Genetics and Genomic Medicine of Inflammatory Diseases


The Laboratory for Genetics and Genomic Medicine has had as a central theme, the development and application of novel approaches to identify causal genes for chronic inflammatory diseases such as Crohns’ Disease (CD), ulcerative colitis (UC) systemic lupus erythematosus (SLE) and multiple sclerosis (MS), as well as to determine their biological impact on health and disease. As a consequence, we have focused our efforts in the following areas:


Understanding the haplotype structure of the human genome.  This research began with our participation in the first large-scale identification, mapping, and genotyping of SNPs in the human genome. This was followed with the co-discovery of the fine haplotype structure of the human genome with our colleagues Daly, Hudson and Lander. We have been particularly interested in the major histocompatibility complex (MHC) region given its importance in transplantation, resistance to infection and susceptibility to immune mediated diseases.


Genetic studies designed to identify causal risk factors for common chronic inflammatory diseases.  We have successfully used targeted and genome-wide association studies (GWAS) to identify and validate hundreds of genetic risk factors either protect or predispose to common inflammatory diseases.  In addition, we have used high-density genotyping and next generation sequencing (NGS) approaches for identifying the causal genes and variants within associated loci.


Bioinformatic, genomic and integrative biology approaches understanding gene function.  The ultimate goal of our work is to translate genetic discoveries into a better understanding of complex biological systems, better clinical & research tools and improved therapies.  To achieve this goal, it is important to develop methods and approaches to systematically generate functional data on putative causal genes & their variants, in models that provide the appropriate cellular context.


Selected Publications

Huang H et al. Fine-mapping inflammatory bowel disease loci to single-variant resolution. Nature. 2017 Jun 28. doi: 10.1038/nature22969.  PMID: 28658209


Rivas MA et al. A protein-truncating R179X variant in RNF186 confers protection against ulcerative colitis. Nat Commun. 2016 Sep 13;7:12869. doi: 10.1038/ncomms12869  PMID: 27619887


Sivanesan D et al. IL23R (Interleukin 23 Receptor) Variants Protective against Inflammatory Bowel Diseases (IBD) Display Loss of Function due to Impaired Protein Stability and Intracellular Trafficking. J Biol Chem. 2016 Apr 15;291(16):8673-85. doi: 10.1074/jbc.M116.715870. Epub 2016 Feb 17.  PMID: 26887945


Cleynen I et al. Inherited determinants of Crohn's disease and ulcerative colitis phenotypes: a genetic association study. Lancet. 2016 Jan 9;387(10014):156-67. PMID: 26490195.


Goyette P, Boucher G et al. High-density mapping of the MHC identifies a shared role for HLA-DRB1*01:03 in inflammatory bowel diseases and heterozygous advantage in ulcerative colitis. Nat Genet. 2015 Feb;47(2):172-9. doi: 10.1038/ng.3176. Epub 2015 Jan 5.  PMID: 25559196


Beaudoin et al. Deep resequencing of GWAS loci identifies rare variants in CARD9, IL23R and RNF186 that are associated with Ulcerative colitis. PLoS Genet. 2013;9(9):e1003723. PMID:24068945


Jostins et al. Host–microbe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature. 2012 Nov 1;491(7422):119-24. PMID: 23128233.


Anderson CA et al. Meta-analysis identifies 29 additional ulcerative colitis risk loci, increasing the number of confirmed associations to 47Nat Genet. 2011 Mar;43(3):246-52.


International Multiple Sclerosis Genetics Consortium and WTCCC2. Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis. Nature. 2011 Aug 10;476(7359):214-9.


Rivas MA et al. Deep resequencing of GWAS loci identifies independent rare variants associated with inflammatory bowel disease. Nat Genet. 2011 Oct 9;43(11):1066-73.


Franke A et al. Genome-wide meta-analysis increases to 71 the number of confirmed Crohn's disease susceptibility loci. Nat Genet. 2010 Dec;42(12):1118-25.


Gardet A et al. LRRK2 is involved in the IFN-gamma response and host response to pathogensJ Immunol. 2010 Nov 1; 185(9):5577-85.


Barrett JC et al. Genome-wide association defines more than thirty distinct susceptibility loci for Crohn’s diseaseNat Genet 2008;40(8):955-62.


Graham RR et al. Genetic variants near TNFAIP3 on 6q23 are associated with systemic lupus erythematosusNat Genet 2008;40(9):1059-61.


Rioux JD et al. Genome-wide association study identifies new susceptibility loci for Crohn disease and implicates autophagy in disease pathogenesisNat Genet 2007;39(5):596-604.


International Multiple Sclerosis Genetics Consortium et al. Risk alleles for multiple sclerosis identified by a genomewide studyN Engl J Med 2007;357(9):851-62.


Duerr RH et al. A genome-wide association study identifies IL23R as an inflammatory bowel disease gene. Science 2006;314(5804):1461-3.


De Bakker P et al. A high resolution HLA and SNP haplotype map for disease association studies in the extended human MHC. Nat Genet 2006 Oct;38(10):1166-1172.  


Giallourakis C et al. A molecular-properties-based approach to understanding PDZ domain proteins and PDZ ligandsGenome Res 2006 Aug; 16(8):1056-72.


Rioux JD et al. Genetic variation in the 5q31 cytokine gene cluster confers susceptibility to Crohn’s disease. Nat Genet 2001;29(2):223-8.


Daly MJ et al. High-resolution haplotype structure in the human genomeNat Genet2001;29(2):229-32.


Wang DG et al. Large-scale identification, mapping, and genotyping of single-nucleotide polymorphisms in the human genomeScience 1998 May 15;280(5366):1077-82.