Genetics of aging, health, and survival: dynamic regulation of human longevity related traits.
BACKGROUND
The roles of genetic factors in human longevity would be better understood if one can use more efficient methods in genetic analyses and investigate pleiotropic effects of genetic variants on aging and health related traits.


METHODS
We used EMMAX software with modified correction for population stratification to perform genome wide association studies (GWAS) of female lifespan from the original FHS cohort. The male data from the original FHS cohort and male and female data combined from the offspring FHS cohort were used to confirm findings. We evaluated pleiotropic effects of selected genetic variants as well as gene-smoking interactions on health and aging related traits. Then we reviewed current knowledge on functional properties of genes related to detected variants.


RESULTS
The eight SNPs with genome-wide significant variants were negatively associated with lifespan in both males and females. After additional QC, two of these variants were selected for further analyses of their associations with major diseases (cancer and CHD) and physiological aging changes. Gene-smoking interactions contributed to these effects. Genes closest to detected variants appear to be involved in similar biological processes and health disorders, as those found in other studies of aging and longevity e.g., in cancer and neurodegeneration.


CONCLUSIONS
The impact of genes on longevity may involve trade-off-like effects on different health traits. Genes that influence lifespan represent various molecular functions but may be involved in similar biological processes and health disorders, which could contribute to genetic heterogeneity of longevity and the lack of replication in genetic association studies.
Biodemography of Aging Research Unit, Center for Population Health and Aging, Social Science Research Institute, Duke University Durham, NC, USA.
Anatoliy I
AI
Yashin
Biodemography of Aging Research Unit, Center for Population Health and Aging, Social Science Research Institute, Duke University Durham, NC, USA.
Deqing
D
Wu
Biodemography of Aging Research Unit, Center for Population Health and Aging, Social Science Research Institute, Duke University Durham, NC, USA.
Liubov S
LS
Arbeeva
Biodemography of Aging Research Unit, Center for Population Health and Aging, Social Science Research Institute, Duke University Durham, NC, USA.
Konstantin G
KG
Arbeev
Biodemography of Aging Research Unit, Center for Population Health and Aging, Social Science Research Institute, Duke University Durham, NC, USA.
Alexander M
AM
Kulminski
Biodemography of Aging Research Unit, Center for Population Health and Aging, Social Science Research Institute, Duke University Durham, NC, USA.
Igor
I
Akushevich
Biodemography of Aging Research Unit, Center for Population Health and Aging, Social Science Research Institute, Duke University Durham, NC, USA ; Integrative Genomic Analysis Shared Resource, Duke Center for Genomic and Computational Biology, Duke University Durham, NC, USA.
Mikhail
M
Kovtun
Biodemography of Aging Research Unit, Center for Population Health and Aging, Social Science Research Institute, Duke University Durham, NC, USA.
Irina
I
Culminskaya
Biodemography of Aging Research Unit, Center for Population Health and Aging, Social Science Research Institute, Duke University Durham, NC, USA.
Eric
E
Stallard
Biodemography of Aging Research Unit, Center for Population Health and Aging, Social Science Research Institute, Duke University Durham, NC, USA.
Miaozhu
M
Li
Biodemography of Aging Research Unit, Center for Population Health and Aging, Social Science Research Institute, Duke University Durham, NC, USA.
Svetlana V
SV
Ukraintseva
CVD; aging changes; gene-environment interaction; genetics of cancer; genetics of longevity; longitudinal data; smoking and life span