title: Genetic Structures of Population Cohorts Change with Increasing Age: Implications for Genetic Analyses of Human aging and Life Span.
abstract: BACKGROUND
  Correcting for the potential effects of population stratification is an important issue in genome wide association studies (GWAS) of complex traits. Principal component analysis (PCA) of the genetic structure of the population under study with subsequent incorporation of the first several principal components (PCs) in the GWAS regression model is often used for this purpose.
  
  
  OBJECTIVE
  For longevity related traits such a correction may negatively affect the accuracy of genetic analyses. This is because PCs may capture genetic structure induced by mortality selection processes in genetically heterogeneous populations.
  
  
  METHODS
  We used the Framingham Heart Study data on life span and on individual genetic background to construct two sets of PCs. One was constructed to separate population stratification due to differences in ancestry from that induced by mortality selection. The other was constructed using genetic data on individuals of different ages without attempting to separate the ancestry effects from the mortality selection effects. The GWASs of human life span were performed using the first 20 PCs from each of the selected sets to control for possible population stratification.
  
  
  RESULTS
  The results indicated that the GWAS that used the PC set separating population stratification induced by mortality selection from differences in ancestry produced stronger genetic signals than the GWAS that used PCs without such separation.
  
  
  CONCLUSIONS
  The quality of genetic estimates in GWAS can be improved when changes in genetic structure caused by mortality selection are taken into account in controlling for possible effects of population stratification.
authors.affiliation: Biodemography of Aging Research Unit, Duke University, USA.
authors.forename: Anatoliy I
authors.initials: AI
authors.lastname: Yashin
authors.affiliation: Duke Cancer Institute, Duke University, USA.
authors.forename: Deqing
authors.initials: D
authors.lastname: Wu
authors.forename: Konstantin G
authors.initials: KG
authors.lastname: Arbeev
authors.forename: Liubov S
authors.initials: LS
authors.lastname: Arbeeva
authors.forename: Igor
authors.initials: I
authors.lastname: Akushevich
authors.forename: Alexander
authors.initials: A
authors.lastname: Kulminski
authors.forename: Irina
authors.initials: I
authors.lastname: Culminskaya
authors.forename: Eric
authors.initials: E
authors.lastname: Stallard
authors.forename: Svetlana V
authors.initials: SV
authors.lastname: Ukraintseva
keywords: Genetic associations; Genetic structure; Genetics of aging; Heterogeneous population; Longevity; Mortality selection; Principal component analysis