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Correspondence: B.W.K (bkunkle@miami.edu), J.-C. L. (jean-charles.lambert@pasteur-lille.fr) or M.A.P. (mpericak@miami.edu)

Author Contributions ADGC: Study design or conception: A.C.N., A.A.-W., E.R.M., K.H.-N., A.B.K., B.N.V., G.W.B., O.V., M.Butkiewicz, W.B., Y.Song, G.D.S., M.A.P.-V

Sample contribution: S.Mukherjee, P.K.C., R.B., P.M.A., M.S.A., D. Beekly, D. Blacker, R.S. Doody, T.J.F., M.P.F., B.Ghetti, R.M.H., M.I.K., M.J.K., C.K., W.K., E.B.L., R.B.L., T.J.M., R.C.P., E.M.R., J.S.R., D.R.R., M. Sano, P.S.G.-H., D.W.T., C.K.W., R.L.A., L.G.A., S.E.A., S.A., C.S.A., C.T.B., L.L.B., S. Barral, T.G.B., J.T.B., E.H.B., T.D.B., B.F.B., J.D.B., A.Boxer, J.R.B., J.M.B., J.D.Buxbaum

N.J.C., C. Cao, C.S.C., C.M.C., R.M.C., H.C.C., D.H.C., E.A.C., C.DeCarli, M.Dick, R.D., N.R.G.-R., D.A.E., K.M.F., K.B.F., D.W.F., M.R.F., S.F., T.M.F., D.R.G., M.Gearing, D.H.G., J.R.G., R.C.G., J.H.G., R.L.H., L.E.H., L.S.H., M.J.H., C.M.H., B.T.H., G.P.J., E.A., L.W.J., G.R.J., A. Karydas, J.A.K., R.K., N.W.K., J.H.K., F.M.L., J.J.L., J.B.L., A.I.L., A.P.L., K.L.L., C.G.L.,

D.C.M., F.M., D.C.Mash, E.M., W.C.M., S.M.M., A.N.M., A.C.M., M.M., B.L.M., C.A.M., J.W.M., J.C.M., A.J.M., S.O., J.M.O., J.E.P., H.L.P., E.P., A.P., W.W.P., H.P.,

J.F.Q., A.Raj, M.R., B.R., C.R., J.M.R., E.D.R., E.R., H.J.R., R.N.R., M.A.S., A.J.S., M.L.C., J. Vance, J.A.S., L.S.S., W.W.S., A.G.S., J.A.Sonnen, S. Spina, R.A.S., R.H.S., R.E.T., J.Q.T., J.C.T., V.M.V.D., L.J.V.E., H.V.V., J.P.V., S.W.

K.A.W.-B., K.C.W., J.Williamson, T.S.W., R.L.W., C.B.W., C.-E.Y., L.Y., D.B., P.L.D.J., C.Cruchaga, A.M.G., N.E.-T., S.G.Y., D.W.D., H.H., L.A.F., J.Haines, R.Mayeux, L.-S.W., G.D.S., M.A.P.-V.

Data generation: B.W.K., K.H.-N., A.B.K., O.V., L.Q., Y.Z., W.P., S.Slifer, J.Malamon, B.A.D., P.W., L.B.C., M.A., M.Tang, J.R.G., L.-S.W. Analysis: B.W.K., A.C.N., A.A.-W., E.R.M., K.H.-N., A.B.K., M.Tang, M.M.C., B.N.V., G.W.B., O.V., M.Butkiewicz, W.B., Y.S., G.D.S., M.A.P.-V.

Manuscript preparation: B.W.K., G.D.S., M.A.P.-V.

Study supervision/ management: B.W.K., L.A.F., J.Haines, R.Mayeux, L.-S.W., G.D.S., M.A.P.-V.

Author contributions EADI: Study design or conception: P.A., J.-C.L.

