Strong impact of natural-selection-free heterogeneity in genetics of age-related phenotypes.

Journal Article (Journal Article)

A conceptual difficulty in genetics of age-related phenotypes that make individuals vulnerable to disease in post-reproductive life is genetic heterogeneity attributed to an undefined role of evolution in establishing their molecular mechanisms. Here, we performed univariate and pleiotropic genome-wide meta-analyses of 20 age-related phenotypes leveraging longitudinal information in a sample of 33,431 individuals and dealing with the natural-selection-free genetic heterogeneity. We identified 142 non-proxy single nucleotide polymorphisms (SNPs) with phenotype-specific (18 SNPs) and pleiotropic (124 SNPs) associations at genome-wide level. Univariate meta-analysis identified two novel (11.1%) and replicated 16 SNPs whereas pleiotropic meta-analysis identified 115 novel (92.7%) and nine replicated SNPs. Pleiotropic associations for most novel (93.9%) and all replicated SNPs were strongly impacted by the natural-selection-free genetic heterogeneity in its unconventional form of antagonistic heterogeneity, implying antagonistic directions of genetic effects for directly correlated phenotypes. Our results show that the common genome-wide approach is well adapted to handle homogeneous univariate associations within Mendelian framework whereas most associations with age-related phenotypes are more complex and well beyond that framework. Dissecting the natural-selection-free genetic heterogeneity is critical for gaining insights into genetics of age-related phenotypes and has substantial and unexplored yet potential for improving efficiency of genome-wide analysis.

Full Text

Duke Authors

Cited Authors

  • Kulminski, AM; Huang, J; Loika, Y; Arbeev, KG; Bagley, O; Yashkin, A; Duan, M; Culminskaya, I

Published Date

  • March 2018

Published In

Volume / Issue

  • 10 / 3

Start / End Page

  • 492 - 514

PubMed ID

  • 29615537

Pubmed Central ID

  • PMC5892700

Electronic International Standard Serial Number (EISSN)

  • 1945-4589

International Standard Serial Number (ISSN)

  • 1945-4589

Digital Object Identifier (DOI)

  • 10.18632/aging.101407


  • eng