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Study Design

Background

Last Update: June 26, 2018

An initiative that is responsive to the National Alzheimer’s Project Act (NAPA) was announced to fight Alzheimer's Disease (AD) on February 7, 2012. The project is called the Alzheimer's Disease Sequencing Project (ADSP). The project is sequencing and analyzing the genomes of a large number of well characterized individuals in order to identify a broad range of AD risk and protective gene variants. The ultimate goal is to facilitate the identification of new pathways for therapeutic approaches and prevention. The analysis will also provide insight as to why individuals with known risk factor genes escape from developing AD. Relevant funding opportunity announcements are listed at the end of this document.

The overarching goals of the ADSP are to: (1) identify new genomic variants contributing to increased risk of developing Late-Onset Alzheimer's Disease (LOAD), (2) identify new genomic variants contributing to protection against developing Alzheimer's Disease (AD), (3) provide insight as to why individuals with known risk factor variants escape from developing AD, and (4) examine these factors in multi-ethnic populations as applicable in order to identify new pathways for disease prevention. These factors will be studied in multi-ethnic populations to identify new pathways for disease prevention. Such a study of human genomic variation and its relationship to health and disease requires examination of a large number of study participants and needs to capture information about common and rare variants (both single nucleotide and copy number) in well phenotyped individuals. The ADSP conducts and facilitates analysis of sequence data to extend previous discoveries that may ultimately result in new directions for AD therapeutics. Data are being made available to the scientific community through NIH-approved data repositories including the database for genotypes and phenotypes (dbGaP) and the NIA Genetics of Alzheimer’s Disease Data Storage Site (NIAGADS). Investigators who are outside of the ADSP are encouraged to access and analyze these data.

From 2012 through 2017 the National Human Genome Research Institute (NHGRI) funded Large Scale Sequencing and Analysis Centers (LSACs): Baylor College of Medicine Human Genome Sequencing Center, the Broad Institute, the McDonnell Genome Institute at Washington University, and the New York Genome Center, participated in generating whole genome and whole exome sequence data for the first part of the study. In 2018, and Department of Defense-funded Uniformed Services University of the Health Sciences (USUHS), The American Genome Center (TAGC), began participating in the project.

The ADSP research plan includes (See figure 1):

  1. The ADSP Discovery Phase
  2. The ADSP Extension Phase
  3. The ADSP Follow-Up Phase
  4. The ADSP Augmentation Phase

Figure 1. For the initial part of the ADSP (Discovery and Discovery Extension Phases), the National Human Genome Research Institute (NHGRI) and the National Institute on Aging (NIA) developed a large scale sequencing project to analyze the genomes of a large number of well characterized individuals. Data for ADSP Augmentation Studies are generated under NIA and private funding and are shared with the research community through NIAGADS. For the ADSP Follow-Up Study sequencing of cohorts from ethnically diverse populations is being done by USUHS under NIA funding. This part of the study will include Caucasians, African Americans, Hispanics, and Asian cohorts.

 

Description of the Major Components of the ADSP

 

The ADSP Discovery Phase

The initial phase of the ADSP research plan is called the Discovery Phase. Samples were selected from well-characterized study cohorts of individuals with or without an AD diagnosis and the presence or absence of known risk factor genes. The ADSP generated three sets of genome sequence data for these samples as part of the Discovery Phase: (1) WGS for 584 samples from 113 multiplex families (two or more affected per family), (2) Whole Exome Sequence (WES) for 5,096 AD cases and 4,965 controls, and (3) WES of an Enriched sample set comprised of 853 AD cases from multiply affected families and 171 Hispanic controls. The Case-Control and Enriched Case Study spans 24 cohorts provided by the Alzheimer’s Disease Genetics Consortium (ADGC) and the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium (see infrastructure below.

As part of the Discovery Phase, the NIA ADSP genetics investigators funded under PAR-12-183 and the NHGRI funded Large Scale Sequencing and Analysis Centers (LSACs) conducted analysis of sequence data, including quality assessments and variant calling. Analysis of the Discovery Phase sequence data is anticipated to identify many new variations in the genome that may be implicated as new genetic risk or protective factors in older adults at risk for AD. Because the initial analysis of WGS data in subjects from families multiply affected with AD revealed the occurrence of variations in the genome that were intergenic and intronic, in February of 2016 the external consultants to the ADSP recommended that further sequencing for the project should be of whole genomes.

