Alzheimer's Disease Sequencing Project

Background (from the ADSP MOU)

On February 7, 2012, a new Presidential Initiative was announced to fight Alzheimer’s Disease (AD). As part of this effort, the National Human Genome Research Institute (NHGRI) was asked by the Director of the National Institutes of Health (NIH) to use $25M already committed to its

Large-Scale Sequencing Centers (LSSC) for genomic studies in AD. The NIH director asked the National Institute on Aging (NIA) and the NHGRI to work together to develop and execute a large scale sequencing project to analyze the genomes of a large number of well characterized individuals in order to identify a broad range of AD risk and protective gene variants, with the ultimate goal of facilitating 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. The project developed jointly by NIA and NHGRI is called the Alzheimer’s Disease Sequencing Project (ADSP).

The overarching goals of the ADSP are to: (1) identify new genomic variants contributing to increased risk of developing AD, (2) identify new genomic variants contributing to protection against developing AD, and (3) provide insight as to why individuals with known risk factor variants escape from developing AD. 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). Using existing samples from NIH funded and other studies,the NHGRI LSSC will produce the DNA sequence data and generate variant calls, that will be made available to the scientific community through NIH-approved data repositories. Statistical analysis of the sequence data is anticipated to identify new genetic risk and protective factors. Both fundamental scientific discovery and leading edge analytic approaches will be needed to achieve the research goals. The ADSP will conduct and facilitate analysis of sequence data to extend previous discoveries that may ultimately result in new directions for AD therapeutics.

The specific aims of the ADSP are to: (1) identify protective genomic variants in older adults at risk for AD, (2) identify new risk variants among AD cases, and (3) examine these factors in multi-ethnic populations as applicable in order to identify new pathways for disease

prevention. The samples for the ADSP will be selected from well-characterized, cohorts of individuals characterized for AD diagnosis as well as having known AD genetic risk factors.

CHARGE involvement in ADSP:

• Approximately 20% of the cases and 40% of the ADSP controls for the Exome Sequencing aim will come from CHARGE member studies.

• Some families for the Whole Genome Sequencing component will be drawn from member cohorts of the CHARGE consortium.