Identification of 99 genes implicated in Crohn’s disease
Crohn’s disease (CD) was virtually unheard of in the early nineteen hundreds. Since then it’s incidence (as that of a series of other inflammatory diseases including asthma) has dramatically increased in industrialized societies: nowadays, more than one in 500 people will suffer from CD (or ulcerative colitis (UC), the other form of inflammatory bowel disease) at some point in their lifetime. This clearly points towards a key role of as of yet poorly defined environmental and/or behavioral risk factors. It appears, however, that we are not all equally sensitive to these environmental/behavioral risk factors, and that these inter-individual differences are to a large extent genetically determined. This has opened the possibility to use the very effective genetic approaches to decipher the molecular basis of these inter-individual differences as a means to gain new insights in the mechanisms underlying Crohn’s disease as well as to identify novel drug targets.
From 2006 until 2015, the Unit of Animal Genomics (UAG) (Dr. M. Georges) and the Unit of Gastroenterology of the GIGA Institute at the University of Liège (Dr. E. Louis) have been major contributors to the field of genome-wide association studies (GWAS) that have now identified more than 200 regions in the genome that underlie the inter-individual differences in the sensitivity to IBD (“GWAS identified IBD risk loci”). Since then, they have focused on so-called “post-GWAS” studies, that focus on gaining a detailed understanding of what is happening within these risk loci. In one of these studies, the have searched for genes whose expression level (rather than the amino-acid sequence) is perturbed in susceptible individuals using an approached dubbed “analysis of cis-eQTL”. They have generated a unique dataset involving nine disease-relevant cell types in more than 300 individuals in which they have studied the expression of close to 2,000 genes mapping to the 200 IBD risk loci. By applying newly developed methods, they have found 99 genes in 63 of the 200 IBD risk loci that are very likely to be directly implicated in triggering Crohn’s disease. These constitute a very rich source of potential new targets for drug development. The corresponding results have been published in the prestigious scientific journal Nature Communications.
The work was primarily conducted by two young scientists: Yukihide Momozawa, first as postdoctoral fellow at the UAG in GIGA and then as senior scientist at the RIKEN institute in Yokohama (Japan), and Julia Dmitrieva, postdoctoral bioinformatician at the UAG.
This work was supported by grants to Michel Georges from WELBIO (CAUSIBD), BELSPO (BeMGI), and Horizon 2020 (SYSCID).
IBD risk loci are enriched in multigenic regulatory modules encompassing causative genes.
Yukihide Momozawa, Julia Dmitrieva, Emilie Theatre, Valérie Deffontaine, Souad Rhamouni, Benoit Charloteaux, Françoise Crins, Elisa Docampo, Mahmoud Elansary, Anne-Stephan Gori, Christelle Lecut, Rob Mariman, Myriam Mni, Cécile Oury, Ilya Altukhov, Dmitry Alexeev, Yurii Aulchenko, Leila Amininejad, Gerd Bouma, Frank Hoentjen, M Lowenberg, Bas Oldenburg, Marieke Pierik, Andrea van der Meulen-de Jong, Janneke van der Woude, Marijn C Visschedijk, Mark Lathrop, Jean-Pierre Hugot, Rinse Weersma, Martine de Vos, Denis Franchimont, Severine Vermeire, Edouard Louis, and Michel Georges.
Nature Communications, 2018 DOI: 10.1038/s41467-018-04365-8