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Transcript 
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%
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.
Identifying susceptibility
variants: why?
 Understanding pathogenesis
 Identifying novel drug targets
 Predictive, personalized medicine (?)
How? Positional cloning
Polymorphism
How? Positional cloning
Linkage
How? Positional cloning
Linkage disequilibrium
How? Positional cloning
Originally a three step process
Mapping  linkage
Fine-mapping  LD
Identifying causal
variants and genes
NOD2, archetypal example of
successfull positional cloning
A long and winding road …
The “GWAS” concept
Risch & Merikangas, Science 273:1516 (1996)
Enabling GWAS
HapMap
Common SNPs
Enabling GWAS
Illumina & Affymetrix
“Breakthrough of the year”
2007
Inflammatory Bowel Disease
Rich harvest …
Barret et al. 2008
Franke et al.
2010
Locus ≠ gene ≠ variant
New insights in pathogenesis
Pervasive “pleiotropy”
Limited variance explained
Limited variance explained …
Missing heritability issue
Overestimated heritabilities
Incomplete genome coverage
Structural variants
Incomplete LD between SNPs
and causative variants
“Imputation”
In silico genotype imputation
Highly penetrant rare variants
not tagged by common SNPs
Highly penetrant rare variants
not tagged by common SNPs
(Nature 411: 599-603 2001.)
5%
17%
Quasi-infinitesimal architecture
GxG interactions or epistasis
Non-Mendelian modes of
inheritance
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 …
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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