Sample contribution: K.S., M.Hiltunen, J.E., M.D.Z., I.M., F.S.-G., M.C.D.N., D.Wallon, S.E., R.V., P.D.D., A.Squassina, E.R.-R., C.M.-F., Y.A.B., H.T., V.Giedraitis, L.Kilander, R.Brundin, L.C., S.Helisalmi, A.M.K., A.Haapasalo, V.S., V.Frisardi, V.Deramecourt, N.F., O.H., C.Dufouil, A.Brice, K.R., B.D., H.Soininen, L.Fratiglioni, L.K.,

F.Panza, D.H., P.C., F.S., P.B., L.Lannfelt, F.P., M.Ingelsson, C.G., P.S.-J., A.L., J.Clarimon, C.Berr, S.D., J.-F.D., A.Pilotto, M.J.B., P.Bosco, E.C., G.N., D.C., C.V.B., P.A., J.-C.L.

Data generation: R.O., J.-G.G., M.-L.M., D.Bacq, F.G., B.F., S.Meslage

nalysis: B.G.-B., V.D., C.Bellenguez

Manuscript preparation: B.G.-B., P.A., J.-C.L.

Study supervision/management: J.-F.Deleuze, A.Boland, P.A., J.-C.L.

Author contributions GERAD/PERADES: Study design or conception: R.Sims, M.C.O., M.J.O., A.R., P.A.H., J.W.

Sample contribution: R.Raybould, T.Morgan, P.Hoffmann, D.Harold, O.P., N.D., N.C.F., J.T.H., Y.P., M.Daniilidou, J.U., D.Galimberti, E.Scarpini, J.Kornhuber, S.Sordon., M.Mayhaus, W.G., A.M.H., S.Lovestone, R.Sussams, C.Holmes, W.M., A.Kawalia, S.Moebus, J.Turton, J.Lord, I.K., A.L., B.L., M.Gill, M.D.-F., I.A., A.Ciaramella

C.Cupidi, R.G.M., R.Cecchetti, M.T., D.Craig, D.A., A.G., M.K., O.G., H.Hampel, D.C.R., L.F., B.M., J.A.J., P.Passmore, J.M.S., J.D.W., M.K.L., P.Proitsi, J.Powell, J.S.K.K., M.Mancuso, U.B., A.M., G.Livingston, N.J.B., J.Hardy, J.B., R.Guerreiro, E.F., C.Masullo, G.B., L.M., A.H., M.Scherer, M.Riemenschneider, R.Heun, H.K.,

M.Leber, I.H., I.G., M.Hull, J.M., K.Mayo, T.F., D.Drichel, T.D.C., P.Hollingworth, R.Marshall, A.Meggy, G.M., G.L., D.G., G.R., F.J., B.V., E.V., K.-H.J., M.Dichgans, D.Mann, S.P.-B., N.K., H.W., K.M., K.Brown, C.Medway, M.M.N., N.M.H., A.Daniele, A.Bayer, J.G., H.V.D.B., C.Brayne, S.R.-H., A.A.-C., C.E.S., J.Wiltfang, V.A., A.B.S., J.C., S.M., M.Rossor,

N.S.R., B.N., S.Sorbi, E.S., G.S., C.Caltagirone, M.D.O., R.C., A.D.S., D.W., G.W., A.C.B., M.G., Y.B.-S., P.M., P.P., V.B., N.W., P.D., R.G., P.G.K., S.L., C.C., J.T., R.Munger, A.R., J.W. Data generation: R.Sims, R.Raybould, T.Morgan, P.Hoffmann, D.Harold, A.Gerrish, N.D., P.Hollingworth, R.Marshall, A.Meggy, A.R., J.W.

Analysis: R.Sims, M.V., A.F., N.Badarinarayan, D.Harold, G.M., G.L., D.G., V.E.-P., A.R., J.W., P.A.H.

Manuscript preparation: R.Sims, T.D.C., P.A.H., J.W.

Study supervision/management: R.Sims, L.J., V.E.-P., A.R., P.A.H., J.W.

Author contributions CHARGE: Study design or conception: A.L.D., C.M.V.D., S.S.