The fully quality control checked (QC’d) data for the Discovery Phase study using Genome Reference Consortium Human Build 37 (GRCh37) was released in March of 2016 through the database of Genotypes and Phenotypes (dbGaP). Discovery Phase data called on Genome Reference Consortium Human Build 38 (GRCh38) are being shared through NIAGADS. Applicants for sequence data can obtain: (1) cleaned, quality control checked sequence data, (2) information on the composition of the study cohorts (e.g. case-control, family based, and epidemiology cohorts), (3) descriptions of the study cohorts included in the analysis, (4) accompanying phenotypic information such as age at disease onset, gender, diagnostic status, and cognitive measures, and (5) epidemiological information such as educational level and certain demographic data available on the subjects genotyped. Details about the samples are available at the NIA Genetics of Alzheimer ‘s Disease Data Storage Site (NIAGADS)

The ADSP Discovery Extension Study

This study has two parts, a Family-Based and a Case-Control component.

The ADSP Discovery Family-Based Extension Study:

To further assess the genomes in multiply affected families, under funding provided by NHGRI, an additional 428 samples were whole genome sequenced. This included 107 additional samples from families studied under the Discovery Phase, 207 samples from 77 new families, and 114 Hispanic Controls. This portion of the study is called the Discovery Extension Phase. The Family Based Study spans seven cohorts provided by the Alzheimer’s Disease Genetics Consortium (ADGC) and the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium (see infrastructure below). Quality control checked Build 38 data for this portion of the study are available through NIAGADS.

The ADSP Discovery Case-Control Based Extension Study:

Under funding provided by NHGRI, an additional 3,000 subjects were whole genome sequenced. This included 1,466 cases and 1,534 controls. Of these 1,000 each of Non-Hispanic White (NHW), Caribbean Hispanic (CH), and African American (AA) descent were sequenced. Of these a total of 739 autopsy samples were sequenced [568 cases (500 NHW cases and 68 AA cases) and 171 controls (164 NHW and 7 AA)]. The Case-Control and Enriched Case Study spans 24 cohorts provided by the Alzheimer’s Disease Genetics Consortium (ADGC) and the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. Quality control checked Build 38 data for this portion of the study are available through NIAGADS.

The Alzheimer’s Disease Neuroimaging Initiative (ADNI)

A public-private partnership, the purpose of ADNI is to develop a multisite, longitudinal, prospective, naturalistic study of normal cognitive aging, mild cognitive impairment (MCI), and early Alzheimer's disease as a public domain research resource to facilitate the scientific evaluation of neuroimaging and other biomarkers for the onset and progression of MCI and Alzheimer's disease. In 2017, ADNI geneticists began collaborations with the ADSP. Whole genome sequence data on 809 ADNI subjects (cases, mild cognitive impairment, and controls) have been harmonized using the ADSP pipeline. Data will be available through NIAGADS for joint analysis. Applicants for ADNI data must receive permission to access the data by first applying through ADNI.

The ADSP Follow-up Study (FUS)

A majority of the samples from the ADSP Discovery and Discovery Extension phases are non-Hispanic white (NHW) in origin, making the addition of ethnically diverse samples to the study critical to identification of both shared and novel genetic risk factors for Alzheimer’s disease (AD) between populations. Collection and sequencing of ethnically diverse cohorts is emphasized in the ADSP FUS, the goal being that additional existing cohorts with unrelated AD cases that encompass the richest possible ethnic diversity be given the highest priority for inclusion. To fulfill the goals of this ADSP FUS, eight existing elderly cohorts of African-American (AA) and pan-Hispanic (pan-HI) ancestry with a total of 13,745 samples (N=2,456 AA AD cases and 4,126 AA controls and 2,588 Hispanic AD cases and 4,475 Hispanic controls) are being whole genome sequenced (WGS) at USUHS TAGC in coordination with existing NIH-funded AD infrastructure including the National Cell Repository for Alzheimer’s Disease (NCRAD), NIAGADS, and the Genome Center for Alzheimer’s Disease (GCAD). 1,500 NHW autopsy cases and 1,500 controls are also being sequenced to increase the underpowered NHW sample with WGS. Brief descriptions of the cohorts selected for sequencing are provided below.

ADSP FUS Cohort Descriptions

The Alzheimer’s Disease Genetics Consortium (ADGC) African-American Cohort, is a cohort of 1,240 cases and 1,643 controls collected from several cohorts including from the GenerAAtions Study, Indianapolis-Ibadan Study, Rush University, University of Miami, Case Western Reserve University, North Carolina A & T University, and The Mirage Study.

The Mexican Health and Aging Study (MHAS), sponsored by the National Institutes of Health (NIH) National Institute on Aging (NIA), is prospective study of health and aging in Mexico that began in 2001 (MHAS 2001). The ADSP FUS will sequence 200 MHAS cases and 2,600 MHAS controls from this study starting in 2018.

