hüll, Kevin Mayo, Gill Livingston, Nicholas J. Bass, Hugh Gurling, Andrew McQuillin, Rhian Gwilliam, Panagiotis Deloukas, Ammar Al-Chalabi, Christopher E. Shaw, Andrew B. Singleton, Rita Guerreiro, Giancarlo Russo, Karl Heinz Jöckel, Susanne Moebus, Norman Klopp, H. Erich Wichmann, Li Ma, Gina Bisceglio, Elizabeth Fisher, Nick Warner, Stuart Pickering-Brown, David Craig, Janet A. Johnston, Bernadette McGuinness, Stephen Todd, David C. Rubinsztein, Simon Lovestone, Anthony Bayer, John Gallacher, Petroula Proitsi, Sara Ortega-Cubero

Research output: Contribution to journal › Article › peer-review

211 Scopus citations

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 9207 controls) and APOE ε4- (7184 cases and 26 968 controls) subgroups as well as in the total sample testing for interaction between a single-nucleotide polymorphism (SNP) and APOE ε4 status. Suggestive associations (P<1 × 10-4) in stage 1 were evaluated in an independent sample (stage 2) containing 4203 subjects (APOE ε4+: 1250 cases and 536 controls; APOE ε4-: 718 cases and 1699 controls). Among APOE ε4- subjects, novel genome-wide significant (GWS) association was observed with 17 SNPs (all between KANSL1 and LRRC37A on chromosome 17 near MAPT) in a meta-analysis of the stage 1 and stage 2 data sets (best SNP, rs2732703, P=5·8 × 10-9). Conditional analysis revealed that rs2732703 accounted for association signals in the entire 100-kilobase region that includes MAPT. Except for previously identified AD loci showing stronger association in APOE ε4+ subjects (CR1 and CLU) or APOE ε4- subjects (MS4A6A/MS4A4A/MS4A6E), no other SNPs were significantly associated with AD in a specific APOE genotype subgroup. In addition, the finding in the stage 1 sample that AD risk is significantly influenced by the interaction of APOE with rs1595014 in TMEM106B (P=1·6 × 10-7) is noteworthy, because TMEM106B variants have previously been associated with risk of frontotemporal dementia. Expression quantitative trait locus analysis revealed that rs113986870, one of the GWS SNPs near rs2732703, is significantly associated with four KANSL1 probes that target transcription of the first translated exon and an untranslated exon in hippocampus (P≤1.3 × 10-8), frontal cortex (P≤1.3 × 10-9) and temporal cortex (P≤1.2 × 10-11). Rs113986870 is also strongly associated with a MAPT probe that targets transcription of alternatively spliced exon 3 in frontal cortex (P=9.2 × 10-6) and temporal cortex (P=2.6 × 10-6). Our APOE-stratified GWAS is the first to show GWS association for AD with SNPs in the chromosome 17q21.31 region. Replication of this finding in independent samples is needed to verify that SNPs in this region have significantly stronger effects on AD risk in persons lacking APOE ε4 compared with persons carrying this allele, and if this is found to hold, further examination of this region and studies aimed at deciphering the mechanism(s) are warranted.

Original languageEnglish
Pages (from-to)108-117
Number of pages10
JournalMolecular Psychiatry
Volume21
Issue number1
DOIs
StatePublished - Jan 1 2016

Bibliographical note

Publisher Copyright:
© 2016 Macmillan Publishers Limited All rights reserved.

