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October 2017; 3 (5) Clinical/Scientific NotesOpen Access

The Alzheimer's Disease Sequencing Project: Study design and sample selection

Gary W. Beecham, J.C. Bis, E.R. Martin, S.-H. Choi, A. L. DeStefano, C.M. van Duijn, M. Fornage, S.B. Gabriel, D.C. Koboldt, D.E. Larson, A.C. Naj, B.M. Psaty, W. Salerno, W.S. Bush, T.M. Foroud, E. Wijsman, L.A. Farrer, A. Goate, J.L. Haines, Margaret A. Pericak-Vance, E. Boerwinkle, R. Mayeux, S. Seshadri, G. Schellenberg
First published October 13, 2017, DOI: https://doi.org/10.1212/NXG.0000000000000194
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  1. Gary W. Beecham, PhD,
  2. J.C. Bis, PhD,
  3. E.R. Martin, PhD,
  4. S.-H. Choi, PhD,
  5. A. L. DeStefano, PhD,
  6. C.M. van Duijn, PhD,
  7. M. Fornage, PhD,
  8. S.B. Gabriel, PhD,
  9. D.C. Koboldt, PhD,
  10. D.E. Larson, PhD,
  11. A.C. Naj, PhD,
  12. B.M. Psaty, PhD,
  13. W. Salerno, PhD,
  14. W.S. Bush, PhD,
  15. T.M. Foroud, PhD,
  16. E. Wijsman, PhD,
  17. L.A. Farrer, PhD,
  18. A. Goate, PhD,
  19. J.L. Haines, PhD,
  20. Margaret A. Pericak-Vance, PhD,
  21. E. Boerwinkle, PhD,
  22. R. Mayeux, MD,
  23. S. Seshadri, MD and
  24. G. Schellenberg, PhD
  1. From the John P. Hussman Institute for Human Genomics (G.W.B., E.R.M., M.A.P.-V.) and Dr. John T. Macdonald Foundation Department of Human Genetics (G.W.B., E.R.M., M.A.P.-V.), Miller School of Medicine, University of Miami, FL; Cardiovascular Health Research Unit (J.C.B.), Department of Medicine, Cardiovascular Health Research Unit (B.M.P.), Departments of Medicine, Epidemiology, Health Services, Department of Biostatistics (E.W.), and Division of Medical Genetics (E.W.), Department of Medicine, University of Washington, Seattle; Department of Biostatistics (S.-H.C., A.D., L.A.F.), Boston University School of Public Health, MA; The Framingham Heart Study (A.D., S.S.), MA; Department of Neurology (A.D., L.A.F., S.S.), Boston University School of Medicine, MA; Department of Epidemiology (C.M.v.D), Erasmus MC, Rotterdam, Netherlands; Brown Foundation Institute of Molecular Medicine (M.F.) and Human Genetics Center (M.F.), University of Texas Health Science Center, Houston; The Eli and Edythe L. Broad Institute of Massachusetts Institute of Technology (S.B.G.), Cambridge; Harvard University (S.B.G.), Cambridge, MA; The McDonnell Genome Institute (D.C.K., D.E.L.) and Department of Genetics (D.E.L.), Washington University, St. Louis, MO; Department of Biostatistics and Epidemiology (A.C.N.) and Perelman School of Medicine (G.S.), University of Pennsylvania, Philadelphia; Group Health Research Institute (B.M.P.), Group Health Cooperative, Seattle, WA; Human Genome Sequencing Center (W.S., E.B.), Baylor College of Medicine, Houston, TX; Department of Epidemiology and Biostatistics (W.S.B., J.L.H.), Case Western Reserve University, Cleveland, OH; Department of Medical and Molecular Genetics (T.M.F.), Indiana University School of Medicine, Indianapolis; Department of Medicine (Biomedical Genetics) (L.A.F.), Department of Ophthalmology (L.A.F.), and Department of Epidemiology (L.A.F.), Boston University School of Medicine and Public Health, MA; Department of Neuroscience (A.G.), Icahn School of Medicine at Mount Sinai, New York, NY; Human Genetics Center (E.B.), UT Health School of Public Health, Houston, TX; Taub Institute for Research on Alzheimer's Disease and the Aging Brain (R.M.) and Gertrude H. Sergievsky Center (R.M.), Columbia University Medical Center, New York, NY; Department of Neurology (R.M.), Columbia University Medical Center and New York Presbyterian Hospital, NY; and Department of Epidemiology (R.M.), Mailman School of Public Health, Columbia University, New York, NY.
  1. Correspondence to Dr. Beecham: gbeecham{at}med.miami.edu
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Research Support, Government Entities:

  1. Dr. Beecham receives funding from the National Institutes of Health (R21HD080410, co-investigator, 2016-18; R01AG054080, PI, 2016-21; R01AG054074, MPI, 2016-21; U54AG052427, co-investigator, 2016-21; U01AG052410, MPI, 2016-21; U54NS0657, co-investigator, 2009-19; R01AG042437, subcontract PI, 2014-18; UF1AG047133, co-investigator, 2014-18; T32EY023194, co-investigator, 2013-2017; P50NS071674, co-investigator, 2010-17;U01G032984, co- investigator, 2009-2020; R01NS075764, co-investigator, 2012-17; R01AG027944, coinvestigator, 2008-2015) and the Department of Defense (W81XWH-14-1-0097, co-investigator, 2014-18).

