Genome-wide association (GWA) methods have now been successfully used to detect disease-related susceptibility genes numerous genetically complex disorders. In these studies, a critical element for success is that the sample size be large enough so that there is adequate power to detect genes with small effect sizes at a genome-wide significance level. As an example, type 2 diabetes, susceptibility genes with odds ratios of ~1.3 were detected with cohorts of ~15,000 cases and a comparable number of controls. For AD, preliminary GWA studies utilized samples of 1,000 cases or less have been performed. These studies have the power to detect modest effect loci but not the small effect genes typically found in the analysis of other complex disorders. The primary goals of this application are to: 1) Assemble enough AD cases and comparable elderly normal controls to detect small effect loci;2) Perform GWA studies using a high- density genotyping platform to detect small effect loci that contribute to AD susceptibility;3) Analyze a large familial AD collection using the same genotyping platform so that family-based methods can be applied to AD gene discovery;4) Provide a DNA, phenotype, and genotype resource of well- characterized AD cases, mild cognitive impaired (MCI) subjects, and controls for the genetics community to analyze. The cases, MCI subjects, and controls will be the approximately 16,500 subjects currently being studied by the 29 NIA-funded Alzheimer's Disease Centers (ADC's). Extensive phenotype data as a Uniform Data Set (UDS) for these subjects is in a centralized database (National Alzheimer Coordinating Center or NACC). DNA from these subjects will be deposited in the National Cell Repository for Alzheimer's Disease (NCRAD), an existing repository. A second cohort will be multiplex families with extensive phenotype data and DNA currently available from the NIMH Genetics Initiative repository. This study will make use of the infrastructure of the existing Alzheimer's Disease Genetics Consortium (ADGC) to coordinate that data from multiple GWA studies for subsequent meta and combined analysis of multiple AD GWA studies, and to provide investigators with AD GWA data for subsequent analysis.

Public Health Relevance

Alzheimer's disease affects over 5 million people in the US costing the Federal Government over $100 billion dollars/year. Because our population is aging, in 2050, if the disease remains untreatable, there will be 16 million people in the US with AD costing $1 trillion dollars/year. Presently there are no methods of preventing AD or halting progression. Thus, more fundamental knowledge on disease mechanism is needed.

National Institute of Health (NIH)
National Institute on Aging (NIA)
High Impact Research and Research Infrastructure Programs (RC2)
Project #
Application #
Study Section
Special Emphasis Panel (ZAG1-ZIJ-5 (O4))
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
Lobach, Iryna; Sampson, Joshua; Alekseyenko, Alexander et al. (2018) Case-control studies of gene-environment interactions. When a case might not be the case. PLoS One 13:e0201140
Lobach, Iryna (2018) Bias in parameter estimates due to omitting gene-environment interaction terms in case-control studies. Genet Epidemiol 42:838-845
Sims, Rebecca (see original citation for additional authors) (2017) Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease. Nat Genet 49:1373-1384
Mez, Jesse; Chung, Jaeyoon; Jun, Gyungah et al. (2017) Two novel loci, COBL and SLC10A2, for Alzheimer's disease in African Americans. Alzheimers Dement 13:119-129
Monsell, Sarah E; Mock, Charles; Fardo, David W et al. (2017) Genetic Comparison of Symptomatic and Asymptomatic Persons With Alzheimer Disease Neuropathology. Alzheimer Dis Assoc Disord 31:232-238
Jun, Gyungah R; Chung, Jaeyoon; Mez, Jesse et al. (2017) Transethnic genome-wide scan identifies novel Alzheimer's disease loci. Alzheimers Dement 13:727-738
Bonham, Luke W; Geier, Ethan G; Fan, Chun C et al. (2016) Age-dependent effects of APOE ?4 in preclinical Alzheimer's disease. Ann Clin Transl Neurol 3:668-77
Karch, Celeste M; Ezerskiy, Lubov A; Bertelsen, Sarah et al. (2016) Alzheimer's Disease Risk Polymorphisms Regulate Gene Expression in the ZCWPW1 and the CELF1 Loci. PLoS One 11:e0148717
Mez, Jesse; Mukherjee, Shubhabrata; Thornton, Timothy et al. (2016) The executive prominent/memory prominent spectrum in Alzheimer's disease is highly heritable. Neurobiol Aging 41:115-121
Ridge, Perry G; Hoyt, Kaitlyn B; Boehme, Kevin et al. (2016) Assessment of the genetic variance of late-onset Alzheimer's disease. Neurobiol Aging 41:200.e13-200.e20

Showing the most recent 10 out of 41 publications