The Alzheimer's Disease Sequencing Project (ADSP) undertook whole exome sequencing in 5,740 late-onset Alzheimer disease (AD) cases and 5,096 cognitively normal controls primarily of European ancestry (EA), among whom 218 cases and 177 controls were Caribbean Hispanic (CH). An age-, sex- and APOE based risk score and family history were used to select cases most likely to harbor novel AD risk variants and controls least likely to develop AD by age 85 years. ~1.5 million single nucleotide variants (SNVs) and 50,000 insertion-deletion polymorphisms (indels) were tested for association to AD, using multiple models considering individual variants as well as gene-based tests aggregating rare, predicted functional, and loss of function variants.
This dataset contain results for single variant and gene-based rare variant aggregation tests, performed separately by ancestry (European ancestry, Caribbean Hispanic) and meta-analyzed. Three sets of covariate adjustment models were employed in the genotype-phenotype association analyses:
Model 0 included only principal components and sequencing center;
Model 1 further adjusted for sex and age at AD or last-known dementia-free age for controls;
Model 2 further adjusted for APOE E2 and E4 genotypes.
Rare variants were aggregated by Ensembl genes, with variants selected using various filtering strategies based on predicted function. All analyzes were performed using seqMeta.
A p-value only version of the raw data fileset will be available soon.
The Alzheimer’s Disease Sequencing Project (ADSP) is comprised of two Alzheimer’s Disease (AD) genetics consortia and three National Human Genome Research Institute (NHGRI) funded Large Scale Sequencing and Analysis Centers (LSAC). The two AD genetics consortia are the Alzheimer’s Disease Genetics Consortium (ADGC) funded by NIA (U01 AG032984), and the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) funded by NIA (R01 AG033193), the National Heart, Lung, and Blood Institute (NHLBI), other National Institute of Health (NIH) institutes and other foreign governmental and non-governmental organizations. The Discovery Phase analysis of sequence data is supported through UF1AG047133 (to Drs. Farrer, Haines, Mayeux, Pericak-Vance, and Schellenberg); U01AG049505 to Dr. Seshadri; U01AG049506 to Dr. Boerwinkle; U01AG049507 to Dr. Wijsman; and U01AG049508 to Dr. Goate and the Discovery Extension Phase analysis is supported through U01AG052411 to Dr. Goate, U01AG052410 to Dr. Pericak-Vance and U01 AG052409 to Drs. Seshadri and Fornage. Data generation and harmonization in the Follow-up Phases is supported by U54AG052427 to Drs. Schellenberg and Wang. The ADGC cohorts include: Adult Changes in Thought (ACT supported by NIA grant U01AG006781 to Drs. Larson and Crane), the Alzheimer’s Disease Centers (ADC), the Chicago Health and Aging Project (CHAP), the Memory and Aging Project (MAP), Mayo Clinic (MAYO), Mayo Parkinson’s Disease controls, University of Miami, the Multi-Institutional Research in Alzheimer’s Genetic Epidemiology Study (MIRAGE), the National Cell Repository for Alzheimer’s Disease (NCRAD), the National Institute on Aging Late Onset Alzheimer's Disease Family Study (NIA-LOAD), the Religious Orders Study (ROS), the Texas Alzheimer’s Research and Care Consortium (TARC), Vanderbilt University/Case Western Reserve University (VAN/CWRU), the Washington Heights-Inwood Columbia Aging Project (WHICAP supported by NIA grant RF1AG054023 to