Research Support, Academic Entities:

  1. NONE

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  1. NONE

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  1. NONE

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  1. NONE

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  1. NONE

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  1. NONE

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  1. NONE

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  1. NONE

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  1. NONE

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  1. NONE

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  1. NONE

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  1. NONE

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  1. NONE

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  1. NONE

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  1. NONE

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  1. Frontiers in Statistical Genetics and Methodology, Associate Editor, Nov. 2010 - present

Patents:

  1. Invrntor, US Patenet No. 6697739 Test for Linkage and Association in General Pedigrees: The Pedigree Disequilibrium Test

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  1. 1. NIH/NIDDK R01 DK099269, PI, 07/01/14-06/30/18 2. NIH/NHLBI HHSN268201500001, Statistical Geneticist 02/01/02-03/31/20 3. NIH/NIA 5 R01 AG033193-04, Co-investigator 07/01/13-06/30/17 4. NIH/NIA U01 AG049505-01 Co-investigator 02/01/13-01/31/17 5. NIH/NIA R01 AG054076-01 Statistical Geneticist 09/01/16 - 05/31/21

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Employment, Commercial Entity:

  1. I work for a non-profit entity

Consultancies:

  1. Wilmer-Hale Guidepoint Global

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  1. NONE

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  1. I receive a co-inventor's share of license revenue for VarScan, a software tool for next-generation sequencing analysis. Licensing and disbursements are handled by my former institution, Washington University in St. Louis. In the past two years, paying licensees included:(1) Bina Technologies (2) Janssen (3) Fera Science (4) Philips Electronics (5) WuXi NextCODE

Royalty Payments, Technology or Inventions:

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  1. NONE

Research Support, Government Entities:

  1. (1) NIH, 1U41HG007635, Bioinformatician/Analysis, 2013-2016 (2) NIH, 1UM1HG008853, Bioinformatician/Analysis, 2016-2017 (3) NIH, 5R01CA178397, Bioinformatician/Analysis, 2015 (4) NIH, 5U01HG006517, Bioinformatician/Analysis, 2013-2016 (5) NIH, 5U54HG003079, Bioinformatician/Analysis, 2013-2015 (6) St. Jude Children's Research Hospital, Pediatric Cancer Genome Project Phase II, Bioinformatician/Analysis, 2013-2016

Research Support, Academic Entities:

  1. NONE

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  1. NONE

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Gifts:

  1. NONE

Funding for Travel or Speaker Honoraria:

  1. (1) Pfizer, presentation of a scientific talk

Editorial Boards:

  1. (1) Associate Editor, PLoS ONE

Patents:

  1. NONE

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  1. NONE

Employment, Commercial Entity:

  1. NONE

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  1. NONE

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  1. NONE

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  1. NONE

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  1. NONE

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  1. NONE

Research Support, Government Entities:

  1. (1) NIA, R01 AG054060, PI, 10/2016-9/2020 (2) NIA, U54 NS100693, Co-I, 9/2016-6/2020 (3) NIA, U54 AG052427, Co-I, 7/2016-6/2018 (4) NIA, U01 AG032984, Co-I, 6/2015-3/2020 (5) NIA, U24 AG041689, Co-I, 4/2015-3/2017 (6) NIA, R01 AG042437, Co-I, 9/2014-6/2018 (7) NIA, UF1 AG047133, Co-I, 6/2014-5/2018

Research Support, Academic Entities:

  1. NONE

Research Support, Foundations and Societies:

  1. (1) BrightFocus Foundation, Co-I, 7/2016-6/2018 (2) Penn Institute on Aging, PI, 7/2016-6/2017

Stock/Stock Options/Board of Directors Compensation:

  1. NONE

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  1. NONE

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  1. NONE

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  1. NONE

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  1. NONE

Scientific Advisory Boards:

  1. Psaty serves on the DSMB of a clinical trial for a device funded by the manufacturer (Zoll LifeCor) and on the Steering Committee for the Yale Open Data Access project funded by Johnson & Johnson.

Gifts:

  1. NONE

Funding for Travel or Speaker Honoraria:

  1. NONE

Editorial Boards:

  1. Contributing writer for JAMA.

Patents:

  1. NONE

Publishing Royalties:

  1. NONE

Employment, Commercial Entity:

  1. NONE

Consultancies:

  1. NONE

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  1. NONE

Other Activities:

  1. NONE

Clinical Procedures or Imaging Studies:

  1. NONE

Research Support, Commercial Entities:

  1. NONE

Research Support, Government Entities:

  1. Listed in the acknowledgement

Research Support, Academic Entities:

  1. NONE

Research Support, Foundations and Societies:

  1. NONE

Stock/Stock Options/Board of Directors Compensation:

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Employment, Commercial Entity:

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Consultancies:

  1. LaserGen

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  1. NONE

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  1. NONE

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Research Support, Foundations and Societies:

