Pleiotropic Meta-Analysis of Age-Related Phenotypes Addressing Evolutionary Uncertainty in Their Molecular Mechanisms.

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • Kulminski, AM; Loika, Y; Huang, J; Arbeev, KG; Bagley, O; Ukraintseva, S; Yashin, AI; Culminskaya, I

Published Date

  • January 2019

Published In

Volume / Issue

  • 10 /

Start / End Page

  • 433 -

PubMed ID

  • 31134135

Pubmed Central ID

  • PMC6524409

Electronic International Standard Serial Number (EISSN)

  • 1664-8021

International Standard Serial Number (ISSN)

  • 1664-8021

Digital Object Identifier (DOI)

  • 10.3389/fgene.2019.00433


  • eng