@article {8257,
	title = {Strong impact of natural-selection-free heterogeneity in genetics of age-related phenotypes.},
	journal = {Aging (Albany NY)},
	volume = {10},
	year = {2018},
	month = {2018 03 29},
	pages = {492-514},
	abstract = {<p>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.</p>},
	keywords = {Aging, Computational Biology, Gene Expression Regulation, Genome-Wide Association Study, Genotype, Humans, Polymorphism, Single Nucleotide},
	issn = {1945-4589},
	doi = {10.18632/aging.101407},
	author = {Kulminski, Alexander M and Huang, Jian and Loika, Yury and Arbeev, Konstantin G and Bagley, Olivia and Yashkin, Arseniy and Duan, Matt and Culminskaya, Irina}
}