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Funding for Travel or Speaker Honoraria:

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Editorial Boards:

  1. BMC Biodata Mining, Editorial Board Member, 2012 - Present PLoS One, Statistical Advisory Board, 2013 - Present

Patents:

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Publishing Royalties:

  1. NONE

Employment, Commercial Entity:

  1. NONE

Consultancies:

  1. LaserGen

Speakers' Bureaus:

  1. NONE

Other Activities:

  1. NONE

Clinical Procedures or Imaging Studies:

  1. NONE

Research Support, Commercial Entities:

  1. NONE

Research Support, Government Entities:

  1. NIA, AG054074, Co-I, 2016-Present NIA, AG052410, Co-I, 2016-Present NIA, AG052426, Co-I, 2016-Present

Research Support, Academic Entities:

  1. NONE

Research Support, Foundations and Societies:

  1. NONE

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Scientific Advisory Boards:

  1. 1) National Advisory Council on Alcohol Abuse and Alcoholism 2) Washington University Alzheimer?s Disease Research Center External Advisory Board3) NIA Genetics of Alzheimer's Disease Data Storage Site, External Advisory Board

Gifts:

  1. NONE

Funding for Travel or Speaker Honoraria:

  1. 1) Michael J Fox Foundation for Parkinson's Research, travel 2) NIH, travel 3) Univ of Pittsburgh, travel 4) Univ of Chicago, travel 5) Univ of Texas at Austin, travel & speaker honoraria

Editorial Boards:

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Patents:

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Publishing Royalties:

  1. NONE

Employment, Commercial Entity:

  1. NONE

Consultancies:

  1. LaserGen

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  1. NONE

Other Activities:

  1. NONE

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Research Support, Commercial Entities:

  1. NONE

Research Support, Government Entities:

  1. 1) NIH, PI or Co-I, 1997-2017 2) US Dept of Defense, W81XWH-14-2-0151, 2016-2017

Research Support, Academic Entities:

  1. 1) Columbia Univ 2) San Diego State University 3) Univ Calif San Diego 4) Univ of Mass 5) Univ of Pennsylvania 6) State Univ of New York

Research Support, Foundations and Societies:

  1. Michael J Fox Foundation for Parkinson's Research

Stock/Stock Options/Board of Directors Compensation:

  1. NONE

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Scientific Advisory Boards:

  1. Non-profit entity: NIH NHLBI National Registry for Genetically Triggered Thoracic Aortic Aneurisms and Cardiovascular Conditions, DSMB, 2007-2015

Gifts:

  1. NONE

Funding for Travel or Speaker Honoraria:

  1. NONE

Editorial Boards:

  1. BMC Proceedings, Editor, 2014-2016 Faculty of 1000, Editor, Bioinformatics section, 2013-present

Patents:

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Publishing Royalties:

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Employment, Commercial Entity:

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Consultancies:

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  1. NONE

Other Activities:

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Clinical Procedures or Imaging Studies:

  1. NONE

Research Support, Commercial Entities:

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Research Support, Government Entities:

  1. US National Institutes of Health: P30 AG05136, PI, Data Management/Biostatistics Core, 2005-current R37 GM46255, Co-I, 2008-current R01 MH094293, PI, 2012-current U01 AG049507, PI, 2014-current R24 OD021324, site PI, 2016-current R21 AI127493, PI, 2016-current R21 AI119715, PI, 2015-current

Research Support, Academic Entities:

  1. NONE

Research Support, Foundations and Societies:

  1. Metropolitan Life Foundation Award for Medical Research

Stock/Stock Options/Board of Directors Compensation:

  1. NONE

License Fee Payments, Technology or Inventions:

  1. NONE

Royalty Payments, Technology or Inventions:

  1. NONE

Stock/Stock Options, Research Sponsor:

  1. NONE

Stock/Stock Options, Medical Equipment & Materials:

  1. NONE

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  1. NONE

Scientific Advisory Boards:

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Gifts:

  1. NONE

Funding for Travel or Speaker Honoraria:

  1. NONE

Editorial Boards:

  1. 1. American Journal of Alzheimer's Disease & Other Dementias, editorial board, 1997-present 2. Clinical Genetics, editorial board, 1999-present

Patents:

  1. one patent pending for use of PLXNA4 as a drug target and biomarker for Alzheimer disease

Publishing Royalties:

  1. NONE

Employment, Commercial Entity:

  1. NONE

Consultancies:

  1. 1. Novartis Pharmaceuticals, consultant, 2007-2010 2. Gerson Lerman, consultant, 2009-present 3. Guidepoint Global, 2009 - present

Speakers' Bureaus:

  1. NONE

Other Activities:

  1. NONE

Clinical Procedures or Imaging Studies:

  1. NONE

Research Support, Commercial Entities:

  1. NONE

Research Support, Government Entities:

  1. NIH - R01-AG25259, PI, 2006-2112 NIH - U01-AG032984, SubK PI, 2009-present NIH - UF1-AG046198, PI of a multi PI grant, 2014-present NIH - R01-AG048927, PI, 2015-present

Research Support, Academic Entities:

