02525nas a2200313   4500008004100000022001400041245009700055210006900152260001500221300001200236490000700248520159500255653001001850653002601860653003101886653003401917653001301951653001101964653003601975100002802011700001602039700001602055700002602071700001902097700002102116700001502137700002302152856003602175       2018                        eng d  a1945-458900aStrong impact of natural-selection-free heterogeneity in genetics of age-related phenotypes.0 aStrong impact of naturalselectionfree heterogeneity in genetics   c2018 03 29  a492-5140 v103 a<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>10aAging10aComputational Biology10aGene Expression Regulation10aGenome-Wide Association Study10aGenotype10aHumans10aPolymorphism, Single Nucleotide1 aKulminski, Alexander, M1 aHuang, Jian1 aLoika, Yury1 aArbeev, Konstantin, G1 aBagley, Olivia1 aYashkin, Arseniy1 aDuan, Matt1 aCulminskaya, Irina  uhttps://chs-nhlbi.org/node/8257