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 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 General introduction to epidemiology, genetic epidemiology and genetic association studies Success stories leading to ? Real power of genetic association studies ConclusionsOUTLINE General introduction to epidemiology, genetic epidemiology and genetic association studies Success stories leading to ? Real power of genetic association studies Conclusions

PLoS Med Aug;2(8):e124.

WSJ. 2004Sep14.

Case-control genetic association studies are more common than cohort studies or linkage studiesWhy?

- 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 Design Tower & Spector, 2007 (www)www

When used for scientific enquiries, however, genetic association studies yield very informative results Following is a brief history of genetic epidemiology and examples of good use of genetic association studies

Handbook of Statistical Genetics (John Wiley & Sons) Fig.28-1 (www)www GENETIC EPIDEMIOLOGIC RESEARCH METHODS

ROCHE Genetic Education (www)(www) Odds Ratio: % CI = 1.3 to 10.4

Martin, 2000 (www)www Mapping Disease Susceptibility Genes by Association Studies Plot of minus log of P value for case-control test for allelic association with AD, for SNPs immediately surrounding APOE (<100 kb)

(www)www Mapping Disease Susceptibility Genes by Association Studies

culprit?

GWAS Success Stories

The most robust association in GWAS to date rs380390

GWAS Success Stories The most robust association in GWAS to date rs >>> Y402H OR = 7.4 (r) 96 cases & 50 controls 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

(www)www ? GWAS Success Stories ?

(www)www

(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 in Genetic Association Studies Grimes & Schulz, 2002 (www) (PDF)wwwPDF

(www)www Effect Modification by an Environmental Factor

wt wt variant variant protection risk High cancer risk low iron levels High cancer risk high iron levels Low iron environment High iron environment iron levels Iron Regulatory Gene Variants and Modification of Cancer Risk

Mendelian Randomization

Effect Modification by Gender Despite that males and females are almost different species, the gender effect is almost always disregarded in the analysis of biomedical research results

IBD3 maps to chromosome 6p in linkage studies and known as the HLA-linked IBD susceptibility locus Inflammatory Bowel Disease

HLA-DRB4 Association in Childhood ALL Homozygosity for HLA-DRB4 family is associated with susceptibility to childhood ALL in boys only (P < , OR = 6.1, 95% CI = 2.9 to 12.6 ) Controls are an unselected group of local newborns (201 boys & 214 girls) * Case-only analysis P = (OR = 5.6; 95% CI = 1.8 to 17.6) % % Boys, n=64 * Girls, n=53 * Effect Modification by Gender

HMOX1 5 flanking region rs G>A -10kb-416 rs A>T STR P (sex) = P (sex; case-only) = 0.01 Effect Modification by Gender

NRAMP2 rs shows sex-specific associations in childhood leukemia Effect Modification by Gender

CONCLUSIONS Observational epidemiologic studies are useful to explore disease biology and generate hypotheses when used appropriately Identification of the whole of genetic component of disease susceptibility requires more than DNA sequence analysis Dorak Lab is open for business!CONCLUSIONS Observational epidemiologic studies are useful to explore disease biology and generate hypotheses when used appropriately Identification of the whole of genetic component of disease susceptibility requires more than DNA sequence analysis Dorak Lab is open for business!

ACKNOWLEDGMENTS Anyone who has ever taught me anything My current team Malar, Amy and Sandeep Florida International University RSCPHSW EOHACKNOWLEDGMENTS Anyone who has ever taught me anything My current team Malar, Amy and Sandeep Florida International University RSCPHSW EOH