  1. NONE

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  1. PSEN mutations in AD Tau mutations in FTD TDP43 mutations in ALS\FTD

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  1. 1. NIA 1R01AG035083- (Goate) PI 9/1/10-8/31/15 2. NIA 1U01AG032984-01 (Schellenberg\Goate) Co- Investigator/Core Director 4/1/09-3/31/14 3. NIA U01 AG049508-01 Goate (PI) 6/11/14-5/31/18 4. NIA R01 AGO41797-03 Goate Site PI 4/1/12-3/13/17 5. NIA U01 AG052411 Goate (PI) 8/1/2016-7/31/2020 6. NIA RF1AG05401 Goate (PI) 08/01/16-06/30/21 7. NIA 5U01AG032438-07 (Morris) Co-Investigator/Core Director 9/15/08-6/30/19 8. NIAAA 5U10AA08401-25 (Goate/ site PI) Co-Investigator 9/29/89-8/31/19

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  1. 2014/06/15-2018/05/31 UF1AG047133, NIH/NIA Consortium for Alzheimer?s Sequence Analysis (CASA) The goal of the CASA grant is to analyze and interpret genotyping and sequencing data from a large dataset of Alzheimer cases, controls, and families Role: KP (PI)2013/02/01-2018/01/31 R01EY023164, NIH/NEI Stambolian (U. Penn) (PI) Genetic Epidemiology of Age-Related Macular Degeneration in the Old Order Amish The goal of this project is to understand the genetic architecture of AMD phenotypes in the Amish Role: KP (PI of subcontract)2011/09/01-2016/08/31 R01EY020928, NIH/NEI Wiggs (Mass. Eye & Ear) (PI) Genetic and Environmental Risk Factors for Exfoliation Syndrome and Glaucoma The goal of this project is to generate GWAS data on glaucoma patients and examine the results for both gene and gene environment effects. Role: KP (PI of subcontract)2000/06/15-2016/07/31 R01EY012118, NIH/NEI Haines, Jonathan L. (PI) Genomic Architecture of Progression and Treatment Response in AMD The goal of this project is to dissect the genetic etiology of Macular Degeneration Role: PI2012/04/01-2016/03/31 R01EY022310, NIH/NEI Haines, Jonathan L. (PI) Advancing Genetics through the AMD Gene Consortium The goal of this project is to combine data and results from multiple different investigators to further understand the genetic architecture of age-related macular degeneration Role: PI2012/08/01-2019/07/31 R01EY022305, NIH/NEI Wiggs (Mass. Eye & Ear) (PI) The NEIGHBORHOOD: POAG Heritable Overall Operational Database The goal of this project is to combine data and results from multiple different investigators to further understand the genetic architecture of Primary Open AngleGlaucoma. Role: KP (PI of subcontract)

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  1. 5U01HG007416-03 (North) NIH/NHGRI Univ. of NC at Chapel Hill 09/01/2013 - 05/31/2018 Genetic Epidemiology of Causal Variants Across the Life Course Phase 2 (CALiCo 2) CALiCo is an ethnically diverse consortium of population based studies that investigate the genetic architecture of variants associated with complex diseases. Role: Consortium PI 5U01AG049506-03 (Boerwinkle) NIH/NIA 06/15/2014 - 05/31/2018 Sequence-based Discovery of AD Risk & Protective Alleles This project seeks to identify genes from whole genome sequence data associated with increased risk of or protection from Alzheimer's Disease. Role: PI 5R01NS087541-03 (Fornage/Boerwinkle) NIH/NINDS 04/01/2014 - 03/31/2018 An Integrated Genetic and Epigenetic Approach to Cerebral Small Vessel Disease This study aims to identify epigenetic variation (DNA methylation) influencing cerebral small vessel disease. Role: Multi-PI 1UM1HG008898-01 (Gibbs) NIH/NHGRI Baylor College of Medicine 11/01/2015 ?10/31/2019 Genomic Architecture of Common Disease in Diverse Populations In this project, whole genome sequencing will be performed to identify genomic regions influencing the human serum metabolome. Role: Consortium PI 5UL1TR000371-09 (McPherson) NIH/NCATS 06/27/2012 - 05/31/2018 Center for Clinical and Translational Sciences The goal of the Center for Clinical and Translational Sciences (CCTS) is to facilitate clinical and translational research at The University of Texas Health Science Center at Houston, The University of Texas M.D. Anderson Cancer Center, and the Memorial Hermann Hospital System. Role: Co-Investigator HHSN268201700001I (Couper) NIH/NHLBI Univ. of NC at Chapel Hill 11/15/2016-11/14/2022 Atherosclerosis Risk in Communities (ARIC) Study This project maintains longitudinal samples collected as part of the well-established NHLBI ARIC study and analyzes large scale genomic data and gene-environment interactions of cardiovascular disease related phenotypes and risk factors. Role: Consortium PI 5R01HL120393-03 (Psaty) NIH/NHLBI Univ. of Washington Rare Variants and NHLBI Traits in Deeply Phenotyped Cohorts 04/01/2014 - 03/31/2018 This research investigates the impact of rare variants in heart, lung and blood phenotypes in a consortium of large population-based cohorts, such as the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. Role: Consortium PI 1R01DK101505-02 (Kelly) NIH/NIDDK Tulane University 08/21/2015 ? 05/31/2020 Whole-exome Sequencing Study of Diabetic Nephropathy This study proposes to identify novel genes and functional variants associated with diabetic nephropathy (DN) by conducting whole-exome sequencing, follow-up targeted sequencing, and replication in a multiethnic cohort. Role: Co-Investigator 2R01HL105756-04 (Psaty) NIH/NHLBI U of Washington 03/01/2014 ? 03/31/2018 Charge Consortium: Gene Discovery for CVD and Aging Phenotypes We will perform statistical analysis of cardiovascular disease and related aging phenotypes in ARIC genetic data as part of the CHARGE consortium. Role: Consortium PI 1U01HG008664-01 (Gibbs) NIH/NHGRI Baylor College of Medicine 09/01/2015 ? 05/31/2019 DNA Sequencing Support for the eMERGE Network Annotation will be customized and revalidated for whole genome sequence data collected as part of the eMERGE program. Role: Consortium PI 1R01HL131136-01A1 (Boerwinkle) NIH/NHLBI 12/15/2016 ? 11/30/2020 Epigenetics of Successful Aging This project will test the hypothesis that DNA methylation signatures measured in the blood of middle-adults are associated with successful aging patterns later in life. Role: PI UM1HG006542 (Valle) NIH/NHGRI Johns Hopkins University 12/05/2011 ? 11/30/2019 Baylor-Johns Hopkins Center for Mendelian Genetics This project analyzes sequence data to identify genes leading to targeted Mendelian disorders. Role: Co-Investigator 4R01GM104411-04 (Xiong) NIH/NIGMS 04/01/2013 - 01/31/2018 Unified Statistical Methods for Sequence-Based Association Studies This project develops and tests innovative genetic models, statistical methods and computational algorithms for sequence-based association studies and QTL analysis. Role: Multi-PI

