How Genes Modulate Patterns of Aging-Related Changes on the Way to 100: Biodemographic Models and Methods in Genetic Analyses of Longitudinal Data

摘要

Background and ObjectiveTo clarify mechanisms of genetic regulation of human aging and longevity traits, a number of genome-wide association studies (GWAS) of these traits have been performed. However, the results of these analyses did not meet expectations of the researchers. Most detected genetic associations have not reached a genome-wide level of statistical significance, and suffered from the lack of replication in the studies of independent populations. The reasons for slow progress in this research area include low efficiency of statistical methods used in data analyses, genetic heterogeneity of aging and longevity related traits, possibility of pleiotropic (e.g., age dependent) effects of genetic variants on such traits, underestimation of the effects of (i) mortality selection in genetically heterogeneous cohorts, (ii) external factors and differences in genetic backgrounds of individuals in the populations under study, the weakness of conceptual biological framework that does not fully account for above mentioned factors. One more limitation of conducted studies is that they did not fully realize the potential of longitudinal data that allow for evaluating how genetic influences on life span are mediated by physiological variables and other biomarkers during the life course. The objective of this paper is to address these issues.