Copy 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.

© 2015 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.

Overview publication

TitleCopy number variation associates with mortality in long-lived individuals: a genome-wide assessment.
DateFebruary 1st, 2016
Issue nameAging cell
Issue numberv15.1:49-55
DOI10.1111/acel.12407
PubMed26446717
AuthorsNygaard M, Debrabant B, Tan Q, Deelen J, Andersen-Ranberg K, de Craen AJ, Beekman M, Jeune B, Slagboom PE, Christensen K & Christiansen L
Keywordsaging, copy number variation, deletions, genetics, long-lived individuals, mortality
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