Functional genomics approach to elucidate the role of genes implicated in cognitive function in human longevity

Abstract

There is increasing evidence that longevity-associated genes protect against cognitive decline, dementia and Alzheimer's disease, suggesting common underlying physiologic pathways act at the interface of longevity and cognitive function. Genome-wide association studies conducted in long-lived individuals suggest that individuals with exceptional longevity harbor protective variants, most of which are rare in frequency in general population, that buffer against deleterious variants that increase common disease risks. We hypothesized that protective variants in genes implicated in cognitive function may promote exceptional longevity in humans. The ultimate goals of this study are to identify functional genetic variants in candidate genes implicated in cognitive function and to reveal underlying molecular mechanisms by which these variants contribute to human longevity.;To accomplish these goals, first I established and streamlined a high-throughput target capture and next-generation sequencing (Capture-seq) to discover all possible variants including rare variants in 568 candidate genes in 51 centenarians and 51 controls and performed gene-based association analysis to identify candidate longevity-associated genes. Second , I established and streamlined a cost-effective pooled-DNA target capture sequencing (Pool-seq) to identify all variants in top candidate genes and pathways in 450 centenarians and 500 controls and performed genotyping analysis for candidate variants. Third, I conducted functional analyses both in silico and in vitro cell culture models to investigate molecular outcomes of prioritized longevity-associated gene variants. By taking this hierarchical, multidisciplinary approach, I found a genetic signature of human longevity in PKC and NF-kappaB signaling, providing a molecular insight by which genetic variants in these pathways contribute to longevity in humans.;In summary, by performing a state-of-the-art variant discovery study and a combined in silico analysis and in vitro functional analysis, we provide evidence that the evolutionary conserved PKC and NF-kappaB signaling pathway may play a role in human longevity as has been demonstrated in model organisms.