Culminskaya Irina, Kulminski Alexander M, Yashin Anatoli I
Biodemography of Aging Research Unit, Social Science Research Institute, Duke University, USA.
Ann Gerontol Geriatr Res. 2016;3(1). Epub 2016 May 4.
A role of non-Mendelian inheritance in genetics of complex, age-related traits is becoming increasingly recognized. Recently, we reported on two inheritable clusters of SNPs in extensive genome-wide linkage disequilibrium (LD) in the Framingham Heart Study (FHS), which were associated with the phenotype of premature death. Here we address biologically-related properties of these two clusters. These clusters have been unlikely selected randomly because they are functionally and structurally different from matched sets of randomly selected SNPs. For example, SNPs in LD from each cluster are highly significantly enriched in genes (p=7.1×10 and p=5.8×10), in general, and in short genes (p=1.4×10 and p=4.6×10), in particular. Mapping of SNPs in LD to genes resulted in two, partly overlapping, networks of 1764 and 4806 genes. Both these networks were gene enriched in developmental processes and in biological processes tightly linked with development including biological adhesion, cellular component organization locomotion, localization, signaling, (p<10, q<10 for each category). Thorough analysis suggests connections of these genetic networks with different stages of embryogenesis and highlights biological interlink of processes enriched for genes from these networks. The results suggest that coordinated action of biological processes during embryogenesis may generate genome-wide networks of genetic variants, which may influence complex age-related phenotypes characterizing health span and lifespan.
非孟德尔遗传在复杂的、与年龄相关的性状遗传学中的作用正日益得到认可。最近，我们在弗雷明汉心脏研究（FHS）中报道了两个处于广泛全基因组连锁不平衡（LD）状态的单核苷酸多态性（SNP）可遗传簇，它们与过早死亡的表型相关。在此，我们探讨这两个簇的生物学相关特性。这些簇不太可能是随机选择的，因为它们在功能和结构上与随机选择的SNP匹配集不同。例如，一般来说，来自每个簇的处于连锁不平衡状态的SNP在基因中高度显著富集（p = 7.1×10和p = 5.8×10），特别是在短基因中（p = 1.4×10和p = 4.6×10）。将处于连锁不平衡状态的SNP映射到基因上，得到了两个部分重叠的、分别包含1764个和4806个基因的网络。这两个网络在发育过程以及与发育紧密相关的生物学过程中都富含基因，包括生物黏附、细胞成分组织运动、定位、信号传导（每个类别p < 10，q < 10）。深入分析表明这些遗传网络与胚胎发生的不同阶段存在联系，并突出了这些网络中富含基因的过程之间的生物学相互联系。结果表明，胚胎发生过程中生物学过程的协同作用可能会产生全基因组范围的遗传变异网络，这可能会影响表征健康寿命和寿命的复杂的、与年龄相关的表型。
