Cognitive decline among older persons is a large and growing public health problem. To date, studies of decline in cognitive function seeking to identify the responsible genetic variants have been largely limited to linkage and candidate gene association studies using the more extreme categorical phenotype of Alzheimer's disease. These approaches have identified several rare and one well-validated common risk allele, the APOE ?4 allele, but the results have also shown substantial inconsistency. A theme of the proposed work is that much of this inconsistency is attributable to the designs typically used in these studies, and that an approach using the design features of population-based studies can complement existing genetic studies. These features (adequate size, rigorous and prospective designs, and participation from a high proportion of age-eligible residents of a defined geographic area) are especially pertinent to efforts to deconstruct the mixture of genetic and non-genetic factors that is found in complex diseases. The proposed work combines outstanding ability to characterize variation in the human genome at the Broad Institute with the rich characterization of the cognitive decline phenotype from two longitudinal studies: an exploratory cohort from a long-term study of cognitive decline (the Religious Orders Study or ROS) and a confirmatory sample from a rigorous population study (the Chicago Health and Aging Project or CHAP). Advantages of these studies include: (1) existing longitudinal data on decline in cognitive function, (2) availability of DMA samples from most subjects, (3) extensive records of non-genetic covariates and, (4) for the confirmatory cohort, a rigorous base in the general population and an ethnic composition of 50% non- Hispanic black and 50% non-Hispanic white. It is proposed to conduct a genome-wide association scan (550,000 SNPs) in 940 people of European ancestry from the exploratory cohort to identify loci associated with cognitive decline. Using a panel of 1500 SNPs selected according to strength of association with cognitive decline, associations found in the exploratory cohort will be validated in the 1128 people of European ancestry from the confirmatory cohort. Validated alleles will be assessed in the 1128 African Americans from the confirmatory cohort and fine mapping will be conducted for alleles found to be validly associated with cognitive decline among European American or African American subjects. ? ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG030146-02
Application #
7499600
Study Section
Special Emphasis Panel (ZRG1-HOP-B (02))
Program Officer
Wagster, Molly V
Project Start
2007-09-30
Project End
2012-07-31
Budget Start
2008-08-01
Budget End
2009-07-31
Support Year
2
Fiscal Year
2008
Total Cost
$611,861
Indirect Cost
Name
Rush University Medical Center
Department
Type
Organized Research Units
DUNS #
068610245
City
Chicago
State
IL
Country
United States
Zip Code
60612
Bennett, Rachel E; Robbins, Ashley B; Hu, Miwei et al. (2018) Tau induces blood vessel abnormalities and angiogenesis-related gene expression in P301L transgenic mice and human Alzheimer's disease. Proc Natl Acad Sci U S A 115:E1289-E1298
De Jager, Philip L; Ma, Yiyi; McCabe, Cristin et al. (2018) A multi-omic atlas of the human frontal cortex for aging and Alzheimer's disease research. Sci Data 5:180142
Felsky, Daniel; Patrick, Ellis; Schneider, Julie A et al. (2018) Polygenic analysis of inflammatory disease variants and effects on microglia in the aging brain. Mol Neurodegener 13:38
McAninch, Elizabeth A; Rajan, Kumar B; Evans, Denis A et al. (2018) A Common DIO2 Polymorphism and Alzheimer Disease Dementia in African and European Americans. J Clin Endocrinol Metab 103:1818-1826
Dobbyn, Amanda; Huckins, Laura M; Boocock, James et al. (2018) Landscape of Conditional eQTL in Dorsolateral Prefrontal Cortex and Co-localization with Schizophrenia GWAS. Am J Hum Genet 102:1169-1184
Deming, Yuetiva; Dumitrescu, Logan; Barnes, Lisa L et al. (2018) Sex-specific genetic predictors of Alzheimer's disease biomarkers. Acta Neuropathol 136:857-872
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
Ben-Avraham, Dan; Karasik, David; Verghese, Joe et al. (2017) The complex genetics of gait speed: genome-wide meta-analysis approach. Aging (Albany NY) 9:209-246
Felsky, Daniel; Xu, Jishu; Chibnik, Lori B et al. (2017) Genetic epistasis regulates amyloid deposition in resilient aging. Alzheimers Dement 13:1107-1116

Showing the most recent 10 out of 88 publications