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Methodological problems in genetic association studies of longevity--the apolipoprotein E gene as an example
Sarah J Lewis1, Eric J Brunner
1International Centre for Health and Society, Department of Epidemiology and Public Health, University College London, London, UK. s.j.lewis@bristol.ac.uk
International Journal of Epidemiology
|August 21, 2004
Summary
Genetic studies on longevity rely on flawed assumptions about allele frequencies and mortality risks. APOE epsilon4 allele frequency interacts with mortality, questioning the validity of these genetic association studies.
Area of Science:
- Genetics
- Longevity Research
- Population Genetics
Background:
- Cross-sectional genetic association studies are common for identifying longevity genes.
- These studies assume similar initial allele frequencies across age groups and constant genotype-specific mortality risks over time.
Purpose of the Study:
- To evaluate the validity of assumptions underlying genetic association studies of longevity.
- To examine the role of apolipoprotein E (APOE) gene polymorphisms in longevity.
Main Methods:
- Reviewed 15 cross-sectional studies on apolipoprotein E (APOE) polymorphisms and longevity.
- Assessed the assumptions of similar allele frequencies and birth year-independent mortality risks.
Main Results:
- Observed higher epsilon2 and lower epsilon4 allele frequencies in older populations.
- Found significant variation in APOE allele frequencies (4-21%) and heterogeneity between populations.
- Demonstrated an association between APOE epsilon4 allele frequency and mortality risk, and noted context-specific mortality causes over time.
Conclusions:
- The assumptions of genetic association studies for longevity are questionable.
- Population-specific allele frequencies and gene-environment interactions that vary over time challenge study validity.
- Results suggest caution when interpreting genetic studies of longevity, particularly those using case-control designs.