The REasons for Geographic And Racial Differences in Stroke (REGARDS) Study, sponsored by the NIH’s National Institute for Neurological Disorders and Stroke (NINDS), is a national study of risk factors for stroke in adults 45 years or older that includes measurements of traditional stroke risk factors such as blood pressure and cholesterol levels, and an echocardiogram of the heart (Longstreth 2006). The ADSP FUS will sequence 1,000 African-American cases and 1,500 African-American controls from this study starting in 2018.

The Alzheimer’s Disease Genetics Consortium (ADGC) African-American Cohort, is a cohort of 1,240 cases and 1,643 controls collected from several cohorts including from the GenerAAtions Study, Indianapolis-Ibadan Study, Rush University, University of Miami, Case Western Reserve University, North Carolina A & T University, and The Mirage Study.

The Mexican Health and Aging Study (MHAS), sponsored by the National Institutes of Health (NIH) National Institute on Aging (NIA), is prospective study of health and aging in Mexico that began in 2001 (MHAS 2001). The ADSP FUS will sequence 200 MHAS cases and 2,600 MHAS controls from this study starting in 2018.

The REasons for Geographic And Racial Differences in Stroke (REGARDS) Study, sponsored by the NIH’s National Institute for Neurological Disorders and Stroke (NINDS), is a national study of risk factors for stroke in adults 45 years or older that includes measurements of traditional stroke risk factors such as blood pressure and cholesterol levels, and an echocardiogram of the heart (Longstreth 2006). The ADSP FUS will sequence 1,000 African-American cases and 1,500 African-American controls from this study starting in 2018.

The Northern Manhattan Study (NOMAS), funded by the NIH’s NINDS, is a study focused on stroke or related neurological syndromes (Sacco et al. 2004). The ADSP FUS will sequence 88 Hispanic cases and 175 Hispanic controls, and 22 African-American cases and 43 African-American controls from this study starting in 2019.

The Puerto Rican 10/66 Study, is an Alzheimer’s Disease International study of dementia in Puerto Rico that began in 2007 (Prince et al. 2007). The ADSP FUS will sequence 1000 Puerto Rican cases and 1000 Puerto Rican controls from this study starting in 2021.

The Puerto Rican Alzheimer’s Disease Initiative (PRADI), a NIH NIA study of late-onset Alzheimer disease focused on the Caribbean-Hispanic Puerto Rican population. The ADSP FUS will sequence 500 cases and 500 controls from this study starting in 2020.

The Research in African-American Alzheimer’s Disease Initiative (REAAADI), a NIH NIA study focused on identifying genetic factors for Alzheimer disease within the African-American population in order to detect new targets for drug development and improve accessibility to Alzheimer’s disease education within the community. The ADSP FUS will sequence 300 cases and 300 controls from this study starting in 2020.

The Estudio Familiar de Influencia Genetica en Alzheimer (EFIGA) Study, a study of LOAD patients with Caribbean-Hispanic ancestry. The ADSP FUS will sequence 800 cases and 300 controls from this study starting in 2019.

The Alzheimer’s Disease Center Autopsy (ADC) Cohort includes 1,500 cases with autopsy and 1,500 controls from the National Institute on Aging’s ADC’s. These individuals are well phenotyped and will help to increase the currently underpowered NHW sample with WGS data from the ADSP Discovery and Discovery Extension Phases (1,212 cases and 524 controls).

The ADSP Augmentation Phase

The ADSP Augmentation Phase encompasses sequencing done under private and NIH funding by investigators who are not members of the ADSP. The investigators for these studies have agreed to share their GWAS, WGS and WES data with the ADSP. Private funding has been provided by industry and anonymous donors. Under the NIA AD Genetics Sharing Policy and the NIAGADS Data Distribution Agreement, individual NIA funded investigators studying the genetics and the genomics of AD provide their data to NIAGADS, and in turn these data will be shared with the ADSP. These data will be made publically available as soon as they are fully QC’d and harmonized with ADSP data.

 

Infrastructure Support for the ADS

 

Alzheimer’s Disease Genetics Consortium (ADGC)

The ADGC is a large and highly collaborative National Institute on Aging (NIA)-funded consortium in the United States dedicated to Alzheimer’s disease (AD) genetics research. The ADGC has been a major contributor to the identification of many of the recently identified genetic variants known to late onset Alzheimer’s disease (LOAD). Working with the Alzheimer’s Disease Centers (ADC), the National Alzheimer’s Coordinating Committee (NACC), and the National Cell Repository for Alzheimer’s Disease (NCRAD), the ADGC identifies and studies the genetics of well characterized AD patients and cognitively unaffected controls. The ADGC also studies subjects from families multiply affected by the disease. Single Nucleotide Polymorphisms (SNP), whole exome, and whole genome sequences from subjects agreeing to participate in these studies are generated using cutting-edge DNA technologies. These genetic data are analyzed together with genetic data from other participating studies to identify genes contributing to the risk of AD.

The Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium (CHARGE)

CHARGE was formed to facilitate genome-wide association studies meta-analyses and replication opportunities among multiple large population-based cohort studies, which collect data in a standardized fashion- a preferred method for estimating disease incidence. The design of the CHARGE includes five prospective cohort studies from the United States and Europe: the Age, Gene/Environment Susceptibility—Reykjavik Study, the Atherosclerosis Risk in Communities Study, the Cardiovascular Health Study, the Framingham Heart Study, and the Rotterdam Study. With genome-wide data on several thousand individuals, these cohort studies have a large number of health-related phenotypes, including AD, measured in similar ways.

Genome Center for Alzheimer’s Disease (GCAD)

Raw ADSP sequence data are processed and harmonized by the Genome Center for Alzheimer’s Disease (GCAD) into analysis-ready genotype data. GCAD is funded through a cooperative agreement from NIA to facilitate AD gene discovery by performing quality control checks, data harmonization, and coordination of the diverse analyses of all ADSP genetic and phenotypic data. To meet this goal, GCAD assembles all data generated by the Alzheimer’s Disease Sequence Project (ADSP) with data from non-ADSP sources, including those generated by NIA funded grants and cooperative agreements. GCAD 1) has created and now supports a collaborative network of AD genetics investigators; 2) harmonizes all genetic and phenotype data and fully annotate all variants; 3) coordinates the development and implementation of analysis protocols for all data; 4) works with NIAGADS (see below) to broadly distribute primary data, harmonized annotated analysis-ready files, and analyses results. GCAD presently handles a petabyte (PB) of level genomic data.

GCAD is collaborating with other NIH-funded large scale sequencing projects including NHLBI funded Trans-Omics for Precision Medicine (TOPMed) and NHGRI funded Centers for Common Disease Genomics (CCDG) to develop a high-quality parallel and equivalent workflow for processing whole genome sequencing experiments across NIH using the latest human reference genome assembly (hg38). This level of team work will result in facilitation of the ability to analyze data across multiple studies.

NIA Genetics of Alzheimer’s Disease Data Storage Site (NIAGADS)

NIAGADS organizes, stores, and shares data from NIA funded genetic studies. NIAGADS is funded by NIA through a cooperative agreement to build a one-stop access portal for Alzheimer’s disease genetics, in anticipation to the large influx of high-throughput sequencing data. NIAGADS currently hosts 37 high quality human genetics datasets in addition to ADSP data, with ~38,000 subjects and 24.5 billion genotypes, and has a genomics database for cross-referencing and visualizing known genomic variants and annotations with AD genetic analysis findings.

NIAGADS is the ADSP Data Coordinating Center that supports ADSP data production, management, and sharing. NIAGADS ‘s many responsibilities include to: (1) host sample information and study plan, (2) track sequencing progress, assist sample tracking, and coordinate sequencing data production and transfer, (3) schedule, prepare, and maintain public data releases, (4) manage files and datasets for ADSP workgroups, (5) maintain the ADSP website and facilitate community access to ADSP data, (6) ensure the security of sensitive data. NIAGADS is charged with developing a HIPAA/FISMA-compliant, fully featured data sharing service for ADSP using cloud technology.

Funding opportunity Announcements related to the ADS

Limited Competition: Renewal of, and Revisions to, the Alzheimer's Disease Genetics Consortium (U01): PAR-14-070

NIA Coordinating Center for Genetics and Genomics of Alzheimer's Disease (U54) RFA-AG-16-001

National Institute on Aging Genetics of Alzheimer's Disease Data Storage Site (U24) PAR-16-047

The National Institute on Aging (NIA) Late Onset of Alzheimer's Disease (LOAD) Family Based Study (FBS) (U24) PAR-16-205

National Institute on Aging Analysis of Alzheimer's Disease Genome Sequencing Project Data [U19] PAR-12-183

Alzheimer's Disease Sequencing Project (ADSP) Replication Phase Analysis Studies (U01) RFA-AG-16-002

Limited Competition: Additional Sequencing for the Alzheimer's Disease Sequencing Project (U01) PAR-16-406

