Kulminski Alexander M, Huang Jian, Loika Yury, Arbeev Konstantin G, Bagley Olivia, Yashkin Arseniy, Duan Matt, Culminskaya Irina
Biodemography of Aging Research Unit, Social Science Research Institute, Duke University, Durham, NC 27708, USA.
Aging (Albany NY). 2018 Mar 29;10(3):492-514. doi: 10.18632/aging.101407.
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.
与年龄相关的表型的遗传学中存在一个概念性难题，即这些表型会使个体在生殖后期易患疾病，而这种难题归因于进化在建立其分子机制方面的作用不明确所导致的遗传异质性。在此，我们利用33431名个体样本中的纵向信息，对20种与年龄相关的表型进行了单变量和多效性全基因组荟萃分析，并处理了无自然选择的遗传异质性问题。我们在全基因组水平上鉴定出142个非代理单核苷酸多态性（SNP），它们具有表型特异性关联（18个SNP）和多效性关联（124个SNP）。单变量荟萃分析鉴定出两个新的（11.1%）并重复了16个SNP，而多效性荟萃分析鉴定出115个新的（92.7%）和9个重复的SNP。大多数新的（93.9%）和所有重复的SNP的多效性关联都受到无自然选择的遗传异质性以其非常规形式的拮抗异质性的强烈影响，这意味着直接相关表型的遗传效应具有拮抗方向。我们的结果表明，常见的全基因组方法非常适合处理孟德尔框架内的同质单变量关联，而大多数与年龄相关表型的关联更为复杂，远远超出了该框架。剖析无自然选择的遗传异质性对于深入了解与年龄相关表型的遗传学至关重要，并且在提高全基因组分析效率方面具有巨大且尚未探索的潜力。
