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ADSP Umbrella Study

The Study as a Whole: The ADSP “Umbrella” Study

Last Update: June 6, 2016

On February 7, 2012, a Presidential Initiative announced genetic efforts to fight Alzheimer’s disease (AD). The National Institute on Aging (NIA) and the National Human Genome Research Institute (NHGRI) were asked to develop and execute a large scale sequencing project to identify AD risk and protective gene variants. The initiative is called the “Alzheimer’s Disease Sequencing Project” (ADSP). The long-term objective is to facilitate identification of new pathways for therapeutic approaches and prevention of AD. $25M was committed by NHGRI to its Large-Scale Sequencing and Analysis Centers (LSACs) for genomic studies. Next generation sequencing was to include whole exome sequencing (WES) and whole genome sequencing (WGS) and analysis on large numbers of well characterized subjects to identify AD risk and protective gene variants.  The ADSP is an integral component of a National Alzheimer Project Act (NAPA) milestone for strategy 1.B: “Expand Research Aimed at Preventing and Treating Alzheimer's Disease.  Action 1. B. 2. Expand genetic epidemiologic research to identify risk and protective factors for Alzheimer's Disease.”

This study of human genetic variation and its relationship to health and disease involves a large number of study participants and will capture not only common single nucleotide variations but also rare copy number and structural variants that are increasingly thought to play an important role in complex disease. The overarching goals of the ADSP are to:  

  • Identify new genes involved in AD
  • Identify gene alleles contributing to increased risk for or protection against the disease
  • Provide insight as to why individuals with known risk factor genes escape from developing AD
  • Identify potential avenues for therapeutic approaches and prevention of the disease

The ADSP has robust support from the NIA funded National Cell Repository for Alzheimer’s Disease (NCRAD), the National Alzheimer’s Coordinating Center (NACC), the Alzheimer’s Disease Centers (ADCs), the NIA Genetics of Alzheimer’s Disease Data Storage Site (NIAGADS), and the NIA Coordinating Center for Genetics and Genomics of Alzheimer’s Disease (CGAD).

Qualified investigators 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, and (4) accompanying phenotypic information such as age at disease onset, gender, diagnostic status, and cognitive measures.

Below are the files available to download based on Institutional Review Board (IRB) consent:

  • Sequencing Data: contains sequencing read and mapping information (BAM files) stored as the Sequencing Read Archive (SRA) format and quality controlled genotypes in PLINK and variant call formatted (VCF).
  • Subject Phenotype Data: contains phenotype data from consented study subjects being sequenced.
  • Connecting Family Phenotype Data: contains phenotype data from consented connecting family member subjects not being sequenced.
  • Sample Attributes Data: contains attributes of study samples including body site where the sample was collected, analyte type, tumor status (not applicable to ADSP), and where the sample was sequenced.
  • Subject Consent: contains a list of all subjects being sequenced as well as those that are connecting family members not being sequenced, their associated consent group, and their dbGaP aliases if they have previously been submitted for another project.
  • Subject Sample Mapping: relates each Subject ID with the sequenced Sample ID.
  • Pedigree File: records genealogical relationships of subjects within the study.

Application for the ADSP data can be made at: ADSP dbGaP.

The ADSP research plan includes:

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

The ADSP Discovery Phase

The ADSP Discovery Phase is comprised of a Family-Based study and a Case-Control Study. Sample sets were selected from well-characterized, ethnically diverse study cohorts of individuals with or without an AD diagnosis and the presence or absence of known risk factor genes.  The Family-Based study includes whole genome sequencing (WGS) on multiplex families where DNA for at least two members per family was available and includes Caucasians and Caribbean Hispanic families.  The Case-Control sample set includes Caucasians and Caribbean Hispanic families.  The Family Based Study spans seven cohorts while the Case-Control and Enriched Case Study spans twenty four cohorts provided by the Alzheimer’s Disease Genetics Consortium (ADGC) and the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium.

Sequencing was performed at three NHGRI funded large scale sequencing centers: Baylor, Broad, and Washington University. NIA has provided funding for the analysis of Discovery Phase ADSP data through cooperative agreements under NIA PAR-12-183.html. Analysis of the Discovery Phase sequence data is anticipated to identify many new sequence variants that may be implicated as new genetic risk and protective factors in older adults at risk for AD. The fully QC’d data for the Discovery Phase study was released in March of 2016. Investigators who are outside of the ADSP are encouraged to access and analyze these data.  

The Discovery Phase dataset contains WGS data on 584 subjects from 113 families, and pedigree data for more than 4000 subjects; WES data on 5096 cases 4965 controls; and whole exome sequence data on an additional 853 (682 Cases [510 Non-Hispanic, 172 Hispanic]), and 171 Hispanic Control subjects from families that are multiply affected with AD. Details about the samples are available at NIAGADS.  

The ADSP Discovery Extension Phase

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.  To this end, 107 subjects from families studied in the Discovery Phase, 213 subjects from new families, and 115 Hispanic controls were selected and sequenced by the LSACs.  Subjects were selected based on how informative the data could be for analysis of family data.  This Phase is called the “ADSP Discovery Extension Phase.” 

The ADSP Follow-up Phase

The ADSP Follow-Up Study (FUS) is comprised of several components. First, WGS on up to 3,000 subjects (cases and controls) is to be done by LSACs with funds remaining from the original $25M allocation provided by NHGRI. Second, studies funded under RFA AG 10-002 (NIA) will provide genome wide association study (GWAS), WES and WGS data on cases and controls and on multiply affected families to the ADSP. Third, 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 will provide their data to NIAGADS and the Database of Genotypes and Phenotypes (dbGaP), and in turn these data will be shared with the ADSP. Fourth, NIA has in the planning stages sequencing and analysis on additional subjects. These data will be made publically available as soon as they are fully QC’d. 

The ADSP Augmentation Phase

The ADSP Augmentation Phase encompasses sequencing done under private funding, in part funded by NIA.  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. These data will be made publically available as soon as they are fully QC’d.

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