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

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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.

Original languageEnglish
Pages (from-to)414-430
Number of pages17
JournalNature Genetics
Issue number3
StatePublished - Mar 1 2019

Bibliographical note

Funding Information:
D. Blacker is a consultant for Biogen, Inc. R.C.P. is a consultant for Roche, Inc.; Merck, Inc.; Genentech, Inc.; Biogen, Inc.; GE Healthcare; and Eisai, Inc. A.R.W. is a former employee and stockholder of Pfizer, Inc., and a current employee of the Perelman School of Medicine at the University of Pennsylvania Orphan Disease Center in partnership with the Loulou. A.M.G. is a member of the scientific advisory board for Denali Therapeutics. N.E.-T. is a consultant for Cytox. J.Hardy holds a collaborative grant with Cytox cofunded by the Department of Business (Biz). F.J. acts as a consultant for Novartis, Eli Lilly, Nutricia, MSD, Roche and Piramal. Neither J.M. nor his family owns stock or has equity interest (outside of mutual funds or other externally directed accounts) in any pharmaceutical or biotechnology company. J.M. is currently participating in clinical trials of antidementia drugs from Eli Lilly and Company, Biogen and Janssen. J.M. serves as a consultant for Lilly USA. He receives research support from Eli Lilly/Avid Radiopharmaceuticals and is funded by NIH grant nos. P50AG005681, P01AG003991, P01AG026276 and UF01AG032438. C.Cruchaga receives research support from Biogen, EISAI, Alector and Parabon. The funders of the study had no role in the collection, analysis or interpretation of data; in the writing of the report; or in the decision to submit the paper for publication. C.Cruchaga is a member of the advisory board of ADx Healthcare. M.R.F. receives grant/research support from AbbVie, Accera, ADCS Posiphen, Biogen, Eisai, Eli Lilly, Genentech, Novartis and Suven Life Sciences, Ltd. He is a consultant/advisory board/DSMB board member for Accera, Avanir, AZTherapies, Cognition Therapeutics, Cortexyme, Eli Lilly & Company, Longeveron, Medavante, Merck and Co. Inc., Otsuka Pharmaceutical, Proclara (formerly Neurophage Pharmaceuticals), Neurotrope Biosciences, Takeda, vTv Therapeutics and Zhejian Hisun Pharmaceuticals. He has a transgenic mouse model patent that is licensed to Elan. R.A.S. receives consulting fees as a member of the Alzheimer’s Disease Advisory Board, Biogen; and as member of the Executive Committee for AZD3293 Alzheimer’s Disease Studies, Eli Lilly. R.B.L. receives consulting fees from Merch, Inc. E.M.R. receives grant funding from several NIH grant and research contracts with Genentech/Roche, Novartis/ Amgen and Avid/Lilly. He is a compensated scientific advisor to Alkahest, Alzheon, Aural Analytics, Denali, Takeda and Zinfandel. He is an advisor to Roche and Roche Diagnostics, which reimburse his expenses only. T.G.B. has research support/contracts from the National Institutes of Health, State of Arizona, Michael J Fox Foundation, Avid Radiopharmaceuticals, Navida Biopharmaceuticals and Aprinoia Therapeutics. He is an advisory board member with Vivid Genomics and has consultancy work with Roche Diagnostics. A.G.S. conducts multiple industry-funded clinical trials, but all funds go to her academic institution. They have current (within last 12 months) research contracts with Eli Lilly, Novartis, Roche, Janssen, AbbVie, Biogen, NeuroEM, Suven and Merck. She does not receive personal compensations from these organizations. G.D.S. is a consultant for Biogen, Inc. J.M.B. is participating in clinical trials of antidementia drugs for Eli Lilly, Toyama Chemical Company, Merck, Biogen, AbbVie, vTv Therapeutics, Janssen and Roche. He has received research grants from Eli Lilly, Avid Radiopharmaceuticals and Astra Zeneca. He is a consultant for Stage 2 Innovations. L.F. is a consultant for Allergan, Eli Lilly, Avraham Pharmaceuticals, Axon Neuroscience, Axovant, Biogen, Boehringer Ingelheim, Eisai, Functional Neuromodulation, Lundbeck, MerckSharpe & Dohme, Novartis, Pfizer, Pharnext, Roche and Schwabe Pharma. M.B has consulted as an advisory board member for Araclon, Grifols, Lilly, Nutricia, Roche and Servier. She received fees for lectures and funds for research from Araclon, Grifols, Nutricia, Roche and Servier. She has not received personal compensations from these organizations. A.Ruiz has consulted for Grifols and Landsteiner Genmed. He received fees for lectures or funds for research and/or reimbursement of expenses for congresses attendance from Araclon and Grifols. He has not received personal compensations from these organizations. O.P. acts as a consultant for Roche and Biogen, Inc. He is currently participating in clinical trials of antidementia drugs from Novartis, Genentech, Roche and Pharmatrophix. B.T.H. is a consultant for Aztherapy, Biogen, Calico, Ceregene, Genentech, Lilly, Neurophage, Novartis and Takeda, and receives research support from Abbvie, Amgen, Deanli, Fidelity Biosciences, General Electric, Lilly, Merck, Sangamo and Spark therapeutics. BTH owns Novartis stock. H.Hampel serves as Senior Associate Editor for the Journal Alzheimer’s & Dementia; he received lecture fees from Biogen and Roche, research grants from Pfizer, Avid and MSD AVENIR (paid to the institution), travel funding from Functional Neuromodulation, Axovant, Eli Lilly and company, Takeda and Zinfandel, GE Healthcare and Oryzon Genomics, consultancy fees from Jung Diagnostics, Cytox Ltd., Axovant, Anavex, Takeda and Zinfandel, GE Healthcare, Oryzon Genomics and Functional Neuromodulation, and participated in scientific advisory boards of Functional Neuromodulation, Axovant, Eli Lilly and company, Cytox Ltd., GE Healthcare, Takeda and Zinfandel, Oryzon Genomics and Roche Diagnostica. Harald Hampel is a co-inventor on numerous patents relating to biomarker measurement but has received no royalties from these patents. A.A.-C. has consultancies for GSK, Cytokinetics, Biogen Idec, Treeway Inc, Chronos Therapeutics, OrionPharma and Mitsubishi-Tanabe Pharma, and was Chief Investigator for commercial clinical trials run by OrionPharma and Cytokinetics.

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

ASJC Scopus subject areas

  • Genetics


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