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  1. RO1 AG037212 Epidemiology of Biomarkers of Risk and Progression in Late onset Alzheimer?s Disease. Principal Investigator RF1 AG015473 Genetic Studies of Alzheimer's Disease in Caribbean Hispanics. Principle Investigator

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  1. Alzheimer's Disease Center Directors Meeting - travel/lodging CurePSP International Research Symposium, travel/lodging Robert Katzman Memorial Lecture, University of California, San Diego, California Alzheimer?s Disease ? From Fundamental Insights to Light at the End of the Translational Tunnel, Keystone, Colorado 25th Annual Southern California Alzheimer?s Disease Research Conference, University of California Institute for Memory Impairment and Neurological Disorders, Costa Mesa, California CurePSP International Research Symposium, Baltimore, Maryland Biomarkers in Neuropsychiatric Disorders, Toronto, Canada Alzheimer?s Disease Sequence Project meeting, National Institutes of Health, Bethesda, Maryland Path to Treatment and Prevention, National Institutes of Health, Bethesda, Maryland Novartis Institutes for Biomedical Research, Inc., Novartis, Cambridge, Massachusetts McKnight Brain Institute, University of Florida, Gainesville, Florida Alzheimer?s Disease Center Directors Meeting, Washington, DC. NIA Scientific Retreat, National Institutes of Health, Bethesda, Maryland Keep Memory Alive Event Center, Cleveland Clinic Lou Ruvo Center for Brain Health, Las Vegas, NV Accelerated Medicines Program Alzheimer?s Disease F2F Target Discovery and Preclinical Validation Project Meeting. ?Alzheimer?s Disease Sequencing Project ? status?, NIA/FNIH/NIH, Bethesda, MD ?Genetics of PSP and Tauopathies?, PSP/Lewy Body Disease Think-Tank. Journey from Tau to Lewy bodies. McKnight Brain Institute, University of Florida, Gainesville, Florida ?ADGC Update, NIAGADS Update? Alzheimer?s Disease Center Directors Meeting, Washington, DC. ?Update on Alzheimer?s Disease Sequence Project?, 2015 NIA Scientific Retreat, National Institutes of Health, Bethesda, Maryland ?GWAS and ?Omics Implications for Combination Therapy,? Keep Memory Alive Event Center, Cleveland Clinic Lou Ruvo Center for Brain Health, Las Vegas, NV Accelerated Medicines Program Alzheimer?s Disease F2F Target Discovery and Preclinical Validation Project Meeting. ?Alzheimer?s Disease Sequencing Project ? status?, NIA/FNIH/NIH, Bethesda, MD American Association of Neuropathologists, ?Alzheimer?s Disease Genetics? Denver, CO. Fusion Conference, Personalized Medicine, ?Personalized Medicine and Neurodegenerative disorders. What does the future hold?? Tucson, AZ. CurePSP Symposium, ?Progressive supranuclear palsy genetics ? update?. La Jolla, CA Center for Public Health Genomics, Genome Sciences Seminar, University of Virginnia, ?Progress in Neurodegenerative Disease Genetics?, Charlottesville, VA. Neurology Grand Rounds, Columbia University, ?Genetics of Progressive supranuclear palsy and corticobasal degeneration?, New York, NY.

