Copy number variation associates with mortality in long‐lived individuals: a genome‐wide assessment

Abstract

SummaryCopy number variants (CNVs) represent a significant source of genetic variation in the human genome and have been implicated in numerous diseases and complex traits. To date, only a few studies have investigated the role of CNVs in human lifespan. To investigate the impact of CNVs on prospective mortality at the extreme end of life, where the genetic component of lifespan appears most profound, we analyzed genomewide CNV data in 603 Danish nonagenarians and centenarians (mean age 96.9 years, range 90.0–102.5 years). Replication was performed in 500 long‐lived individuals from the Leiden Longevity Study (mean age 93.2 years, range 88.9–103.4 years). First, we assessed the association between the CNV burden of each individual (the number of CNVs, the average CNV length, and the total CNV length) and mortality and found a significant increase in mortality per 10 kb increase in the average CNV length, both for all CNVs (hazard ratio (HR) = 1.024, P = 0.002) and for duplications (HR = 1.011, P = 0.005), as well as per 100 kb increase in the total length of deletions (HR = 1.009, P = 0.0005). Next, we assessed the relation between specific deletions and duplications and mortality. Although no genome–wide significant associations were discovered, we identified six deletions and one duplication that showed consistent association with mortality in both or either of the sexes across both study populations. These results indicate that the genome–wide CNV burden, specifically the average CNV length and the total CNV length, associates with higher mortality in long‐lived individuals.

Allelic distribution of ABO gene in Chinese centenarians

“…[33][34][35][36] Over the past decades, huge efforts have been made to evaluate the genetic contribution to human longevity, leading to the identification of several genes or loci associated with centenarians or exceptionally long-lived individuals through a candidate gene approach or genome-wide association study. [21][22][23]37,38 Human ABO blood groups are genetically determined and have been shown to influence diseases and personalities 39 ; therefore, they could possibly influence lifespan, including longevity.…”

Involvement of SPATA31 copy number variable genes in human lifespan

“…In fact, it is unlikely that causative copy number polymorphisms would be picked up in GWAS experiments, since copy number changes tend to evolve faster than their associated SNPs. There have also been two association studies for mortality in long-lived individuals which have focused on copy number variants [ 39 , 40 ]. However, the regions identified in these studies do not overlap with the annotations of the SPATA31 genes.…”

Somatically acquired structural genetic differences: a longitudinal study of elderly Danish twins

“…Sample estimates of signal intensity values (log R ratio (LRR) and B allele frequency (BAF)) for each SNP were exported from GenomeStudio (Illumina Inc.), and the population frequency of the B allele of included SNPs was supplied from another study. 12 GC correction 13 was applied to correct signal intensity waves associated with the GC content in the 500 kb on each side of the SNPs as specified by the UCSC GC annotation file (http://hgdownload.cse.ucsc.edu/ goldenPath/hg19/database/gc5Base.txt.gz).…”