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

• Published in: Nature genetics Vol. 43; no. 1; pp. 43 - 47
• Main Authors: Georges, Michel, Momozawa, Yukihide, Mni, Myriam, Nakamura, Kayo, Coppieters, Wouter, Almer, Sven, Amininejad, Leila, Cleynen, Isabelle, Colombel, Jean-Frédéric, de Rijk, Peter, Dewit, Olivier, Finkel, Yigael, Gassull, Miquel A, Goossens, Dirk, Laukens, Debby, Lémann, Marc, Libioulle, Cécile, O'Morain, Colm, Reenaers, Catherine, Rutgeerts, Paul, Tysk, Curt, Zelenika, Diana, Lathrop, Mark, Del-Favero, Jurgen, Hugot, Jean-Pierre, de Vos, Martine, Franchimont, Denis, Vermeire, Severine, Louis, Edouard
• Format: Journal Article Web Resource
• Language: English
• Published: New York Nature Publishing Group US 01.01.2011; Nature Publishing Group
• Subjects: 631/208/205/2138; 631/208/727/2000; 692/699/1503/257/1402; Agriculture; Animal Genetics and Genomics; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; Blood pressure; Cancer Research; Candidates; Case-Control Studies; Colorectal carcinoma; Confidence intervals; Crohn Disease - genetics; Fundamental and applied biological sciences. Psychology; Gastroenterology & hepatology; Gastroenterology. Liver. Pancreas. Abdomen; Gastroentérologie & hépatologie; Gene Function; Genes; Genetic aspects; Genetic Predisposition to Disease; Genetic variance; Genetic Variation; Genetics; Genetics & genetic processes; Genetics of eukaryotes. Biological and molecular evolution; Genetik; Genome-Wide Association Study; Genomics; Génétique & processus génétiques; Human Genetics; Human health sciences; Humans; Inflammatory bowel disease; Inflammatory bowel diseases; Inflammatory Bowel Diseases - genetics; letter; Life sciences; Medical sciences; MEDICIN; Medicin och hälsovetenskap; MEDICINE; Nod2 Signaling Adaptor Protein - genetics; Other diseases. Semiology; Phenotype; Physiological aspects; Polymorphism, Single Nucleotide; Prevention; Receptors, Interleukin - genetics; Sciences de la santé humaine; Sciences du vivant; Sequence Analysis, DNA; Single nucleotide polymorphisms; Standard deviation; Stomach. Duodenum. Small intestine. Colon. Rectum. Anus; Studies; Variant; Inflammatory bowel disease; Crohn disease; Frequency; Digestive diseases; Intestinal disease; Identification; Inflammatory disease; Ulcerative colitis
• ISSN: 1061-4036; 1546-1718; 1546-1718
• DOI: 10.1038/ng.733

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.