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  1. Advisory Board for the Dementia Section, Journal of Neural Transmission Editorial Board, Alzheimer's Research Editorial Board, American Journal of Alzheimer?s Disease and other Dementias. Editorial Board, Neurodegenerative Diseases Editorial Board, Current Alzheimer Research Editorial Board - Pathology and Laboratory Medicine International

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  1. NIA/NIH

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  1. CurePSP CBD Solutions

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Late-onset Alzheimer disease (LOAD) is the leading cause of dementia worldwide, with substantial economic and public health implications.1 LOAD is a neurodegenerative disease characterized by progressive dementia typically manifesting in the seventh to ninth decades. Neuropathological changes precede clinical symptoms by 10–20 years, resulting in clinically asymptomatic individuals carrying neuropathologic features of LOAD.2 Much of the heritability of LOAD remains unexplained, despite LOAD having a high heritability (60%–80%) and despite the identification of the APOE locus, a major genetic determinant for LOAD.3 Genetic analyses have identified more than 25 other variants associated with smaller individual effects on disease risk.4

To identify novel genetic variation influencing AD risk and protection, the Alzheimer's Disease Sequencing Project (ADSP) was implemented as a collaborative effort of the National Institutes on Aging, the National Human Genome Research Institute, and the Alzheimer disease research community. Individual contributors include the Alzheimer's Disease Genetics Consortium, the Neurology Phenotype Working Group of the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium, and the Large Scale Sequencing and Analysis Centers at Baylor University, the Broad Institute, and Washington University.

Study design and sample selection were conducted to address issues of phenotypic heterogeneity and maximize statistical power. The study design includes 2 primary phases: a whole-genome sequencing (WGS) family-based study and a whole-exome sequencing (WES) case-control study. The WGS study was designed to target rarer variation through allelic segregation and linkage analyses in multiplex AD families. The WES case-control study was designed to target low-frequency coding variation in genes that contribute to AD risk or protection.

ADSP family study design.

Approximately 1,400 multiplex LOAD families were reviewed for inclusion. Families were required to have multiple members with LOAD, genomic DNA, and available APOE genotypes. Families meeting initial criteria were assigned a priority rank based on number and age at onset of affected individuals, number of generations affected, and presence of APOE ε4 alleles. Priority was given to families heavily loaded for AD (≥4 affected members with DNA available) with minimal APOE ε4 alleles. Cases met National Institute of Neurological Diseases–Alzheimer's NINCDS-ADRDA (National Institute of Neurological and Communicative Disorders and Stroke, and the Alzheimer's Disease and related Disorders Association; now, Alzheimer's Association) criteria for possible, probable, or definite AD. Controls were free of clinical AD on cognitive assessment. A detailed description of the family design is in Appendix 1 at Neurology.org/ng.

In total, we selected 582 individuals (498 affected and 84 unaffected) from 111 families for WGS to identify genomic regions associated with increased risk of LOAD. Selected individuals include 229 European ancestry and 353 Caribbean Hispanic (CH) individuals (table). The European ancestry families included 2 large Dutch families from the Erasmus Rucphen Family study.5 Most of these families were recently analyzed for genetic linkage, an analysis that will be used in the analysis of the sequence data.6,7 By design, no ε4/ε4 individuals were selected for sequencing, and we prioritized ε3/ε4 individuals with earlier disease onset. Twenty-seven percent of families had at least 1 case with autopsy confirmation.

View this table:
Table

Sample demographics for family and case-control studies

ADSP case-control design.

Over 30,000 samples were considered for inclusion in the case-control design. All cases met NINCDS-ADRDA criteria for possible, probable, or definite AD, had documented age at onset or age at death (for pathologically verified cases), and APOE genotyping. All controls were at least 60 years old and were free of dementia by direct, documented cognitive assessment. Three primary case-control selection strategies were evaluated, and ultimately, a design was chosen that targeted cases with minimal risk as predicted by known risk factors (age, sex, and APOE) and targeted controls with the least probability of conversion to AD by age 85 years. The details and rationale of the case-control selection process and the evaluation of alternate study designs are described in detail in Appendix 2.

In total, we selected 5,096 cases and 4,965 controls under the chosen design (table). We selected 682 additional unrelated cases from additional multiplex families that had a strong family history for LOAD. Because some of these 682 cases arose from CH multiplex families, we included 171 cognitively normal CH control samples in the WES.

The sequencing of the nearly 600 whole genomes and 11,000 whole exomes has been completed; the data sets are currently available to the research community through qualified access (dbGaP study phs000572.v7.p4). This data set will be used to identify genetic factors influencing AD risk and protection and will be a critical resource for the LOAD research community.

Standard protocol approvals, registrations, and patient consents.

This study has the approval of the institutional review boards of participating institutions, and informed consent was obtained from all patients.