Dr. Mayeux) and the Washington University Sequencing Project (WUSP), the Columbia University Hispanic- Estudio Familiar de Influencia Genetica de Alzheimer (EFIGA supported by NIA grant RF1AG015473 to Dr. Mayeux), the University of Toronto (UT), and Genetic Differences (GD). Analysis of ADGC cohorts us supported by NIA grants R01AG048927 and RF1AG057519 to Dr. Farrer. Efforts of ADGC investigators were also supported by grants from the NIA (R03AG054936) and National Library of Medicine (R01LM012535). The CHARGE cohorts are supported in part by National Heart, Lung, and Blood Institute (NHLBI) infrastructure grant R01HL105756 (Psaty), RC2HL102419 (Boerwinkle) and the neurology working group is supported by the National Institute on Aging (NIA) R01 grant AG033193. The CHARGE cohorts participating in the ADSP include the following: Austrian Stroke Prevention Study (ASPS), ASPS-Family study, and the Prospective Dementia Registry-Austria (ASPS/PRODEM-Aus), the Atherosclerosis Risk in Communities (ARIC) Study, the Cardiovascular Health Study (CHS), the Erasmus Rucphen Family Study (ERF), the Framingham Heart Study (FHS), and the Rotterdam Study (RS). ASPS is funded by the Austrian Science Fond (FWF) grant number P20545-P05 and P13180 and the Medical University of Graz. The ASPS-Fam is funded by the Austrian Science Fund (FWF) project I904),the EU Joint Programme - Neurodegenerative Disease Research (JPND) in frame of the BRIDGET project (Austria, Ministry of Science) and the Medical University of Graz and the Steiermärkische Krankenanstalten Gesellschaft. PRODEM-Austria is supported by the Austrian Research Promotion agency (FFG) (Project No. 827462) and by the Austrian National Bank (Anniversary Fund, project 15435. ARIC research is carried out as a collaborativestudysupportedbyNHLBIcontracts (HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, and HHSN268201100012C). Neurocognitive data in ARIC is collected by U01 2U01HL096812, 2U01HL096814, 2U01HL096899, 2U01HL096902, 2U01HL096917 from the NIH (NHLBI, NINDS, NIA and NIDCD), and with previous brain MRI examinations funded by R01-HL70825 from the NHLBI. CHS research was supported by contracts HHSN268201200036C, HHSN268200800007C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086, and grants U01HL080295 and U01HL130114 from the NHLBI with additional contribution from the National Institute of Neurological Disorders and Stroke (NINDS). Additional support was provided by R01AG023629, R01AG15928, and R01AG20098 from the NIA. FHS research is supported by NHLBI contracts N01-HC-25195 and HHSN268201500001I. This study was also supported by additional grants from the NIA (R01s AG054076, AG049607 and AG033040 and NINDS (R01NS017950). The ERF study as a part of EUROSPAN (European Special Populations Research Network) was supported by European Commission FP6 STRP grant number 018947 (LSHG-CT-2006-01947) and also received funding from the European Community's Seventh Framework Programme (FP7/2007-2013)/grant agreement HEALTH-F4-2007-201413 by the European Commission under the programme "Quality of Life and Management of the Living Resources" of 5th Framework Programme (no. QLG2-CT-2002-01254). High-throughput analysis of the ERF data was supported by a joint grant from the Netherlands Organization for Scientific Research and the Russian Foundation for Basic Research (NWO-RFBR 047.017.043). The Rotterdam Study is funded by Erasmus Medical Center and Erasmus University, Rotterdam, the