Research Paper Volume 10, Issue 3 pp 492—514
Strong impact of natural-selection–free heterogeneity in genetics of age-related phenotypes
- 1 Biodemography of Aging Research Unit, Social Science Research Institute, Duke University, Durham, NC 27708, USA
received: December 12, 2017 ; accepted: March 24, 2018 ; published: March 29, 2018 ;https://doi.org/10.18632/aging.101407
How to Cite
Copyright: Kulminski et al. This is an open‐access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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.