Funding

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; NIAGADS, U24-AG041689; 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, AG041718; 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 no. 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, Medpace, Merck, Novartis AG, Pfizer, F Homan-La Roche, Schering-Plough, Synarc, 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 Dr D Stephen Snyder and Dr 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. CHARGE AGES: 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). 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 and the Netherlands Organization for Health Research and Development (ZonMW Veni-grant no. 916.13.054). Celine Bellenguez received personal fees from Genoscrenn unrelated to current study. HS reports grants from Austrian Science Fond (FWF) and Österreichische Nationalbank Anniversary Fund during the conduct of the study. FP reports grants from DISTALZ Labex of Excellence (ANR). NF reports payment from Janessen Alzheimer’s Immunotherapty and Pfizer to University College London for contracted image analyses and payment from Bristol Myers Squibb, Eli Lilly, GE Healthcare, Novartis and Sanofi to University College London for consultant services. JH received personal fees from Eisai, Eli Lilly and Roche, outside the current study. AMG received grants from NIA, Genentech, Pfizer and Astra Zeneca, as well as personal fees from Finnegan HC, Cognition Therapeutics, Dickstein Shapiro, Genentech and Amgen, all unrelated to the current study. In addition, AMG has a patent (US20070258898) issued and a patent with royalties paid by Taconic. WM received grants from Eli Lilly and Lundbeck. J-FD received grants and personal fees from IPSEN and Novartis and personal fees from Newron. HH reports personal fees and non-financial support from Boehringer-Ingelheim, Bristol-Myers-Squibb, Elan Corporation, Novartis, Eisai Inc., Pfizer, Sanofi-Aventis, Roche Pharmaceutical Diagnostics, GlaxoSmithKline-Biologicals, Jung-Diagnostics, Avid, Eli Lilly and Cytox and personal fees from GE Healthcare. In addition, HH has pending patents entitled ‘Method for predicting whether subjects with mild cognitive impairment (MCI) will develop Alzheimer's disease’, ‘3-Hydroxykynurenin im Serum als diagnostischer Marker fUr die Demenz vom Alzheimer-Typ’, ‘Neurodegenerative markers for psychiatric conditions’, ‘Ratio A ~ 2/40 im Plasma in der Fruh-und Differentialdiagnose der Alzheimer Krankheit’, Liquordiagnostisches in vitro Verfahren zur Diagnose von Demenz-ErkrankUngen und neuroinfJammatorischen Erkrankungen’, ‘In vitro Verfahren zur Diagnose von neurodegenerativen Erkrankungen’ and ‘In vitro Verfahren zur Diagnose und Fruhdiagnose von neurodegenerativen Erkrankungen’. EBL received personal fees from Up to Date unrelated to the current study. MO received research grants from the Medical Research Council during the course of, but unrelated to, the current study. EMR received personal fees from AstraZeneca, CereSpir, Eisai, Eli Lilly, GlaxoSmithKline and Sanofi and research contracts from Avid/Eli Lilly and Genetech, all unrelated to the current study. JW is a full-time employee and shareholder of Pfizer (2012–present) and a former full-time employee of F. Hoffmann-La Roche (2010–2012). AW is a full-time employee and shareholder of Pfizer (2013–present). MAP-V received personal fees from Athena Neurosciences unrelated to the current study. The other authors declare no conflict of interest. ARIC: 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. EADI 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. ASPS/PRODEM: 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. 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. GERAD 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 NIHR Department of Neurodegenerative Disease collection was supported by the UCLH/UCL NIHR 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. Fundació ACE: 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 Ms Trinitat Port-Carbó and her family for their generous support of Fundació ACE research programs. The Rotterdam Study: The Rotterdam Study was funded by Erasmus Medical Belgium sample collection: 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. Italian sample collections: 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. Erasmus Rucphen Family Study: 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 Organization 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). Spanish sample collection: 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 Dr P Gil and Dr 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. Finish sample collection: 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. Cardiovascular Health Study (CHS): 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. Framingham Heart Study (FHS): 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). Dr Seshadri and Dr 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.