Acknowledgments

Acknowledgment: The Alzheimer's Disease Sequencing Project (ADSP) comprises 2 Alzheimer's Disease (AD) genetics consortia and 3 National Human Genome Research Institute (NHGRI)-funded Large Scale Sequencing and Analysis Centers (LSAC). The 2 AD genetics consortia are the Alzheimer's Disease Genetics Consortium (ADGC) funded by the NIA (U01 AG032984), and the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) funded by the NIA (R01 AG033193), the National Heart, Lung, and Blood Institute (NHLBI), other NIH institutes, and other foreign governmental and nongovernmental organizations. The Discovery Phase analysis of sequence data is supported through UF1AG047133 (to G. Schellenberg, L.A. Farrer, M.A. Pericak-Vance, R. Mayeux, and J.L. Haines); U01AG049505 to S. Seshadri; U01AG049506 to E. Boerwinkle; U01AG049507 to E. Wijsman; and U01AG049508 to A. Goate. Data generation and harmonization in the Follow-up Phases is supported by U54AG052427 (to G. Schellenberg and Wang). The ADGC cohorts include Adult Changes in Thought (ACT), 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, the 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) and the Washington University Sequencing Project (WUSP), the Columbia University Hispanic–Estudio Familiar de Influencia Genetica de Alzheimer (EFIGA), the University of Toronto (UT), and Genetic Differences (GD). The CHARGE cohorts with funding provided by 5RC2HL102419 and HL105756, include the following: the Atherosclerosis Risk in Communities (ARIC) Study which is conducted as a collaborative study supported by NHLBI contracts (HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, and HHSN268201100012C), the Austrian Stroke Prevention Study (ASPS), the Cardiovascular Health Study (CHS), the Erasmus Rucphen Family Study (ERF), the Framingham Heart Study (FHS), and the Rotterdam Study (RS). The 3 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 Investigators institutions and at the National Cell Repository for Alzheimer's Disease (NCRAD, U24AG021886) at Indiana University funded by the 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 the NIA and at the Database for Genotypes and Phenotypes (dbGaP) funded by the NIH. This research was supported in part by the Intramural Research Program of the NIH and the National Library of Medicine. Contributors to the Genetic Analysis Data included Study Investigators on projects that were individually funded by the NIA and other NIH institutes, and by private U.S. organizations, or foreign governmental or nongovernmental organizations.

Footnotes

  • Supplemental data at Neurology.org/ng

  • Author contributions: All authors contributed to the work presented in this article. Drafting: the primary manuscript was prepared by G.W.B., with significant contributions from S.S., E.B., G.S., M.A.P.-V., and J.C.B. All authors participated in the revision and editing of the manuscript. Concept and design: primary study concept and design was by G.W.B., with significant contributions from E.R.M., J.C.B., M.A.P.-V., J.L.H., R.M., S.S., E.B., G.S., L.A.F., A.G., C.M.v.D., A.C.N., and A.D. Analysis and interpretation: review of family data was performed by M.A.P.-V., R.M., E.B., S.S., C.M.v.D., and T.M.F. Primary statistical analyses were performed by G.W.B., with additions from J.C.B., A.C.N., E.R.M., S.-H.C., A.D., and S.S. All authors participated in the interpretation and discussion of results. Acquisition of data: sample data were contributed by C.M.v.D., A.D., T.M.F., L.A.F., A.G., J.L.H., M.A.P.-V., E.B., R.M., S.S., and G.S. Statistical analyses: statistical analyses were primarily conducted by G.W.B.; additional analyses conducted by J.C.B., A.C.N., E.R.M., S.-H.C., A.D., and S.S. (affiliations noted above, all academic). Study supervision and coordination: primary study supervision and coordination was by G.S., R.M., E.B., M.A.P.-V., J.L.H., S.S., A.G., L.A.F., and E.W.

  • Study funding: Supported by the NIH, primarily the NIA, NHLBI, and NHGRI. Primary support includes the Alzheimer's Disease Genetics Consortium (ADGC) funded by the NIA (U01 AG032984), and the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) funded by the NIA (R01 AG033193), 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). Additional funding of contributing sites is noted in the Acknowledgment section.

