Alzheimer's Disease Sequencing Project
Funded under a number of cooperative agreements and research grant awards, the Alzheimer’s Disease Sequencing Project (ADSP) is comprised of more than 100 investigators from dozens of institutions across the United States.
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, and;
- Identify potential avenues for therapeutic approaches and prevention of the 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.
To obtain statistical significance, analysis of a large number of samples is required. Existing phenotype data and DNA samples are identified and analyzed by the Alzheimer’s Disease Genetics Consortium (ADGC) and the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium (CHARGE). The Alzheimer’s Disease Centers (ADCs) provide DNA for genetic analysis by the ADSP. The National Alzheimer’s Coordinating Center (NACC) manages phenotypic data from Alzheimer’s patients enrolled at the Alzheimer’s Disease Centers and provides it to the ADSP.
Components of the ADSP
The ADSP is divided into three phases (ADSP Study Design). Whole genome and whole exome sequencing is complete for the Discovery Phase; and whole genome sequencing is complete for the Discovery Extension Phase; data analysis is in progress. The Follow-Up Study (FUS) Phase commenced in 2017 and is to be completed in 2023. Each of these components has a case-control and a family based study design.
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. Funding for the sequencing was provided by the National Human Genome Research Institute (NHGRI).
The ADSP generated three sets of genome sequence data for these samples as part of the Discovery Phase:
- Whole Genome Sequencing (WGS) for 584 samples from 113 multiplex families;
- Whole Exome Sequence (WES) for 5,096 AD cases and 4,965 controls, and;
- WES of an Enriched sample set comprised of 853 AD cases from multiply affected families and 171 Hispanic controls.
Sequence data are available by application to the Database for Genotypes and Phenotypes (dbGaP) or the NIA Genetics of Alzheimer's Disease Data Storage site (NIAGADS).
Applicants can obtain:
- Cleaned, quality control checked sequence data;
- Information on the composition of the study cohorts (e.g. case-control, family based, and epidemiology cohorts);
- Descriptions of the study cohorts included in the analysis;
- Accompanying phenotypic information such as age at disease onset, gender, diagnostic status, and cognitive measures, and;
- Epidemiological information such as educational level and certain demographic data available on the subjects genotyped.
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.
Discovery Extension Phase
To further assess the genomes in multiply affected families, under funding provided by NHGRI, an additional ~430 samples were sequenced by the Centers for Common Disease Genomics (CCDGs). This portion of the study is called the Discovery Extension Phase.
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 by the CCDGs. This included 107 additional samples from families studied under the Discovery Phase, 207 samples from 77 new families, and 114 Hispanic Controls.
The ADSP Discovery Case-Control Based Extension Study: Also 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)].
Follow Up Phase
The ADSP Discovery Phase has identified a number of variations in the genomes of individuals affected with AD. These findings will be pursued in the ADSP Follow-Up Study (FUS). The long-term goals of the ADSP FUS are:
- To move the field closer to enabling prediction of who will develop AD;
- To fully reveal the genetic architecture of AD in multiple ethnic groups;
- To better understand the underpinnings of AD pathogenesis; and
- To aid the quest for therapeutic targets.
- To examine the AD genome in diverse populations.
The ADSP Discovery Phase and the ADSP Follow-Up Study are described under PAR-16-406 and at the ASDP study description webpage. The ADSP FUS is leveraging existing infrastructure and collaborations; to ensure continuity of ADSP participation. It provides funds for acquisition, archiving, sequencing, quality control (QC) checking, performing genome wide association studies (GWAS), and sharing of data generated on a large number of samples from individuals affected by AD for WGS, as appropriate. Racial/ethnic diversity continues to be an ADSP priority. Well phenotyped subjects were selected with an emphasis on autopsy-confirmed cases/controls and availability of longitudinal data. Funds are being provided for both sequencing and data analysis. This effort will pursue rare variants as comprehensively as possible, including consideration of statistical power, and exploration of a range of different populations containing those that are currently under-represented in sequencing studies.