Resequencing of positional candidates identifies low frequency IL23R coding variants protecting against inflammatory bowel disease

• DOI: 10.1038/ng.733
• Publication Date: 2010-12-12T20:06:28Z
• Authors: Yukihide Momozawa; Myriam Mni; Kayo Nakamura; Wouter Coppieters; Sven Almer; Leila Amininejad; Isabelle Cleynen; Jean-Frédéric Col...; Peter de Rijk; Olivier Dewit; Yigael Finkel; Miquel A Gassull; Dirk Goossens; Debby Laukens; Marc Lémann; Cécile Libioulle; Colm O'Morain; Catherine Reenaers; Paul Rutgeerts; Curt Tysk; Diana Zelenika; Mark Lathrop; Jurgen Del-Favero; Jean-Pierre Hugot; Martine de Vos; Denis Franchimont; Severine Vermeire; Edouard Louis; Michel Georges
• Keywords: COMPLEX DISEASES; GENES; Nod2 Signaling Adaptor Protein; SUSCEPTIBILITY; Polymorphism, Single Nucleotide; 03 medical and health sciences; Crohn Disease; Humans; Genetic Predisposition to Disease; GENOME-WIDE ASSOCIATION; COMMON; Biology; SNPS; 0303 health sciences; HERITABILITY; Genetic Variation; Receptors, Interleukin; Sequence Analysis, DNA; Sciences bio-médicales et agricoles; Science General; Inflammatory Bowel Diseases; CROHNS-DISEASE; 3. Good health; Phenotype; RARE VARIANTS; Case-Control Studies; Human medicine; CONTRIBUTE; Genome-Wide Association Study

Genome-wide association studies (GWAS) have identified dozens of risk loci for many complex disorders, including Crohn's disease. However, common disease-associated SNPs explain at most ∼20% of the genetic variance for Crohn's disease. Several factors may account for this unexplained heritability, including rare risk variants not adequately tagged thus far in GWAS. That rare susceptibility variants indeed contribute to variation in multifactorial phenotypes has been demonstrated for colorectal cancer, plasma high-density lipoprotein cholesterol levels, blood pressure, type 1 diabetes, hypertriglyceridemia and, in the case of Crohn's disease, for NOD2 (refs. 14,15). Here we describe the use of high-throughput resequencing of DNA pools to search for rare coding variants influencing susceptibility to Crohn's disease in 63 GWAS-identified positional candidate genes. We identify low frequency coding variants conferring protection against inflammatory bowel disease in IL23R, but we conclude that rare coding variants in positional candidates do not make a large contribution to inherited predisposition to Crohn's disease.