Kulminski, Alexander M. and Loika, Yury and Huang, Jian and Arbeev, Konstantin G. and Bagley, Olivia and Ukraintseva, Svetlana and Yashin, Anatoliy I. and Culminskaya, Irina (2019) Pleiotropic Meta-Analysis of Age-Related Phenotypes Addressing Evolutionary Uncertainty in Their Molecular Mechanisms. Frontiers in Genetics, 10. ISSN 1664-8021
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Abstract
Age-related phenotypes are characterized by genetic heterogeneity attributed to an uncertain role of evolution in establishing their molecular mechanisms. Here, we performed univariate and pleiotropic meta-analyses of 24 age-related phenotypes dealing with such evolutionary uncertainty and leveraging longitudinal information. Our analysis identified 237 novel single nucleotide polymorphisms (SNPs) in 199 loci with phenotype-specific (61 SNPs) and pleiotropic (176 SNPs) associations and replicated associations for 160 SNPs in 68 loci in a modest sample of 26,371 individuals from five longitudinal studies. Most pleiotropic associations (65.3%, 115 of 176 SNPs) were impacted by heterogeneity, with the natural-selection—free genetic heterogeneity as its inevitable component. This pleiotropic heterogeneity was dominated (93%, 107 of 115 SNPs) by antagonistic genetic heterogeneity, a phenomenon that is characterized by antagonistic directions of genetic effects for directly correlated phenotypes. Genetic association studies of age-related phenotypes addressing the evolutionary uncertainty in establishing their molecular mechanisms have power to substantially improve the efficiency of the analyses. A dominant form of heterogeneous pleiotropy, antagonistic genetic heterogeneity, provides unprecedented insight into the genetic origin of age-related phenotypes and side effects in medical care that is counter-intuitive in medical genetics but naturally expected when molecular mechanisms of age-related phenotypes are not due to direct evolutionary selection.
Item Type: | Article |
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Subjects: | Bengali Archive > Medical Science |
Depositing User: | Unnamed user with email support@bengaliarchive.com |
Date Deposited: | 06 Feb 2023 07:32 |
Last Modified: | 17 Jun 2024 07:16 |
URI: | http://science.archiveopenbook.com/id/eprint/233 |