Netherlands Organization for Health Research and Development (ZonMw), the Research Institute for Diseases in the Elderly (RIDE), the Ministry of Education, Culture and Science, the Ministry for Health, Welfare and Sports, the European Commission (DG XII), and the municipality of Rotterdam. Genetic data sets are also supported by the Netherlands Organization of Scientific Research NWO Investments (175.010.2005.011, 911-03-012), the Genetic Laboratory of the Department of Internal Medicine, Erasmus MC, the Research Institute for Diseases in the Elderly (014-93-015; RIDE2), and the Netherlands Genomics Initiative (NGI)/Netherlands Organization for Scientific Research (NWO) Netherlands Consortium for Healthy Aging (NCHA), project 050-060-810. All studies are grateful to their participants, faculty and staff. The content of these manuscripts is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health or the U.S. Department of Health and Human Services. The ADES-FR study was funded by grants from the Clinical Research Hospital Program from the French Ministry of Health (GMAJ, PHRC, 2008/067), the CNR-MAJ, the JPND PERADES, the GENMED labex (LABEX GENMED ANR-10-LABX-0013), and the FP7 AgedBrainSysBio. Whole exome sequencing in the 3C-Dijon study was funded by the Fondation Leducq. This work was supported by the France Génomique National infrastructure, funded as part of the Investissements d’Avenir program managed by the Agence Nationale pour la Recherche (ANR-10-INBS-09), the Centre National de Recherche en Génomique Humaine, the National Foundation forAlzheimer's disease and related disorders, the Institut Pasteur de Lille, Inserm, the Lille Métropole Communauté Urbaine council, and the French government's LABEX (laboratory of excellence program investment for the future) DISTALZ grant (Development of Innovative Strategies for a Transdisciplinary approach to Alzheimer's disease). The 3C Study supports are listed on the Study Website (www.three-city-study.com). The FinnAD Study at the University of Tampere was supported by The Academy of Finland: grants 286284 (T.L), Competitive State Research Financing of the Expert Responsibility area of Tampere University Hospitals (grant X51001); Juho Vainio Foundation; Paavo Nurmi Foundation; Finnish Foundation for Cardiovascular Research; Finnish Cultural Foundation; Tampere Tuberculosis Foundation; Yrjö Jahnsson Foundation; Signe and Ane Gyllenberg Foundation; and Diabetes Research Foundation of Finnish Diabetes Association. The FinnAD Study at the University of Eastern Finland was supported by the Academy of Finland grant 307866, the Sigrid Jusélius Foundation, and the Strategic Neuroscience Funding of the University of Eastern Finland. The three LSACs are: the Human Genome Sequencing Center at the Baylor College of Medicine (U54 HG003273), the Broad Institute Genome Center (U54HG003067), and the Washington University Genome Institute (U54HG003079).
Biological samples and associated phenotypic data used in primary data analyses were stored at Study Investigator institutions, and at the National Cell Repository for Alzheimer’s Disease (NCRAD, U24AG021886) at Indiana University funded by NIA. Associated Phenotypic Data used in primary and secondary data analyses were provided by Study Investigators, the NIA funded Alzheimer’s Disease Centers (ADCs), and the National Alzheimer’s Coordinating Center (NACC, U01AG016976) and the National Institute on Aging Genetics of Alzheimer’s