title: Large common deletions associate with mortality at old age.
abstract: Copy-number variants (CNVs) are a source of genetic variation that increasingly are associated with human disease. However, the role of CNVs in human lifespan is to date unknown. To identify CNVs that influence mortality at old age, we analyzed genome-wide CNV data in 5178 participants of Rotterdam Study (RS1) and positive findings were evaluated in 1714 participants of the second cohort of the Rotterdam Study (RS2) and in 4550 participants of Framingham Heart Study (FHS). First, we assessed the total burden of rare (frequency <1%) and common (frequency >1%) CNVs for association with mortality during follow-up. These analyses were repeated by stratifying CNVs by type and size. Secondly, we assessed individual common CNV regions (CNVR) for association with mortality. We observed that the burden of common but not of rare CNVs influences mortality. A higher burden of large (≥ 500 kb) common deletions associated with 4% higher mortality [hazard ratio (HR) per CNV 1.04, 95% confidence interval (CI) 1.02-1.07, P = 5.82 × 10(-5)] in the 11 442 participants of RS1, RS2 and FHS. In the analysis of 312 individual common CNVRs, we identified two regions (11p15.5; 14q21.3) that associated with higher mortality in these cohorts. The 11p15.5 region (combined HR 1.59, 95% CI 1.31-1.93, P = 2.87 × 10(-6)) encompasses 41 genes, of which some have previously been related to longevity, whereas the 14q21.3 region (combined HR 1.57, 95% CI 1.19-2.07, P = 1.53 × 10(-3)) does not encompass any genes. In conclusion, the burden of large common deletions, as well as common CNVs in 11p15.5 and 14q21.3 region, associate with higher mortality.
authors.affiliation: Department of Epidemiology, Erasmus Medical Center, Rotterdam, CA 3000, The Netherlands. m.kuningas@erasmusmc.nl
authors.forename: Maris
authors.initials: M
authors.lastname: Kuningas
authors.forename: Karol
authors.initials: K
authors.lastname: Estrada
authors.forename: Yi-Hsiang
authors.initials: YH
authors.lastname: Hsu
authors.forename: Kannabiran
authors.initials: K
authors.lastname: Nandakumar
authors.forename: André G
authors.initials: AG
authors.lastname: Uitterlinden
authors.forename: Kathryn L
authors.initials: KL
authors.lastname: Lunetta
authors.forename: Cornelia M
authors.initials: CM
authors.lastname: van Duijn
authors.forename: David
authors.initials: D
authors.lastname: Karasik
authors.forename: Albert
authors.initials: A
authors.lastname: Hofman
authors.forename: Joanne
authors.initials: J
authors.lastname: Murabito
authors.forename: Fernando
authors.initials: F
authors.lastname: Rivadeneira
authors.forename: Douglas P
authors.initials: DP
authors.lastname: Kiel
authors.forename: Henning
authors.initials: H
authors.lastname: Tiemeier
mesh_terms: D000328:Adult; D000368:Aged; D000375:Aging / Q000235:genetics*; D002880:Chromosomes, Human, Pair 11 / Q000235:genetics; D056915:DNA Copy Number Variations / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D008136:Longevity / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009026:Mortality; D017384:Sequence Deletion / Q000235:genetics*