Case-Control Studies; Crohn Disease/genetics; Genetic Predisposition to Disease; Genetic Variation; Genome-Wide Association Study; Humans; Inflammatory Bowel Diseases/genetics; Nod2 Signaling Adaptor Protein/genetics; Phenotype; Polymorphism, Single Nucleotide; Receptors, Interleukin/genetics; Sequence Analysis, DNA
Abstract :
[en] 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 approximately 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.
Altshuler, D., Daly, M.J. & Lander, E.S. Genetic mapping in human disease. Science 322, 881-888 (2008).
Barrett, J.C. et al. Genome-wide association defnes more than 30 distinct susceptibility loci for Crohn′s disease. Nat. Genet. 40, 955-962 (2008).
Yang, J. et al. Common SNPs explain a large proportion of the heritability for human height. Nat. Genet. 42, 565-569 (2010).
Manolio, T.A. et al. Finding the missing heritability of complex diseases. Nature 461, 747-753 (2009).
Kong, A. et al. Parental origin of sequence variants associated with complex diseases. Nature 462, 868-874 (2009).
Pritchard, J.K. Are rare variants responsible for susceptibility to complex diseases? Am. J. Hum. Genet. 69, 124-137 (2001).
Bodmer, W. & Bonilla, C. Common and rare variants in multifactorial susceptibility to common diseases. Nat. Genet. 40, 695-701 (2008).
Kruglyak, L. The road to genome-wide association studies. Nat. Rev. Genet. 9, 314-318 (2008).
Fearnhead, N.S. et al. Multiple rare variants in different genes account for multifactorial inherited susceptibility to colorectal adenomas. Proc. Natl. Acad. Sci. USA 101, 15992-15997 (2004).
Cohen, J.C. et al. Multiple rare alleles contribute to low plasma levels of HDL cholesterol. Science 305, 869-872 (2004).
Ji, W. et al. Rare independent mutations in renal salt handling genes contribute to blood pressure variation. Nat. Genet. 40, 592-599 (2008).
Nejentsev, S., Walker, N., Riches, D., Egholm, M. & Todd, J.A. Rare variants of IFIH1, a gene implicated in antiviral responses, protect against type 1 diabetes. Science 324, 387-389 (2009).
Johansen, C.T. et al. Excess of rare variants in genes identifed by genome-wide association study of hypertriglyceridemia. Nat. Genet. 42, 684-687 (2010).
Hugot, J.P. et al. Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn′s disease. Nature 411, 599-603 (2001).
Lesage, S. et al. CARD15/NOD2 mutational analysis and genotype-phenotype correlation in 612 patients with infammatory bowel disease. Am. J. Hum. Genet. 70, 845-857 (2002).
Peltekova, V.D. et al. Functional variants of OCTN cation transporter genes are associated with Crohn disease. Nat. Genet. 36, 471-475 (2004).
Libioulle, C. et al. Novel Crohn disease locus identifed by genome-wide association maps to a gene desert on 5p13.1 and modulates expression of PTGER4. PLoS Genet. 3, e58 (2007).
Margulies, M. et al. Genome sequencing in microfabricated high-density picolitre reactors. Nature 437, 376-380 (2005).
Kumar, P., Henikoff, S. & Ng, P.C. Predicting the effects of coding non-synonymous variants on protein function using the SIFT algorithm. Nat. Protoc. 4, 1073-1081 (2009).
Duerr, R.H. et al. A genome-wide association study identifes IL23R as an infammatory bowel disease gene. Science 314, 1461-1463 (2006).
Ramensky, V., Bork, P. & Sunyaev, S. Human non-synonymous SNPs: server and survey. Nucleic Acids Res. 30, 3894-3900 (2002).
Dickson, S.P., Wang, K., Krantz, I., Hakonarson, H. & Goldstein, D.B. Rare variants create synthetic genome-wide associations. PLoS Biol. 8, e1000294 (2010).
Rozen, S. & Skaletsky, H. Primer3 on the WWW for general users and for biologist programmers. Methods Mol. Biol. 132, 365-386 (2000).
