Aging and Longevity in Humans: Functional Annotation of Single Nucleotide Variants in 1000 Genomes

Abstract

Human aging is a gradual decrease in cellular integrity that contributes to multiple complex disorders such as Neurodegenerative disorders, Cancer, Diabetes and Cardiovascular diseases. Since the completion of Human Genome Project nearly a decade ago, the focus has shifted towards the identification of Single Nucleotide Polymorphisms (SNPs) that are correlated with complex disorders. In this regard, Genome-wide association studies (GWAS) play a key role in discovering genetic variations that may contribute towards disease vulnerability. However, mostly disease-associated SNPs lie within non-coding part of the genome; majority of the variants are also present in Linkage Disequilibrium (LD) with the genome-wide significant SNPs (GWAS lead SNPs). We asked whether non-coding variants play a crucial role in the cellular homeostasis; we performed functional annotation of SNPs that lie in the non-coding genomic region ─ using ENCODE datasets via RegulomeDB, HaploregV2 and rSNPBase. Moreover, various bioinformatics tools including STRING, DISEASES, and Gene Network informs us about known and predicted protein-protein interactions, disease-gene associations and gene networks with shared pathways respectively. Overall 600 SNPs were analyzed, out of which 291 returned RegulomeDB scores of 1-6. It was observed that just 4 out of those 291 SNPs show strong evidence for potential regulatory effects with RegulomeDB score < 3, while none of them includes any GWAS lead SNP. Nevertheless, this study demonstrates that by utilizing epigenetic data sets, it is possible to discover potential regulatory variants – moving from GWAS towards understanding disease pathways.