Alzheimer's Disease Sequencing Project

Alzheimer's Disease Sequencing Project
Name	Alzheimer's Disease Sequencing Project
Abbreviation	ADSP
Established	2011
Sponsor	National Institutes of Health
Country	United States
Field	Neuroscience, Genomics

Alzheimer's Disease Sequencing Project is a large-scale coordinated effort to identify genetic variants associated with late-onset and early-onset Alzheimer's disease by applying high-throughput sequencing across multiple cohorts and populations. The initiative was supported by the National Institutes of Health, coordinated with consortia and academic centers, and linked to existing longitudinal studies to combine clinical, neuropathological, and genomic information. The project integrated data from descriptive cohorts, case-control series, and population-based studies to enable discovery of rare and common genetic contributors to neurodegeneration.

Background and objectives

The project was launched to extend findings from genome-wide association studies exemplified by discoveries following work at institutions like Harvard University, Massachusetts General Hospital, and University of California, San Francisco, aiming to move from association signals toward causal inference using whole-exome and whole-genome sequencing. Objectives included cataloging rare coding and noncoding variation across diverse ancestral groups enrolled through centers such as Mayo Clinic, Columbia University, and Johns Hopkins University, and integrating data with neuropathology from repositories like the National Institute on Aging and samples from consortia including the Alzheimer's Disease Neuroimaging Initiative and the Framingham Heart Study. The initiative also sought to inform translational pipelines at pharmaceutical and biotech partners and to guide functional follow-up through collaborations with laboratories at the Broad Institute, Wellcome Trust Sanger Institute, and university research centers.

Study design and cohorts

ADSP aggregated samples from multiple legacy cohorts and population studies, including familial series recruited by centers such as University of Washington, University of Pennsylvania, and Duke University Medical Center, as well as community-based cohorts like the Cardiovascular Health Study, Rotterdam Study, and Atherosclerosis Risk in Communities Study. Case-control datasets included participants evaluated at clinical centers affiliated with Rush University Medical Center, University of Texas Southwestern Medical Center, and University of Pittsburgh Medical Center, while neuropathologically characterized brains were contributed from brain banks such as the National Alzheimer’s Coordinating Center, Harvard Brain Tissue Resource Center, and the Banner Sun Health Research Institute. The sampling strategy permitted stratified analyses across ancestry groups represented by participants from regions connected to institutions like University of Miami, University of Southern California, and Yale University.

Sequencing methods and data processing

Sequencing workflows were executed at high-throughput centers including the Broad Institute, Cold Spring Harbor Laboratory, and the Mayo Clinic Center for Individualized Medicine, employing whole-exome sequencing (WES) and whole-genome sequencing (WGS) pipelines validated against resources like the 1000 Genomes Project and the Genome Aggregation Database. Standardized laboratory protocols referenced platforms from vendors such as Illumina and leveraged alignment and variant calling tools developed in projects like The Cancer Genome Atlas and software originating from groups at University of California, Berkeley and European Bioinformatics Institute. Joint variant calling, quality control, and annotation integrated databases and consortium resources including dbSNP, ClinVar, and functional annotations comparable to work at the ENCODE Project and the Human Genome Project.

Key findings and discoveries

Analyses identified rare variants in genes previously implicated via linkage at centers like Washington University in St. Louis and new risk loci paralleling discoveries made in GWAS led by teams at Imperial College London and Karolinska Institute. Reported associations extended knowledge of pathways involving amyloid and tau that trace to mechanistic studies at Massachusetts Institute of Technology and Stanford University, and implicated immune-related genes echoing immunogenetics research from University of Cambridge and The Rockefeller University. Findings stimulated functional follow-up using model systems developed at Cold Spring Harbor Laboratory and Salk Institute, and influenced pharmacogenomic and therapeutic strategies pursued by companies headquartered near San Francisco, Boston, and Cambridge, UK.

Data sharing and resources

ADSP data were deposited into controlled-access repositories supported by agencies such as the National Center for Biotechnology Information and were linked to phenotype and imaging data streams like those curated by the Alzheimer's Disease Neuroimaging Initiative and the National Alzheimer's Coordinating Center. Investigators from institutions including Johns Hopkins University, University of California, Los Angeles, and Vanderbilt University accessed harmonized datasets via data use agreements to perform secondary analyses. The consortium model reflected data-sharing practices seen in projects like the 1000 Genomes Project and the International HapMap Project, enabling cross-study meta-analyses with cohorts from Columbia University, University of North Carolina, and international partners at University College London.

Ethical, legal, and privacy considerations

The project implemented consent frameworks and governance consistent with policies from the National Institutes of Health and institutional review boards at participating centers including Yale University, University of Michigan, and University of Chicago. Controlled-access mechanisms addressed participant privacy in coordination with repositories such as the Database of Genotypes and Phenotypes and adhered to standards comparable to those promulgated after debates involving entities like European Commission data protection initiatives and national regulations in the United States. Engagement with minority recruitment and return-of-results considerations aligned with outreach models practiced by community-engaged programs at Howard University and research centers at Morehouse School of Medicine.

Category:Genomics projects