FundersFunder number
Johnson and Johnson Pharmaceutical Research and Development
Netherlands Genomics Initiative–Netherlands Organization for Scientific Research
Hersenstichting Nederland Breinbrekend Werk
French Agence Nationale de la Recherche
Canadian Health Research Institute
Southwest Dementia Brain Bank
Eisai
Alzheimer's Association
Direction Générale de la Santé
GE Healthcare
Biomedical Laboratory Research Program
Medizinische Universität Graz
Institut de laLongévité
Royal College of Physicians/Dunhill Medical Trust
Alzheimer’s Research United Kingdom
Alzheimer's Society
Ministerio de Economía, Industria y Competitividad, Gobierno de España
North Bristol NHS Trust Research and Innovation Department and DeNDRoN
Erasmus University Medical Center
Aquitaine and Bourgogne RegionalCouncils
Merck
Banner Alzheimer’s Foundation
National Foundation for Alzheimer’s disease
Bayer Schering
Stockholms Läns Landsting
Welsh Assembly Government
Netherlands Brain Bank
Alzheimer's Disease Research Foundation
Carimonte Foundation
Nederlandse Organisatie voor Wetenschappelijk Onderzoek
Internationale Stichting Alzheimer Onderzoek
Instituto de Salud Carlos III
Kuopion Yliopistollinen Sairaala
Schering Plough Co
Fundación Alzheimur
Institut national de la santé et de la recherche médicale
Vlaamse regering
Newcastle Brain Tissue Resource
Synarc, Inc.
Bristol-Myers Squibb
National Institutes of Health (NIH)
Austrian Stroke Prevention Study
Bristol Research into Alzheimer's and Care of the Elderly
Institut de Neuropatologia
National Institute of Biomedical Imaging and Bioengineering
Boehringer-Ingelheim
Higher Education Funding Council for England
Charles A Dana Foundation
Research Institute for Diseases in the Elderly
Erasmus Medisch Centrum
Belgian Federal Science Policy Office
Bundesministerium für Bildung und Forschung
Fonds Wetenschappelijk Onderzoek
Eli Lilly and Company
UCLH Biomedical Research Centre
BRACE
Health Research Council of New Zealand
Foundation for Barnes-Jewish Hospital
Wellcome Trust
Swedish Brain foundation
Abbott Laboratories
NIHR Department of Neurodegenerative Disease
Konung Gustaf V:s och Drottning Victorias Frimurarestiftelse
Ministerie van Volksgezondheid, Welzijn en Sport
Ulster Garden Villages
Austrian Alzheimer Society
UCL NIHR Biomedical Centre and Queen Square Dementia Biomedical Research Unit
F. Hoffmann-La Roche AG
Consejería de Economía, Innovación, Ciencia y Empleo, Junta de Andalucía
Biomedical Laboratory Research and Development, VA Office of Research and Development
Novartis
Karolinska Institutet
Eisai Global Clinical Development
French ministry of research
Stichting Vanderes
Hjartavernd
National Institute on Deafness and Other Communication Disorders
Astrobiology Research Trust
Netherlands Consortium for Healthy Aging
Universitat de Barcelona
Caisse Nationale Maladie des Travailleurs Salariés
Eaton Corporation
Agence Française de Sécurité Sanitaire des Produits de Santé
Southern California Diabetes Endocrinology Research Center
National Eye Institute (NEI)
GlaxoSmithKline
Robert Dawson Evans Endowment
Newcastle University
DoD Alzheimer's Disease Neuroimaging Initiative
Netherlands Organization for Health Research and Development
Swedish Brain Power network
Fondation de France
Centre National de Génotypage
Alfried Krupp von Bohlen und Halbach-Stiftung
US Department of Veterans Affairs Administration
Oesterreichische Nationalbank
Competence Network Dementia and Competence Network Degenerative Dementia
RIDE2
DISTALZ Labex of Excellence
Alzheimerfonden
Universiteit Antwerpen
Marianne and Marcus Wallenberg Foundation
Italian Ministry of research and University
Institute Pasteur De Lille
MRC London Brain Bank for Neurodegenerative Diseases
Ministerio de Sanidad, Consumo y Bienestar Social
Pfizer
NIA/NIH
International Parkinson Fonds
Fundación Ramón Areces
AstraZeneca
Genentech Incorporated
Ministerie van Onderwijs, Cultuur en Wetenschap
Alzheimer's Drug Discovery Foundation
SAO-FRA
Innogenetics
Glaxo Smith Kline
Howard Hughes Medical Institute
Vanderbilt Digestive Diseases Research Center, Vanderbilt University Medical Center
National Institute on AgingR01AG033193, P50AG005146, R01AG023629, RC2AG036535, RF1AG055477, R01AG048927, P50AG005142, R01AG016495, U01AG024904, U24AG021886, R01AG019085, U01AG046139, R01AG025259, U01AG016976, P01AG010491, RC2AG036528, P50AG005133, P50AG005134, P50AG005131, R01AG031287, K01AG030514, P30AG013854, P30AG028383, N01AG012100, R01AG027944, U24AG056270, P50AG016582, R01AG034504, U01AG010483, P50AG005136, R01AG015928, P50AG025688, R01AG008122, P50AG005138, P50AG023501, R01AG041232, R01AG041797, R01AG021547, P50AG008671, P50AG005681, P30AG028377, R37AG015473, R01AG041718, R01AG026916, P01AG019724, R01AG054076, R01AG030146, U01AG006781, P50AG016573, P50AG016574, P30AG013846, P30AG010133, R01AG030653, U01AG049505, P50AG016570, R01AG017917, P01AG002219, R01AG027058, P50AG005128, R01AG015819, R01AG033040, U01AG032984, R01AG019757, R01AG026390, R01AG020688, R01AG017173, R01AG031581, P30AG008017, U24AG026395, P30AG010124, P30AG012300, U24AG041689, P30AG010161, P01AG003991, P30AG019610, P30AG010129, P30AG008051, R01AG020098, P50AG008702
