Are Alzheimer's and coronary artery diseases genetically related to longevity?

Abstract

Introduction: In the last decade researchers have attempted to investigate the shared genetic architecture of longevity and age-related diseases and assess whether the increased longevity in certain people is due to protective alleles in the risk genes for a particular condition or whether there are specific "longevity" genes increasing the lifespan independently of age-related conditions' risk genes. The aim of this study was to investigate the shared genetic component between longevity and two age-related conditions.

Methods: We performed a cross-trait meta-analysis of publicly available genome-wide data for Alzheimer's disease, coronary artery disease and longevity using a subset-based approach provided by the R package ASSET.

Results: Despite the lack of strong genetic correlation between longevity and the two diseases, we identified 38 genome-wide significant lead SNPs across 22 independent genomic loci. Of them 6 were found to be potentially shared among the three traits mapping to genes including DAB2IP, DNM2, FCHO1, CLPTM1, and SNRPD2. We also identified 19 novel genome-wide associations for the individual traits in this study. Functional annotations and biological pathway enrichment analyses suggested that pleiotropic variants are involved in clathrin-mediated endocytosis and plasma lipoprotein and neurotransmitter clearance processes.

Discussion: In summary, we have been able to advance in the knowledge of the genetic overlap existing among longevity and the two most common age-related disorders.

Keywords: Alzheimer's disease; coronary artery disease; longevity; pleiotropy; subset-based analysis (ASSET).

Figure 1

Summary results per genomic locus identified from the subset-based meta-analysis (ASSET) after LD clumping. The histograms display the size of genomic loci, the number of both candidate SNPs and mapped genes, and the number of genes physically located within the locus.

Figure 2

Functional consequences of ASSET candidate SNPs on genes. The histograms display the proportion of SNPs (all SNPs in LD with independent significant SNPs) which have corresponding functional annotation assigned by ANNOVAR. Bars are colored by log2 (enrichment) relative to all SNPs in the selected reference panel. Enrichment is computed as (proportion of SNPs with an annotation)/(proportion of SNPs with an annotation relative to all available SNPs in the reference panel). Proportion is the fraction of candidate SNPs with the corresponding annotation. Fisher's exact test (two side) is performed for each annotation. *p < 0.05; **p < 0.05/11.