Sample contribution: J.C.B., A.Ruiz, I.D.R., L.M.R., I.Q., A.C., A.L.F., G.E., J.J.H., A.O., M.E.G., H.L., H.Comic, G.Roschupkin, S.Li, I.Hernández, Q.Y., A.S.B., L.T., T.H.M., WT.L., F.R., E.Boerwinkle, J.I.R., A.G.U., S.M.-G., O.L.L., M.B., M.F., N.A., L.J.L., M.A.I., H.S., R.S., V.G., B.M.P.

Data generation: J.C.B., J.Jakobsdottir, A.Ruiz, A.V.S., X.J., S.-H.C., H.H.A., J.A.B., T.A., E.H., C.Sarnowski, D.V., L.A.C. Analysis: J.C.B., S.J.v.d.L., V.C., J.Jakobsdottir, Y.C., Y.Saba, S.Ahmad, A.Ruiz, A.V.S., C.C.W., C.M.V.D., S.S.

Manuscript preparation: S.J.v.d.L., A.Ruiz, B.M.P., C.M.V.D., S.S.

Study supervision/management: C.M.V.D., S.S.

We thank all the participants of this study for their contributions. Additional acknowledgements and detailed acknowledgments of funding sources for the study are provided in the Supplementary Note.

Subjects:

Research Funding:

The National Institutes of Health, National Institute on Aging (NIH-NIA) supported this work through the following grants: ADGC, U01 AG032984, RC2 AG036528; Samples from the National Cell Repository for Alzheimer’s Disease (NCRAD), which receives government support under a cooperative agreement grant (U24 AG21886) awarded by the National Institute on Aging (NIA), were used in this study

Data for this study were prepared, archived, and distributed by the National Institute on Aging Alzheimer’s Disease Data Storage Site (NIAGADS) at the University of Pennsylvania (U24-AG041689-01); NACC, U01 AG016976; NIA LOAD (Columbia University), U24 AG026395, U24 AG026390, R01AG041797; Banner Sun Health Research Institute P30 AG019610; Boston University, P30 AG013846, U01 AG10483, R01 CA129769, R01 MH080295, R01 AG017173, R01 AG025259, R01 AG048927, R01AG33193, R01 AG009029; Columbia University, P50 AG008702, R37 AG015473, R01 AG037212, R01 AG028786; Duke University, P30 AG028377, AG05128

Einstein Aging Study NIA grant at Albert Einstein College of Medicine, P01 AG03949. Emory University, AG025688; Group Health Research Institute, UO1 AG006781, UO1 HG004610, UO1 HG006375, U01 HG008657; Indiana University, P30 AG10133, R01 AG009956, RC2 AG036650;

Johns Hopkins University, P50 AG005146, R01 AG020688; Massachusetts General Hospital, P50 AG005134; Mayo Clinic, P50 AG016574, R01 AG032990, KL2 RR024151; Mount Sinai School of Medicine, P50 AG005138, P01 AG002219; New York University, P30 AG08051, UL1 RR029893, 5R01AG012101, 5R01AG022374, 5R01AG013616, 1RC2AG036502, 1R01AG035137; North Carolina A&T University, P20 MD000546, R01 AG28786-01A1;

Northwestern University, P30 AG013854; Oregon Health & Science University, P30 AG008017, R01 AG026916; Rush University, P30 AG010161, R01 AG019085, R01 AG15819, R01 AG17917, R01 AG030146, R01 AG01101, RC2 AG036650, R01 AG22018; TGen, R01 NS059873;

; University of Alabama at Birmingham, 57 P50 AG016582; University of Arizona, R01 AG031581; University of California, Davis, P30 AG010129; University of California, Irvine, P50 AG016573; 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, AG05144; University of Michigan, P30 AG053760 and AG063760; University of Pennsylvania, P30 AG010124; University of Pittsburgh, P50 AG005133, AG030653, AG041718, AG07562, AG02365; 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, R01 AG042437; University of Wisconsin, P50 AG033514; Vanderbilt University, R01 AG019085; and Washington University, P50 AG005681, P01 AG03991, P01 AG026276. HP was supported by AG025711. ER was supported by CCNA.