Disease Data Storage Site (NIAGADS, U24AG041689) at the University of Pennsylvania, funded by NIA, and at the Database for Genotypes and Phenotypes (dbGaP) funded by NIH. This research was supported in part by the Intramural Research Program of the National Institutes of health, National Library of Medicine. Contributors to the Genetic Analysis Data included Study Investigators on projects that were individually funded by NIA, and other NIH institutes, and by private U.S. organizations, or foreign governmental or nongovernmental organizations. We also acknowledge the investigators who assembled and characterized participants of cohorts included in this study:
Adult Changes in Thought: James D. Bowen, Paul K. Crane, Gail P. Jarvik, C. Dirk Keene, Eric B. Larson, W. William Lee, Wayne C. McCormick, Susan M. McCurry, Shubhabrata Mukherjee, Katie Rose Richmire Atherosclerosis Risk in Communities Study: Rebecca Gottesman, David Knopman, Thomas H. Mosley, B. Gwen Windham,
Austrian Stroke Prevention Study: Thomas Benke, Peter Dal-Bianco, Edith Hofer, Gerhard Ransmayr, Yasaman Saba
Cardiovascular Health Study: James T. Becker, Joshua C. Bis, Annette L. Fitzpatrick, M. Ilyas Kamboh, Lewis H. Kuller, WT Longstreth, Jr, Oscar L. Lopez, Bruce M. Psaty, Jerome I. Rotter,
Chicago Health and Aging Project: Philip L. De Jager, Denis A. Evans
Erasmus Rucphen Family Study: Hieab H. Adams, Hata Comic, Albert Hofman, Peter J. Koudstaal, Fernando Rivadeneira, Andre G. Uitterlinden, Dina Voijnovic
Estudio Familiar de la Influencia Genetica en Alzheimer: Sandra Barral, Rafael Lantigua, Richard Mayeux, Martin Medrano, Dolly Reyes-Dumeyer, Badri Vardarajan
Framingham Heart Study: Alexa S. Beiser, Vincent Chouraki, Jayanadra J. Himali, Charles C. White
Genetic Differences: Duane Beekly, James Bowen, Walter A. Kukull, Eric B. Larson, Wayne McCormick, Gerard D. Schellenberg, Linda Teri
Mayo Clinic: Minerva M. Carrasquillo, Dennis W. Dickson, Nilufer Ertekin-Taner, Neill R. Graff-Radford, Joseph E. Parisi, Ronald C. Petersen, Steven G. Younkin
Mayo PD: Gary W. Beecham, Dennis W. Dickson, Ranjan Duara, Nilufer Ertekin-Taner, Tatiana M. Foroud, Neill R. Graff-Radford, Richard B. Lipton, Joseph E. Parisi, Ronald C. Petersen, Bill Scott, Jeffery M. Vance
Memory and Aging Project: David A. Bennett, Philip L. De Jager
Multi-Institutional Research in Alzheimer's Genetic Epidemiology Study: Sanford Auerbach, Helan Chui, Jaeyoon Chung, L. Adrienne Cupples, Charles DeCarli, Ranjan Duara, Martin Farlow, Lindsay A. Farrer, Robert Friedland, Rodney C.P. Go, Robert C. Green, Patrick Griffith, John Growdon, Gyungah R. Jun, Walter Kukull, Alexander Kurz, Mark Logue, Kathryn L. Lunetta, Thomas Obisesan, Helen Petrovitch, Marwan Sabbagh, A. Dessa Sadovnick, Magda Tsolaki
National Cell Repository for Alzheimer's Disease: Kelley M. Faber, Tatiana M. Foroud
National Institute on Aging (NIA) Late Onset Alzheimer's Disease Family Study: David A. Bennett, Sarah Bertelsen, Thomas D. Bird, Bradley F. Boeve, Carlos Cruchaga, Kelley Faber, Martin Farlow, Tatiana M Foroud, Alison M Goate, Neill R. Graff-Radford, Richard Mayeux, Ruth Ottman, Dolly Reyes-Dumeyer, Roger Rosenberg, Daniel Schaid, Robert A Sweet, Giuseppe Tosto, Debby Tsuang, Badri Vardarajan
