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Michel Georges Unit of Animal Genomics GIGA-R & Faculty of Veterinary Medicine University of Liège

Deciphering the molecular architecture of inflammatory bowel disease and other common complex diseases. Michel Georges Unit of Animal Genomics GIGA-R & Faculty of Veterinary Medicine University of Liège. Inflammatory Bowel Disease. Burril Bernard Crohn, 1921 Mount Sinai Hospital, NY. 0.15%.

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Michel Georges Unit of Animal Genomics GIGA-R & Faculty of Veterinary Medicine University of Liège

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  1. Deciphering the molecular architecture of inflammatory bowel disease and other common complex diseases. Michel Georges Unit of Animal Genomics GIGA-R & Faculty of Veterinary Medicine University of Liège

  2. Inflammatory Bowel Disease Burril Bernard Crohn, 1921 Mount Sinai Hospital, NY 0.15%

  3. Environmentally triggered, yet highly heritable Schreiber S, Rosenstiel P, Albrecht M, Hampe J, Krawczak M. Genetics of Crohn disease, an archetypal inflammatory barrier disease. Nat Rev Genet. 2005 May;6(5):376-88.

  4. Identifying susceptibility variants: why? • Understanding pathogenesis • Identifying novel drug targets • Predictive, personalized medicine (?)

  5. How? Positional cloningPolymorphism

  6. How? Positional cloningLinkage

  7. How? Positional cloningLinkage disequilibrium

  8. How? Positional cloningOriginally a three step process Mapping  linkage Fine-mapping  LD Identifying causal variants and genes

  9. NOD2, archetypal example of successfull positional cloning

  10. A long and winding road …

  11. The “GWAS” concept Risch & Merikangas, Science 273:1516 (1996)

  12. Enabling GWASHapMap Common SNPs

  13. Enabling GWASIllumina & Affymetrix

  14. “Breakthrough of the year” 2007

  15. Inflammatory Bowel DiseaseRich harvest … Barret et al. 2008 Franke et al. 2010

  16. Locus ≠ gene ≠ variant

  17. New insights in pathogenesis

  18. Pervasive “pleiotropy”

  19. Limited variance explained

  20. Limited variance explained …

  21. Missing heritability issue

  22. Overestimated heritabilities

  23. Incomplete genome coverageStructural variants

  24. Incomplete LD between SNPs and causative variants “Imputation”

  25. In silico genotype imputation

  26. Highly penetrant rare variants not tagged by common SNPs

  27. Highly penetrant rare variants not tagged by common SNPs (Nature 411: 599-603 2001.) 5% 17%

  28. Quasi-infinitesimal architecture

  29. GxG interactions or epistasis

  30. Non-Mendelian modes of inheritance

  31. Perspectives • GWAS will continue to yield import pathogenic insights • Small RR don’t preclude large pharmacological effects • Genome-wide RR will be computable soon, with putative utility for society and the individual …

  32. Acknowledgments • ULg • E. Louis & J. Belaiche • C. Libioulle • S. Hansoul • C. Sandor • Y. Momozawa • M. Mni • ULB, KUL, RUG, UCL • D. Franchimont, S. Vermeire, M. De Vos, O. Dewit • CNG, INSERM • M. Lathrop, J-P Hugot • RW - DGTRE • FNRS • Politique Scientifique Fédérale (PAI)

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