Large common deletions associate with mortality at old age.

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.

[1]  Paola Sebastiani,et al.  Genome-Wide Association Studies (GWAS) , 2019, Definitions.

[2]  Bradley P. Coe,et al.  Genome structural variation discovery and genotyping , 2011, Nature Reviews Genetics.

[3]  B. Burke,et al.  Altered expression and coregulation of dopamine signalling genes in schizophrenia and bipolar disorder , 2011, Neuropathology and applied neurobiology.

[4]  Ewout J. N. Groen,et al.  A large genome scan for rare CNVs in amyotrophic lateral sclerosis. , 2010, Human molecular genetics.

[5]  L. Poon,et al.  HRAS1 and LASS1 with APOE are associated with human longevity and healthy aging , 2010, Aging cell.

[6]  Yun Li,et al.  METAL: fast and efficient meta-analysis of genomewide association scans , 2010, Bioinform..

[7]  Raquel E. Gur,et al.  Strong synaptic transmission impact by copy number variations in schizophrenia , 2010, Proceedings of the National Academy of Sciences.

[8]  Sudha Seshadri,et al.  A meta-analysis of four genome-wide association studies of survival to age 90 years or older: the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium. , 2010, The journals of gerontology. Series A, Biological sciences and medical sciences.

[9]  Ulrich Stephani,et al.  Genome-Wide Copy Number Variation in Epilepsy: Novel Susceptibility Loci in Idiopathic Generalized and Focal Epilepsies , 2010, PLoS genetics.

[10]  Jake K. Byrnes,et al.  Genome-wide association study of copy number variation in 16,000 cases of eight common diseases and 3,000 shared controls , 2010 .

[11]  M. Hurles,et al.  Large, rare chromosomal deletions associated with severe early-onset obesity , 2010, Nature.

[12]  Jake K. Byrnes,et al.  Genome-wide association study of copy number variation in 16,000 cases of eight common diseases and 3,000 shared controls , 2010, Nature.

[13]  Tom R. Gaunt,et al.  Gene-centric association signals for lipids and apolipoproteins identified via the HumanCVD BeadChip. , 2009, American journal of human genetics.

[14]  M. Hurles,et al.  Copy number variation in human health, disease, and evolution. , 2009, Annual review of genomics and human genetics.

[15]  Robert T. Schultz,et al.  Autism genome-wide copy number variation reveals ubiquitin and neuronal genes , 2009, Nature.

[16]  D. Spandidos,et al.  Activation of RAS family genes in urothelial carcinoma. , 2009, The Journal of urology.

[17]  M. Ridderstråle,et al.  Genetic Variance in the Adiponutrin Gene Family and Childhood Obesity , 2009, PloS one.

[18]  C. Franceschi,et al.  Human longevity and 11p15.5: a study in 1321 centenarians , 2009, European Journal of Human Genetics.

[19]  A. Reymond,et al.  Copy number variants, diseases and gene expression. , 2009, Human molecular genetics.

[20]  John P. Rice,et al.  Singleton deletions throughout the genome increase risk of bipolar disorder , 2009, Molecular Psychiatry.

[21]  Monique M. B. Breteler,et al.  The Rotterdam Study: 2016 objectives and design update , 2015, European Journal of Epidemiology.

[22]  R. Ophoff,et al.  Analysis of genome-wide copy number variation in Irish and Dutch ALS populations. , 2008, Human molecular genetics.

[23]  Joshua M. Korn,et al.  Integrated detection and population-genetic analysis of SNPs and copy number variation , 2008, Nature Genetics.

[24]  P. Visscher,et al.  Rare chromosomal deletions and duplications increase risk of schizophrenia , 2008, Nature.

[25]  K. Mossman.  The Wellcome Trust Case Control Consortium, U.K. , 2008 .

[26]  P. Sullivan,et al.  Genetic variation in Transaldolase 1 and risk of squamous cell carcinoma of the head and neck. , 2008, Cancer detection and prevention.

[27]  Manuel A. R. Ferreira,et al.  PLINK: a tool set for whole-genome association and population-based linkage analyses. , 2007, American journal of human genetics.

[28]  N. Carter.  Methods and strategies for analyzing copy number variation using DNA microarrays , 2007, Nature Genetics.

[29]  J. Lupski.  Structural variation in the human genome. , 2007, The New England journal of medicine.

[30]  R. Redon,et al.  Relative Impact of Nucleotide and Copy Number Variation on Gene Expression Phenotypes , 2007, Science.

[31]  Kaare Christensen,et al.  Genetic influence on human lifespan and longevity , 2006, Human Genetics.

[32]  C. Franceschi,et al.  A novel VNTR enhancer within the SIRT3 gene, a human homologue of SIR2, is associated with survival at oldest ages. , 2005, Genomics.

[33]  U. Vogel,et al.  Effect of polymorphisms in XPD, RAI, ASE-1 and ERCC1 on the risk of basal cell carcinoma among Caucasians after age 50. , 2005, Cancer detection and prevention.

[34]  M. Ludwig,et al.  Functional evolution of noncoding DNA. , 2002, Current opinion in genetics & development.

[35]  A. Yashin,et al.  An allele of HRAS1 3'variable number of tandem repeats is a frailty allele: implication for an evolutionarily-conserved pathway involved in longevity. , 2002, Gene.

[36]  B. Weir,et al.  Sex-specific longevity associations defined by Tyrosine Hydroxylase–Insulin–Insulin Growth Factor 2 haplotypes on the 11p15.5 chromosomal region , 2001, Experimental Gerontology.

[37]  A A Schäffer,et al.  Heritability of life span in the Old Order Amish. , 2001, American journal of medical genetics.

[38]  Kári Stefánsson,et al.  Inheritance of human longevity in Iceland , 2000, European Journal of Human Genetics.

[39]  P. Allhoff,et al.  The Framingham Offspring Study , 1991 .

[40]  W. Kannel,et al.  An investigation of coronary heart disease in families. The Framingham offspring study. , 1979, American journal of epidemiology.

[41]  W. Kannel,et al.  The Framingham Offspring Study. Design and preliminary data. , 1975, Preventive medicine.

[42]  W. Kannel,et al.  AN APPROACH TO LONGITUDINAL STUDIES IN A COMMUNITY: THE FRAMINGHAM STUDY , 1963, Annals of the New York Academy of Sciences.

[43]  T. Dawber,et al.  Epidemiological approaches to heart disease: the Framingham Study. , 1951, American journal of public health and the nation's health.