  • Disclosures: G.W. Beecham receives funding from the NIH and the Department of Defense. J.C. Bis reports no disclosures. E.R. Martin has served on the editorial board of Frontiers in Statistical Genetics and Methodology and holds US Patent No. 6697739 Test for Linkage and Association in General Pedigrees: The Pedigree Disequilibrium Test. S.-H. Choi reports no disclosures. A. DeStefano has received research support from the NIH. C.M. van Duijn and M. Fornage report no disclosures. S.B. Gabriel is an employee of a nonprofit entity and has been a consultant for WilmerHale Guidepoint Global. D.C. Koboldt receives a coinventor's share of license revenue for VarScan (a software tool for next-generation sequencing analysis), with licensing and disbursements handled by his former institution, Washington University in St. Louis. In the past 2 years, paying licensees included Bina Technologies, Janssen, Fera Science, Philips Electronics, and WuXi NextCODE. D.E. Larson has received research support from the NIH and St. Jude Children's Research Hospital. A.C. Naj has received speaker honoraria from Pfizer; has served on the editorial board of PLoS One; and has received research support from the NIA, the BrightFocus Foundation, and Penn Institute on Aging. B.M. Psaty serves on the DSMB of a clinical trial for a device funded by the manufacturer (Zoll Lifecor) and on the Steering Committee for the Yale Open Data Access project funded by Johnson & Johnson; is a contributing writer for JAMA; and has received research support from an entity/entities listed in the Acknowledgment section. W. Salerno has been a consultant for Lasergen. W.S. Bush serves on the editorial boards of BMC BioData Mining and PLoS One; and has received research support from the NIA. T.M. Foroud has served on the scientific advisory boards of the National Advisory Council on Alcohol Abuse and Alcoholism, the Washington University Alzheimer's Disease Research Center, and the NIA Genetics of Alzheimer's Disease Data Storage Site; has received travel funding from the Michael J. Fox Foundation for Parkinson's Research, the NIH, the University of Pittsburgh, and the University of Chicago; has received travel funding and speaker honoraria from the University of Texas at Austin; and has received research support from the NIH, the US Department of Defense, Columbia University, San Diego State University, the University of California, San Diego, the University of Massachusetts, the University of Pennsylvania, the State University of New York, and the Michael J. Fox Foundation for Parkinson's Research. E. Wijsman has served on the scientific advisory board of NIH NHLBI National Registry of Genetically Triggered Thoracic Aortic Aneurysms and Cardiovascular Conditions; has served on the editorial boards of BMC Proceedings and Bioinformatics; and has received research support from the NIH and the Metropolitan Life Foundation Award for Medical Research. L.A. Farrer has served on the editorial boards of the American Journal of Alzheimer's Disease & Other Dementias and Clinical Genetics; has 1 patent pending for the use of PLXNA4 as a drug target and biomarker for Alzheimer disease; has been a consultant for Novartis Pharmaceuticals, Gerson Lehrman, Guidepoint Global, and Finnegan & Associates, LLP; and has received research support from the NIH, the Fidelity Foundation, and the Thome Memorial Foundation. A. Goate has served on the scientific advisory board of Denali Therapeutics; has received travel funding from the Rainwater Foundation; has served on the editorial board of eLife; holds patents for PSEN mutations in AD, Tau mutations in FTD, and TDP43 mutations in ALS\FTD; has been a consultant for Cognition Therapeutics and AbbVie; has received research support from F-Prime, the NIA, the Rainwater Charitable Foundation, and the JPB Foundation; and receives royalty payments from Taconic Industries for tau mutation patent. J.L. Haines has served on the editorial boards of Neurogenetics, Current Protocols in Human Genetics, and Human Molecular Genetics; receives publishing royalties from John Wiley & Sons; and has received research support from the NIH. M.A. Pericak-Vance serves on the editorial boards of Genetic Epidemiology, Molecular Autism, and Advances in Genomics and Gene Expression; her immediate family member Dr. Jeffery Vance has served on the editorial boards of Neurology Genetics and American Journal of Neurodegenerative Disease; and she has received research support from the NIH and the JJ Vance Foundation. E. Boerwinkle has received a speaker honorarium from the American Society for Bone and Mineral Research; is a Scientific Officer at Codified Genomics, LLC; and has received research support from the NIH. R. Mayeux has received research support from the NIH. S. Seshadri serves on the editorial boards of Journal of Alzheimer's Disease, Stroke, and Neurology and has received research support from the NIA. G. Schellenberg has served on the scientific advisory boards of Alzheimer's Association, the Society of Progressive Supranuclear Palsy, the Alzheimer Research Consortium, the Peebler PSP Research Foundation, the United Kingdom Parkinson Disease Center, University College London, the Alzheimer's Disease Sequence Project, the Structural Variant Work Group, Mayo Clinic, Rochester, Udall Center, the University of Miami, and the Oxford Parkinson's Disease Centre; has received travel funding/speaker honoraria from the Alzheimer's Disease Center, CurePSP, the University of California, San Diego, Keystone Symposia, the University of California, the Institute for Memory Impairment and Neurological Disorders, Biomarkers in Neuropsychiatric Disorders (Toronto, Canada), the NIH, Novartis, the McKnight Brain Institute, the University of Florida, the NIA, the Keep Memory Alive Center (Cleveland Clinic), the Lou Ruvo Center for Brain Health, PSP/Lewy Body Disease Think-Tank, the American Association of Neuropathologists, the Fusion Conference, “What does the future hold?” (Tucson, AZ), “Progressive supranuclear palsy genetics—update” (La Jolla, CA), the Center for Public Health Genomics, Genome Sciences Seminar, the University of Virginia, Neurology Grand Rounds, and Columbia University; has served on the editorial boards of the Journal of Neural Transmission, Alzheimer's Research, the American Journal of Alzheimer's Disease and other Dementias, Neurodegenerative Diseases, Current Alzheimer Research, and Pathology and Laboratory Medicine International; is a professor at the University of Pennsylvania; and has received research support from the NIA/NIH, CurePSP, and CBD Solutions. Go to Neurology.org/ng for full disclosure forms. The Article Processing Charge was funded by the authors.

  • Received May 1, 2017.
  • Accepted in final form August 17, 2017.

This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND), which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.

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