Work

Epistatic Effects on Aging Traits in Sets of Genes Selected With Different Biological Assumptions

Year: 2017

Type: article

Abstract: Several hundred genes have been associated with aging and longevity in various studies. There are also genes and SNPs that do not show individual effects on aging-related traits; however, they may still influence such traits as result of genetic interactions (GxG), also referred to as epistasis. Proper selection of biologically justified candidate genes may help increase chances of capturing the GxG effects on aging and longevity traits and improve interpretation. In this study we estimated GxG effects on aging-related phenotypes in three sets of genes selected based on different assumptions about their biological connections, and compared results across these sets to see how they are influenced by prior biological knowledge. The three sets of genes were selected based on results of our own association studies with phenotypes of physical aging, and on current knowledge about gene functions and their involvement in aging and health, as follows: (i) 53 “aging” genes from the literature, including key genes from known interacting aging pathways (IGF-1/AKT, TP53 and mTOR mediated); (ii) 43 “disease” genes from the NHGRI GWAS Catalog, including genes located in genomic regions enriched for genome-wide significant effects on complex diseases, such as cancer, AD, CHD, diabetes; (iii) 12 genes corresponding to the top SNPs that influenced multiple phenotypes of physical aging in our own analyses of CHS, MESA, FHS and ARIC studies. We selected all SNPs in these three groups of genes available in data, and estimated the effect of pairwise SNPs epistasis on longevity (survival 85+) and phenotypes of physical aging, such as Rosow-Breslau physical ability (R-B), age at BMI maximum, age at menopause, eGFR and hematocrit. Then we compared results of analyses among the groups. No significant GxG effects were found for genes from group (ii) representing major diseases. We identified significant GxG effects on longevity and age at menopause for BCL2 and IGF1R from ‘aging’ group (i), and on longevity and R-B for NRG1 and NRG3 genes from group (iii). The latter genes are located on different chromosomes but both code for ligands of ERBB4, and are both involved in neurons recovery, so they are closely biologically related. These results support pre-selecting biologically relevant and interacting candidate genes for estimating statistical epistasis effects on aging and longevity.

Source: Innovation in Aging

DOI: 10.1093/geroni/igx004.4482