The Kathleen Price Bryan Brain Bank at Duke University Medical Center is funded by NINDS grant # NS39764, NIMH MH60451 and by Glaxo Smith Kline.

Support was also from the Alzheimer’s Association (LAF, IIRG-08-89720; MP-V, IIRG-05- 14147), the US Department of Veterans Affairs Administration, Office of Research and Development, Biomedical Laboratory Research Program, and BrightFocus Foundation (MP-V, A2111048). P.S.G.-H. is supported by Wellcome Trust, Howard Hughes Medical Institute, and the Canadian Institute of Health Research

Genotyping of the TGEN2 cohort was supported by Kronos Science. The TGen series was also funded by NIA grant AG041232 to AJM and MJH, 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),South West 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 58 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.

ADNI data collection and sharing was funded by the National Institutes of Health Grant U01 AG024904 and Department of Defense award number W81XWH-12-2-0012. ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, and through generous contributions from the following: AbbVie, Alzheimer’s Association; Alzheimer’s Drug Discovery Foundation; Araclon Biotech; BioClinica, Inc.; Biogen; Bristol-Myers Squibb Company; CereSpir, Inc.; Eisai Inc.; Elan Pharmaceuticals, Inc.; Eli Lilly and Company; EuroImmun; F. Hoffmann-La Roche Ltd and its affiliated company Genentech, Inc.; Fujirebio; GE Healthcare; IXICO Ltd.; Janssen Alzheimer Immunotherapy Research & Development, LLC.; Johnson & Johnson Pharmaceutical Research & Development LLC.; Lumosity; Lundbeck; Merck & Co., Inc.; Meso Scale Diagnostics, LLC.; NeuroRx Research; Neurotrack Technologies; Novartis Pharmaceuticals Corporation; Pfizer Inc.; Piramal Imaging; Servier; Takeda Pharmaceutical Company; and Transition Therapeutics.

The Canadian Institutes of Health Research is providing funds to support ADNI clinical sites in Canada. Private sector contributions are facilitated by the Foundation for the National Institutes of Health (www.fnih.org).

The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer's Disease Cooperative Study at the University of California, San Diego. ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of Southern California

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Genetics & Heredity
  • Genome-Wide Association
  • Domain-containing oxidoreductase
  • Angiotensin-converting enzyme
  • Amyloid-beta
  • Transcription factor
  • Genotype manipulation
  • Apolipoprotein-E
  • Common variants
  • Onset
  • Mutations

Genetic meta-analysis of diagnosed Alzheimer's disease identifies new risk loci and implicates A beta, tau, immunity and lipid processing

Tools:

Journal Title:

Nature Genetics

Volume:

Volume 51, Number 3

Publisher:

, Pages 414-433

Type of Work:

Article | Post-print: After Peer Review

Abstract:

Risk for late-onset Alzheimer’s disease (LOAD), the most prevalent dementia, is partially driven by genetics. To identify LOAD risk loci, we performed a large genome-wide association meta-analysis of clinically diagnosed LOAD (94,437 individuals). We confirm 20 previous LOAD risk loci and identify five new genome-wide loci (IQCK, ACE, ADAM10, ADAMTS1, and WWOX), two of which (ADAM10, ACE) were identified in a recent genome-wide association (GWAS)-by-familial-proxy of Alzheimer’s or dementia. Fine-mapping of the human leukocyte antigen (HLA) region confirms the neurological and immune-mediated disease haplotype HLA-DR15 as a risk factor for LOAD. Pathway analysis implicates immunity, lipid metabolism, tau binding proteins, and amyloid precursor protein (APP) metabolism, showing that genetic variants affecting APP and Aβ processing are associated not only with early-onset autosomal dominant Alzheimer’s disease but also with LOAD. Analyses of risk genes and pathways show enrichment for rare variants (P = 1.32 × 10−7), indicating that additional rare variants remain to be identified. We also identify important genetic correlations between LOAD and traits such as family history of dementia and education.

Copyright information:

© The Author(s), under exclusive licence to Springer Nature America, Inc. 2019.

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