National Human Genome Research InstituteU01HG006375, U01HG004610, U01HG004402
UK Medical Research Council, Engineering and Physical Sciences Research CouncilMC_U123192748, MC_PC_14095, MC_U123160651, MC_G1000734, MR/L501529/1, MR/L501517/1, MR/N012453/1, G0300429, MR/L023784/1, MR/K006584/1, MR/L010305/1, G0902227, MR/K013041/1
National Institute of Mental HealthP50MH060451, R01MH080295
The Johns Hopkins UniversityR01 AG020688, P50 AG005146
National Childhood Cancer Registry – National Cancer InstituteR01CA129769
University of California DavisP30 AG010129
Institute of Neurological Disorders and Stroke National Advisory Neurological Disorders and Stroke CouncilR01NS017950, R01NS080820, R01NS059873, U54NS100693, P50NS039764
National Heart, Lung, and Blood Institute (NHLBI)N01-HC-55021, N01-HC-55020, R41HL055019, R41HL055018, N01-HC-25195, N01-HC-55022, R01HL038444, UC2HL103010, U01HL080295, N01HC85081, R01HL105756, N01HC85082, R01HL085083, N01HC85080, HHSN268201200036C, N01HC85086, N01HC85083, R01HL120393, N01-HC-55018, N01-HC-55016, N01-HC-55015, R01HL103612, R01HL087641, N01-HC-55019, HHSN268200625226C, U01HL096917, N01HC55222, RC2HL102419, R01HL093029, N01HC85079, R01HL064278, R01HL087652
National Institutes of Health/National Institute of Environmental Health SciencesP30ES013508
University of Northern ArizonaR01 AG031581
National Center for Research ResourcesM01RR000096, UL1RR025005, UL1RR029893
Rush UniversityR01 AG30146, R01 AG15819, R01 NS059873, P30 AG010161, R01 AG17917, R01 AG019085
Michigan Diabetes Research CenterDK063491
ZonMw Memorabel916.13.054
Agencia IDEA841318
University of Southern CaliforniaP50 AG005142
Corporación Tecnológica de Andalucía08/211
Centre for Medical Systems BiologyCMSB2
Seventh Framework Programme201413, FP7/2007-2013, HEALTH-F4-2007-201413
FWF-ANRP20545-P05, P 13180
Northwestern Polytechnical UniversityP30 AG013854
University of KentuckyP30 AG028383
Lance Armstrong FoundationIIRG-05-14147, IIRG-08-89720
The University of Texas Southwestern Medical CenterP30 AG012300
Duke-Kunshan UniversityAG05128, P30 AG028377
Mayo Clinic RochesterP50 AG016574
Vetenskapsrådet521-2010-3134
The Pennsylvania State UniversityP30 AG010124
University of California IrvineP50 AG016577, P50 AG016576, P50 AG016575, P50 AG016573
University of AlabamaUL1RR02777, P50 AG016582
York University, New York, New York, USA bbbUniversity of Rochester, Rochester, New YorkUL1 RR029893, P30 AG08051, MO1RR00096
University of Pittsburgh Medical Center, Children's Hospital of PittsburghAG041718, AG030653, P50 AG005133
Group Health Research InstituteUO1 AG06781, UO1 HG004610, U01 HG006375
Ministerio de Educación y Ciencia, SpainPCT-010000-2007-18, DEX-580000-2008-4
Ministero della SaluteRFPS-2006-7-334858, RF07-08, RF-2010-2319722, RC08-09-10-11-12
Icahn School of Medicine at Mount SinaiP01 AG002219, P50 AG005138
University of California San Diego HealthP50 AG023501, P01 AG019724, P50 AG005131
National Association for Colitis and Crohn's DiseaseU01 AG016976
National Center for Advancing Translational Sciences (NCATS)UL1TR000124, UL1TR001108
NIAGADSU24-AG041689
University of Southern IndianaP30 AG10133
ADGCRC2 AG036528, U01 AG032984
Banner Sun Health Research InstituteP30 AG019610
NCRADU24 AG021886
University Research Committee, Emory UniversityAG025688
Academy of Finland5772708
Univ. of Northern British ColumbiaP50 AG008702, R37 AG015473
Kronos ScienceAG034504
The George Washington UniversityP50 AG005136, P50 AG005681, P01 AG03991
Michigan Diabetes Research Center, University of MichiganP50 AG008671
Indiana Clinical and Translational Sciences InstituteUL1TR000124
University of California, Los AngelesP50 AG016570
Boston University School of Public Health/Boston University Medical CampusP30 AG013846, U01 AG10483, R01 AG017173, R01 MH080295, R01AG33193, R01 CA129769
Massachusetts General HospitalP50 AG005134
European Commission014-93-015
Miami Clinical and Translational Science Institute, University of MiamiAG027944, AG021547, R01 AG027944, AG019757, AG010491
Oregon Health and Science UniversityP30 AG008017, R01 AG026916
National Institute of Diabetes and Digestive and Kidney DiseasesP30DK063491

    ASJC Scopus subject areas

    • Molecular Biology
    • Psychiatry and Mental health
    • Cellular and Molecular Neuroscience

    UN SDGs

    This output contributes to the following UN Sustainable Development Goals (SDGs)

    • SDG 3 - Good Health and Well-being

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