NIA Alzheimer Disease Centers: Erin Abner, Marilyn S. Albert, Roger L. Albin, Liana G. Apostolova, Sanjay Asthana, Craig S. Atwood, Lisa L. Barnes, Thomas G. Beach, David A. Bennett, Eileen H. Bigio, Thomas D. Bird, Deborah Blacker, Adam Boxer, James B. Brewer, James R. Burke, Jeffrey M. Burns, Joseph D. Buxbaum, Nigel J. Cairns, Chuanhai Cao, Cynthia M. Carlsson, Richard J. Caselli, Helena C. Chui, Carlos Cruchaga, Mony de Leon, Charles DeCarli, Malcolm Dick, Dennis W. Dickson, Nilufer Ertekin-Taner, David W. Fardo, Martin R. Farlow, Lindsay A. Farrer, Steven Ferris, Tatiana M. Foroud, Matthew P. Frosch, Douglas R. Galasko, Marla Gearing, David S. Geldmacher, Daniel H. Geschwind, Bernardino Ghetti, Carey Gleason, Alison M. Goate, Teresa Gomez-Isla, Thomas Grabowski, Neill R. Graff-Radford, John H. Growdon, Lawrence S. Honig, Ryan M. Huebinger, Matthew J. Huentelman, Christine M. Hulette, Bradley T. Hyman, Suman Jayadev, Lee-Way Jin, Sterling Johnson, M. Ilyas Kamboh, Anna Karydas, Jeffrey A. Kaye, C. Dirk Keene, Ronald Kim, Neil W Kowall, Joel H. Kramer, Frank M. LaFerla, James J. Lah, Allan I. Levey, Ge Li, Andrew P. Lieberman, Oscar L. Lopez, Constantine G. Lyketsos, Daniel C. Marson, Ann C. McKee, Marsel Mesulam, Jesse Mez, Bruce L. Miller, Carol A. Miller, Abhay Moghekar, John C. Morris, John M. Olichney, Joseph E. Parisi, Henry L. Paulson, Elaine Peskind, Ronald C. Petersen, Aimee Pierce, Wayne W. Poon, Luigi Puglielli, Joseph F. Quinn, Ashok Raj, Murray Raskind, Eric M. Reiman, Barry Reisberg, Robert A. Rissman, Erik D. Roberson, Howard J. Rosen, Roger N. Rosenberg, Martin Sadowski, Mark A. Sager, David P. Salmon, Mary Sano, Andrew J. Saykin, Julie A. Schneider, Lon S. Schneider, William W. Seeley, Scott Small, Amanda G. Smith, Robert A. Stern, Russell H. Swerdlow, Rudolph E. Tanzi, Sarah E Tomaszewski Farias, John Q. Trojanowski, Juan C. Troncoso, Debby W. Tsuang, Vivianna M. Van Deerlin, Linda J. Van Eldik, Harry V. Vinters, Jean Paul Vonsattel, Jen Chyong Wang, Sandra Weintraub, Kathleen A. Welsh-Bohmer, Shawn Westaway, Thomas S. Wingo, Thomas Wisniewski, David A. Wolk, Randall L. Woltjer, Steven G. Younkin, Lei Yu, Chang-En Yu
Religious Orders Study: David A. Bennett, Philip L. De Jager
Rotterdam Study: Kamran Ikram, Frank J Wolters
Texas Alzheimer's Research and Care Consortium: Perrie Adams, Alyssa Aguirre, Lisa Alvarez, Gayle Ayres, Robert C. Barber, John Bertelson, Sarah Brisebois, Scott Chasse, Munro Culum, Eveleen Darby, John C. DeToledo, Thomas J. Fairchild, James R. Hall, John Hart, Michelle Hernandez, Ryan Huebinger, Leigh Johnson, Kim Johnson, Aisha Khaleeq, Janice Knebl, Laura J. Lacritz, Douglas Mains, Paul Massman, Trung Nguyen, Sid O’Bryant, Marcia Ory, Raymond Palmer, Valory Pavlik, David Paydarfar, Victoria Perez, Marsha Polk, Mary Quiceno, Joan S. Reisch, Monica Rodriguear, Roger Rosenberg, Donald R. Royall, Janet Smith, Alan Stevens, Jeffrey L. Tilson, April Wiechmann, Kirk C. Wilhelmsen, Benjamin Williams, Henrick Wilms, Martin Woon
University of Miami: Larry D Adams, Gary W. Beecham, Regina M Carney, Katrina Celis, Michael L Cuccaro, Kara L. Hamilton-Nelson, James Jaworski, Brian W. Kunkle, Eden R. Martin, Margaret A. Pericak-Vance, Farid Rajabli, Michael Schmidt, Jeffery M Vance
University of Toronto: Ekaterina Rogaeva, Peter St. George-Hyslop
University of Washington Families: Thomas D. Bird, Olena Korvatska, Wendy Raskind, Chang-En Yu
Vanderbilt University: John H. Dougherty, Harry E. Gwirtsman, Jonathan L. Haines
Washington Heights-Inwood Columbia Aging Project: Adam Brickman, Rafael Lantigua, Jennifer Manly, Richard Mayeux, Christiane Reitz, Nicole Schupf, Yaakov Stern, Giuseppe Tosto, Badri Vardarajan