Genetic Epidemiology Genetic Epidemiology as a Probe for Disease as a Probe for Disease Biology Biology Mehmet Tevfik DORAK, MD PhD Mehmet Tevfik DORAK, MD PhD Dept of Environmental & Occupational Health Dept of Environmental & Occupational Health Robert Stempel College of Public Health and Social Work Robert Stempel College of Public Health and Social Work College of Medicine, FIU April 15, 2011
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Genetic Epidemiology as a Probe for Disease Biology
Genetic Epidemiology as a Probe for Disease Biology. Mehmet Tevfik DORAK, MD PhD Dept of Environmental & Occupational Health Robert Stempel College of Public Health and Social Work. College of Medicine, FIU April 15, 2011. OUTLINE - PowerPoint PPT Presentation
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Genetic Epidemiology Genetic Epidemiology as a Probe for Disease Biologyas a Probe for Disease Biology
Genetic Epidemiology Genetic Epidemiology as a Probe for Disease Biologyas a Probe for Disease Biology
Mehmet Tevfik DORAK, MD PhDMehmet Tevfik DORAK, MD PhD
Dept of Environmental & Occupational HealthDept of Environmental & Occupational HealthRobert Stempel College of Public Health and Social WorkRobert Stempel College of Public Health and Social Work
Mehmet Tevfik DORAK, MD PhDMehmet Tevfik DORAK, MD PhD
Dept of Environmental & Occupational HealthDept of Environmental & Occupational HealthRobert Stempel College of Public Health and Social WorkRobert Stempel College of Public Health and Social Work
College of Medicine, FIUApril 15, 2011
OUTLINEOUTLINE
General introduction to epidemiology, genetic epidemiology and genetic association studies
Success stories leading to ?
Real power of genetic association studies
Conclusions
OUTLINEOUTLINE
General introduction to epidemiology, genetic epidemiology and genetic association studies
Success stories leading to ?
Real power of genetic association studies
Conclusions
PLoS Med. 2005 Aug;2(8):e124.
WSJ. 2004Sep14.
Case-control genetic association studies are more common than cohort studies or
linkage studies
Why?Why?
- They are cheaper- They are easier- They are quick
- They are easier to analyze
Of course, genetic association studies are performed to find the causal genetic
polymorphisms and to learn more about disease biology.
- They are cheaper- They are easier- They are quick
- They are easier to analyze
However, these advantages have been exploited by many in need of a quick
publication!
Hierarchy of Epidemiologic Study DesignHierarchy of Epidemiologic Study Design
• Chromosomal region 1q31 where CFH maps had been identified as a
candidate region in six linkage studies
• Activated C5b-9 complex has been detected in patients with AMD
• Complement factor H levels increase with age and in smokers; two
risk factors for AMD
• Complement factor H is detectable in the eye
GWAS Success Stories
GWAS Success Stories
GWAS Success Stories
GWAS Success Stories
GWAS Success Stories
(www)
GWAS Success Stories ??
(www)
(www)
It is therefore unlikely that as we perform them now even GWAS do not have sufficient power to decode
the substantial portion of genetic component in disease susceptibility.
Genetic Association Studies are Particularly Powerful:
- To test whether reverse causation is involved (iron deficiency in GI tract cancers; low cholesterol in cancer)
- To unravel effect modification (by gender or an environmental factor)
Genetic association results are cumulative results determined by the whole body and environment unlike results of in vitro experiments on a single cell under extremely controlled
environments
In a case-control study:
• Cause and effect relationship is not clear • The observed association may be caused by a confounder • It may be due to chance • Reverse causation cannot be ruled out
Mendelian randomization may be relied on when the confounder is suspected but not known
Randomization is naturally achieved in genetic association studies
Cause-and-Effect Relationship is Easier to Assess Cause-and-Effect Relationship is Easier to Assess in Genetic Association Studies in Genetic Association Studies
Grimes & Schulz, 2002 (www) (PDF)
(www)
Effect Modification by an Environmental Factor
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High cancer riskHigh cancer risk
low iron levelslow iron levels
High cancer riskHigh cancer risk
high iron levelshigh iron levels
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Iron Regulatory Gene Variants and Modification of Cancer Risk
Mendelian Randomization
Effect Modification by Gender Effect Modification by Gender
Despite that males and females are Despite that males and females are almost different species, the gender almost different species, the gender
effect is almost always disregarded in the effect is almost always disregarded in the analysis of biomedical research resultsanalysis of biomedical research results
• IBD3 maps to chromosome 6p in linkage studies and known as the HLA-linked IBD susceptibility locus