Genetic Epidemiology as a Probe for Disease Biology

1. 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

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

3. PLoS Med. 2005 Aug;2(8):e124.

4. WSJ. 2004Sep14.

5. Case-control genetic association studies are more common than cohort studies or linkage studies Why?

6. - 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.

7. - 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!

8. Hierarchy of Epidemiologic Study Design Tower & Spector, 2007 (www)

9. 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

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

11. Odds Ratio: 3.6 95% CI = 1.3 to 10.4 ROCHE Genetic Education (www)

12. 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) Martin, 2000 (www)

13. Mapping Disease Susceptibility Genes by Association Studies (www)

14. culprit?

15. GWAS Success Stories

16. GWAS Success Stories The most robust association in GWAS to date rs380390

17. GWAS Success Stories The most robust association in GWAS to date rs380390 >>> 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

18. GWAS Success Stories

19. GWAS Success Stories

20. GWAS Success Stories

21. GWAS Success Stories

22. GWAS Success Stories

23. GWAS Success Stories ? (www)

24. (www)

25. 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. (www)

26. 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

27. 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

28. Cause-and-Effect Relationship is Easier to Assess in Genetic Association Studies Grimes & Schulz, 2002 (www) (PDF)

29. Effect Modification by an Environmental Factor (www)

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

31. Mendelian Randomization

32. 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

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

38. Effect Modification by Gender HLA-DRB4 Association in Childhood ALL Homozygosity for HLA-DRB4 family is associated with susceptibility to childhood ALL in boys only (P < 0.0001, 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 = 0.002 (OR = 5.6; 95% CI = 1.8 to 17.6) % % * Girls, n=53 Boys, n=64 *

39. Effect Modification by Gender rs5755709 G>A rs2071746 A>T STR -10kb -416 HMOX1 5’ flanking region P (sex) = 0.015 P (sex; case-only) = 0.01

40. Effect Modification by Gender NRAMP2 rs422982 shows sex-specific associations in childhood leukemia

44. 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!

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