Human Genetics

, Volume 132, Issue 5, pp 553–561 | Cite as

Genetic determinants of mortality. Can findings from genome-wide association studies explain variation in human mortality?

  • Andrea Ganna
  • Fernando Rivadeneira
  • Albert Hofman
  • André G. Uitterlinden
  • Patrik K. E. Magnusson
  • Nancy L. Pedersen
  • Erik Ingelsson
  • Henning Tiemeier
Original Investigation

Abstract

Twin studies have estimated the heritability of longevity to be approximately 20–30 %. Genome-wide association studies (GWAS) have revealed a large number of determinants of morbidity, but so far, no new polymorphisms have been discovered to be associated with longevity per se in GWAS. We aim to determine whether the genetic architecture of mortality can be explained by single nucleotide polymorphisms (SNPs) associated with common traits and diseases related to mortality. By extensive quality control of published GWAS we created a genetic score from 707 common SNPs associated with 125 diseases or risk factors related with overall mortality. We prospectively studied the association of the genetic score with: (1) time-to-death; (2) incidence of the first of nine major diseases (coronary heart disease, stroke, heart failure, diabetes, dementia, lung, breast, colon and prostate cancers) in two population-based cohorts of Dutch and Swedish individuals (N = 15,039; age range 47–99 years). During a median follow-up of 6.3 years (max 22.2 years), we observed 4,318 deaths and 2,132 incident disease events. The genetic score was significantly associated with time-to-death [hazard ratio (HR) per added risk allele = 1.003, P value = 0.006; HR 4th vs. 1st quartile = 1.103]. The association between the genetic score and incidence of major diseases was stronger (HR per added risk allele = 1.004, P value = 0.002; HR 4th vs. 1st quartile = 1.160). Associations were stronger for individuals dying at older ages. Our findings are compatible with the view of mortality as a complex and highly polygenetic trait, not easily explainable by common genetic variants related to diseases and physiological traits.

Supplementary material

439_2013_1267_MOESM1_ESM.docx (391 kb)
Supplementary material 1 (DOCX 390 kb)

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Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • Andrea Ganna
    • 1
  • Fernando Rivadeneira
    • 2
    • 3
    • 4
  • Albert Hofman
    • 2
    • 4
  • André G. Uitterlinden
    • 2
    • 3
    • 4
  • Patrik K. E. Magnusson
    • 1
  • Nancy L. Pedersen
    • 1
  • Erik Ingelsson
    • 1
  • Henning Tiemeier
    • 2
  1. 1.Department of Medical Epidemiology and BiostatisticsKarolinska InstitutetStockholmSweden
  2. 2.Department of EpidemiologyErasmus University Medical CentreRotterdamThe Netherlands
  3. 3.Department of Internal MedicineErasmus University Medical CenterRotterdamThe Netherlands
  4. 4.Netherlands Consortium for Healthy Ageing (NCHA)RotterdamThe Netherlands

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