Project 3 An emerging problem for societies in developed countries is extending years of healthy life. Specialists in biology and genetics argue that major breakthrough in the field can be achieved by revealing genetic variants which can be involved in regulation of health in late life. A puzzling problem is that traits of late life are not the result of direct evolutionary selection that reinforces the role of life-course-related processes in an organism in heterogeneous environment which contribute to a complex spectrum of actions of genes on traits of late life. Analysis of the role of this complexity in genetic effects is not in mainstream of genome-wide association studies (GWAS). The objective of this subproject is to identify genetic underpinnings of major human diseases and related traits of late life using state-of-the-art methods addressing the role of life-course-related processes in an organism shaping genetic associations in heterogeneous environment and to dynamically integrate the revealed allelic variants into the individuals'health-related changes during life course. This challenging goal requires a rich data on the life course health-related processes assessed in the Framingham Heart Study (FHS), the Atherosclerosis Risk in Communities Study (ARIC), the Cardiovascular Health Study (CHS), the Multi-Ethnic Study of Atherosclerosis (MESA), the Late Onset Alzheimer's Disease Family Study (LOADFS), the Health and Retirement Survey (HRS), and the Long Life Family Study (LLFS).
Aim 1. Reveal genetic variants associated with quantitative phenotypes of physiological health given time-repeated observations for the same individuals using the FHS, ARIC, CHS, and MESA.
Aim 2. Reveal genetic variants associated with risks of major human diseases using the FHS, ARIC, CHS, MESA, HRS, and LOADFS.
Aim 3. Elucidate the role of the revealed allelic variants in lifespan and conduct dynamic integration.
Aim 4. Dissect biological role of genes for the revealed SNPs and construct integrated variants.

Public Health Relevance

This project directly addresses concerns which are of inherent relevance to public health including concern on genetic predisposition to medical complications and side-effects as a result of complex nature of gene action on health traits and concern on whether such genes can be considered as eariy life targets for preventive interventions as a result of their important role in health changes during the individuals'life course.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Program Projects (P01)
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Special Emphasis Panel (ZAG1-ZIJ-8 (J2))
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Duke University
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Yashin, Anatoliy I; Arbeev, Konstantin G; Arbeeva, Liubov S et al. (2016) How the effects of aging and stresses of life are integrated in mortality rates: insights for genetic studies of human health and longevity. Biogerontology 17:89-107
Yashin, Anatoliy I; Zhbannikov, Ilya; Arbeeva, Liubov et al. (2016) Pure and Confounded Effects of Causal SNPs on Longevity: Insights for Proper Interpretation of Research Findings in GWAS of Populations with Different Genetic Structures. Front Genet 7:188
Ukraintseva, Svetlana; Yashin, Anatoliy; Arbeev, Konstantin et al. (2016) Puzzling role of genetic risk factors in human longevity: ""risk alleles"" as pro-longevity variants. Biogerontology 17:109-27
Kulminski, Alexander M; Loika, Yury; Culminskaya, Irina et al. (2016) Explicating heterogeneity of complex traits has strong potential for improving GWAS efficiency. Sci Rep 6:35390
Yashin, Anatoliy I; Arbeev, Konstantin G; Wu, Deqing et al. (2016) How Genes Modulate Patterns of Aging-Related Changes on the Way to 100: Biodemographic Models and Methods in Genetic Analyses of Longitudinal Data. N Am Actuar J 20:201-232
He, Liang; Sillanpää, Mikko J; Silventoinen, Karri et al. (2016) Estimating Modifying Effect of Age on Genetic and Environmental Variance Components in Twin Models. Genetics 202:1313-28
Kulminski, Alexander M; Raghavachari, Nalini; Arbeev, Konstantin G et al. (2016) Protective role of the apolipoprotein E2 allele in age-related disease traits and survival: evidence from the Long Life Family Study. Biogerontology 17:893-905
Arbeev, Konstantin G; Cohen, Alan A; Arbeeva, Liubov S et al. (2016) Optimal Versus Realized Trajectories of Physiological Dysregulation in Aging and Their Relation to Sex-Specific Mortality Risk. Front Public Health 4:3
Arbeev, Konstantin G; Ukraintseva, Svetlana V; Yashin, Anatoliy I (2016) Dynamics of biomarkers in relation to aging and mortality. Mech Ageing Dev 156:42-54
Kulminski, Alexander M; Culminskaya, Irina; Arbeev, Konstantin G et al. (2015) Birth Cohort, Age, and Sex Strongly Modulate Effects of Lipid Risk Alleles Identified in Genome-Wide Association Studies. PLoS One 10:e0136319

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