This proposal, entitled the Consortium for Alzheimer's Sequence Analysis (CASA) describes plans to analyze whole exome and whole genome sequence data generated from subjects with Alzheimer's disease (AD) and elderly normal controls. These data will be generated by the National Human Genome Institute Large-Scale Sequence Program. The goal of the planned analyses is to identify genes that have alleles that protect against or increase susceptibility to AD. This is a multiple PI proposal, a collaboration between five senior AD genetics investigators (Farrer, Haines, Mayeux, Pericak-Vance, Schellenberg). CASA has 4 cores and 3 projects. Core A is the Administrative core that will coordinate all aspects of CASA. Core B is the Analysis Statistics and Innovation core that will design and assist analysis by other cores/projects and devise novel methods of statistical analysis. Core C is that Data Management and Information Transfer Core that will implement analyses designed by Core B and the projects. Core C will provide high-performance computing for CASA. These three cores are mandated by FOA PAR-12-183. Core D is the In Silico Functional Genomics Core that will annotate AD-associated variants and perform pathway and interaction analyses. Project 1 will evaluate variants detected in the sequence data for association with AD to identify protective and susceptibility alleles. Project 2 will evaluate sequence data from multiplex AD families to identify variants associated with AD risk and protection, and evaluate variant co-segregation with AD. Project 3 will focus on structural variants (insertion-deletions, copy number variants, and chromosomal rearrangements). The project will use existing methods and develop and implement novel approaches for detecting structural variants. The projects and cores are highly interdependent. For example, structural variants identified by Project 3 will be integrated with single nucleotide AD-associated variants identified by Projects 1 and 2. Likewise variants identified by Project 1 will be tested in the family-based data sets. Core B will assist all projects in designing analyses and Core C will implement Project analyses. Core D will annotate and help interpret results from all projects.

Public Health Relevance

Alzheimers disease (AD) affects 3-5 million people costing the US over $100 billion dollars/year. By 2050, there will be 16 million people with AD costing the US $1 trillion dollars/year. There is no way to prevent AD, and current therapies are marginally effective and do not halt disease progression. More fundamental knowledge on disease mechanism is needed and will come in part from the genetic studies proposed here.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Multi-Year Funded Research Project Cooperative Agreement (UF1)
Project #
Application #
Study Section
Special Emphasis Panel (ZAG1-ZIJ-5 (J1))
Program Officer
Miller, Marilyn
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Pennsylvania
Schools of Medicine
United States
Zip Code
Butkiewicz, Mariusz; Haines, Jonathan L; Bush, William S (2017) Introducing COCOS: codon consequence scanner for annotating reading frame changes induced by stop-lost and frame shift variants. Bioinformatics 33:1561-1562
Butkiewicz, Mariusz; Bush, William S (2016) In Silico Functional Annotation of Genomic Variation. Curr Protoc Hum Genet 88:Unit 6.15
Kunkle, Brian W; Jaworski, James; Barral, Sandra et al. (2016) Genome-wide linkage analyses of non-Hispanic white families identify novel loci for familial late-onset Alzheimer's disease. Alzheimers Dement 12:2-10
Kenna, Kevin P; van Doormaal, Perry T C; Dekker, Annelot M et al. (2016) NEK1 variants confer susceptibility to amyotrophic lateral sclerosis. Nat Genet 48:1037-42
Tosto, Giuseppe; Reitz, Christiane (2016) Genomics of Alzheimer's disease: Value of high-throughput genomic technologies to dissect its etiology. Mol Cell Probes 30:397-403
Butkiewicz, Mariusz; Cooke Bailey, Jessica N; Frase, Alex et al. (2016) Pathway analysis by randomization incorporating structure-PARIS: an update. Bioinformatics 32:2361-3
Reitz, Christiane (2015) Novel susceptibility loci for Alzheimer's disease. Future Neurol 10:547-558
Barral, Sandra; Cheng, Rong; Reitz, Christiane et al. (2015) Linkage analyses in Caribbean Hispanic families identify novel loci associated with familial late-onset Alzheimer's disease. Alzheimers Dement 11:1397-1406