Limited Competition: Analysis of Data from NIA's Alzheimer's Disease Sequencing Project Follow-Up Study (U01) PAR-17-214

Major Opportunities for Research in Epidemiology of Alzheimer's Disease and Cognitive Resilience (R01) PAR-15-356

Notice of Information: The Alzheimer's Disease Sequencing Project Policy (ADSP) on the Publication of Study-Related Data NOT-AG-16-033

Notice of Information: Alignment Among the Disease Definitions Utilized to Govern Genetic and Genomic Data Sharing for Studies Involving Alzheimer's Disease NOT-AG-17-007

NIH Genomic Data Sharing Policy NOT-OD-14-1224

Leveraging Existing Cohort Studies to Clarify Risk and Protective Factors for Alzheimer’s Disease and Related Dementias (R01): PAR-17-054

ADSP Publications including Working Group Studies

Whole-exome sequencing in 20,197 persons for rare variants in Alzheimer’s disease. Raghavan, S, and the Alzheimer’s Disease Sequencing Project. Annals of Clinical and Translational Neurology: epub ahead of print.

Quality control and integration of genotypes from two calling pipelines for whole genome sequence data in the Alzheimer's disease sequencing project. Naj AC et al, on behalf of the Alzheimer’s Disease Sequencing Project. Genomics. 2018 May 29. pii: S0888-7543(18)30281-7. doi: [Epub ahead of print].

Analysis of pedigree data in populations with multiple ancestries: Strategies for dealing with admixture in Caribbean Hispanic families from the ADSP. Nafikov RA, Nato AQ Jr, Sohi H, Wang B, Brown L, Horimoto AR, Vardarajan BN, Barral SM, Tosto G, Mayeux RP, Thornton TA, Blue E, Wijsman EM. Genet Epidemiol. 2018 Jun 3. doi: 10.1002/gepi.22133. [Epub ahead of print]

Whole genome sequencing of Caribbean Hispanic families with late-onset Alzheimer's disease. Vardarajan BN et al. on behalf of the Alzheimer's Disease Sequencing Project, Ann Clin Transl Neurol. 2018 Mar 13;5(4):406-417. eCollection 2018 Apr

Genetic Variation in Genes Underlying Diverse Dementias May Explain a Small Proportion of Cases in the Alzheimer's Disease Sequencing Project. Blue EE, et al, on behalf of the Alzheimer’s Disease Sequencing Project. Dement Geriatr Cogn Disord. 2018;45(1-2):1-17. [Epub ahead of print].

Alzheimer's Disease Sequencing Project discovery and replication criteria for cases and controls: Data from a community-based prospective cohort study with autopsy follow-up. Crane PK, Foroud T, Montine TJ, Larson EB. Alzheimers Dement. 2017 Dec;13(12):1410-1413.

Funding Sources for ADSP Discovery and Discovery Extension Data Analysis: PAR-12-183

  • UF1 AG047133. Consortium for Alzheimer’s Sequence Analysis (CASA). University of Pennsylvania, Philadelphia PA, Columbia University, NY, NY; Miami University, Mimi Fla; Case Western Reserve University, Cleveland, OH.; Boston University, Boston, MA.
  • U01 AG049505. CHARGE: Identifying Risk & Protective SNV for AD in ADSP Case-control Sample. Boston University.
  • U01 AG049506. Sequence-based Discovery of AD Risk & Protective Alleles. Baylor University, Houston, TX.
  • U01 AG049507. Sequence-based Discovery of AD Risk & Protective Alleles. University of Washington, Seattle, Washington
  • U01-AG-049508. Modifier Genes that Influence Age at Onset or Protect Against Development of Alzheimer’s Disease (AD); Icahn School of Medicine at Mount Sinai.

Funding Sources for Sequencing: ADSP Discovery Phase

  • U54HG003079. National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA
  • U54HG003273. National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA
  • U54HG003076. National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA

Funding Sources for Sequencing: ADSP Follow-Up Study PAR-16-406

  • U01 AG057659. Whole Genome Sequencing in Ethnically Diverse Cohorts for the ADSP Follow-Up Study (FUS). Miami University, Miami. FLA; Columbia University, New York, NY. Sequencing was funded as a subcontract to Uniformed Services University for the Health Sciences (USUHS), The American Genome Center (TAGC).

Acknowledgement Statement: Please cite/reference the use of dbGaP data by including the dbGaP accession phs000572.v7.p4. Additionally, use the statement listed in the Data Use Certification (DUC) Agreement to acknowledge the submitter(s) of this study. The acknowledgement statement for the ADSP is found at: www.niagads.org/adsp/content/acknowledgement-statement

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