Nature Genetics
14, 199 - 202 (1996)
doi:10.1038/ng1096-199
Two stage genome−wide search in inflammatory bowel disease provides evidence for susceptibility loci on chromosomes 3, 7 and 12Jack Satsangi1, 2, 6, Miles Parkes1, 2, Edouard Louis1, 2, Lara Hashimoto2, Norihiro Kato2, Ken Welsh3, Joseph D. Terwilliger2, 4, G. Mark Lathrop2, John I. Bell2, 5
& Derek P. Jewell1
1Gastroenterology Unit, Nuffield Department of Medicine, Raddiffe Infirmary, Woodstock Road, Oxford OX2 6HE, UK
2The Wellcome Trust Centre for Human Genetics, Windmill Road, Headington, Oxford OX3 7BN, UK
3Transplant Immunology Unit, Nuffield Department of Surgery, Churchill Hospital, Old Road, Oxford OX3 7LJ, UK
4Columbia University Department of Genetics and Development and Department of Psychiatry, 722 West 168th Street, New York, New York 10032, USA
5Nuffield Department of Clinical Medicine, John Radcliffe Hospital, Headington, Oxford OX3 9DU, UK
6Correspondence should be addressed to J.S. Crohn's disease (CD) and ulcerative colitis (UC), the chronic inflammatory bowel diseases (CIBD), are common causes of gastro-intestinal disease in the Western world, with a combined prevalence of 100−200/100,000 (ref. 1). Epidemiological studies, particularly concordance rates in twin pairs and siblings, strongly implicate genetic susceptibility in the pathogenesis of CIBD2−5. In fact, the relative contribution of genetic factors to the pathogenesis of CD may be greater than in schizophrenia, asthma or hypertension, and at least equivalent to that in insulin-dependent diabetes6,7. Systematic screening of the entire human genome now provides a strategy for the identification of susceptibility genes in complex polygenic disorders8−10. We undertook a two-stage genome search for susceptibility genes in inflammatory bowel disease involving 186 affected sibling pairs from 160 nuclear families. We provide strong evidence for the presence of susceptibility loci for both CD and UC on chromosome 3, 7 and 12. We obtained the highest lod score (5.47; P = 2.66  10-7 with the marker D12S83 and lod scores of 3.08 and 2.69 for D7S669 and D3S1573, respectively. Our data suggest that CD and UC are closely related, but distinct, polygenic disorders that share some, but not all, susceptibility genes.
REFERENCES
- Calkins, B. & Mendeloff, A. The epidemiology of idiopathic inflammatory bowel disease, in Inflammatory Bowel Disease (eds Kirsner, J.B. & Shorter, R.G.) 31−68 (Williams and Wilkins, Baltimore, 1995).
- Satsangi, J., Rosenberg, W.M.C. & Jewell, D.P. The prevalence of inflammatory bowel disease in relatives of patients with Crohn's disease. Eur. J. Gastro. Hepatol. 6, 413−416 (1994). | ISI |
- Probert, C.S.J., Jayanthi, V., Hughes, A.D., Thompson, J.R., Wicks, A.C.B. & Mayberry, J.F. Prevalence and family risk of ulcerative colitis and Crohn's disease: an epidemiological study among Europeans and South Asians in Leicestershire. Gut 34, 1547−1551 (1993). | PubMed | ISI | ChemPort |
- Yang, H. et al. Familial empirical risks for inflammatory bowel disease: differences between Jews and non-Jews. Gut 34, 517−524 (1993). | PubMed | ISI | ChemPort |
- Tysk, C., Lindberg, E., Järnerot, G. & Flodérus-Myrhed, B. Ulcerative colitis and Crohn's disease in an unselected population of monozygotic and dizygotic twins. A study of heritability and the influence of smoking. Guf 29, 990−996 (1988). | ChemPort |
- Satsangi, J., Jewell, D.R., Rosenberg, W.M.C. & Bell, J.I. Genetics of inflammatory bowel disease. Gut 35, 696−700 (1994). | PubMed | ISI | ChemPort |
- Lander, E.S. & Schork, N.J. Genetic dissection of complex traits. Science 265, 2037−2048 (1994). | PubMed | ISI | ChemPort |
- Weeks, D.E. & Lathrop, G.M. Polygenic disease: methods for mapping complex disease traits. Trends Genet. 11, 513−519 (1995). | Article | PubMed | ISI | ChemPort |
- Hashimoto, L. et al. Genetic mapping of a susceptibility locus for insulin-dependent diabetes on chromosome 11 q. Nature 371, 161−164 (1994). | Article | PubMed | ISI | ChemPort |
- Davies, J.L. et al. A genome-wide search for human type 1 diabetes susceptibility genes. Nature 371, 130−136 (1994). | Article | PubMed | ISI | ChemPort |
- Hugot, J.P. et al. Mapping of a susceptibility locus for Crohn's disease on chromosome 16. Nature 379, 821−823 (1996). | Article | PubMed | ISI | ChemPort |
- Kruglyak, L. & Lander, E. Genetic dissection of complex traits: guidelines for interpreting and reporting linkage results. Nature Genet. 11, 241−247 (1995). | PubMed | ISI | ChemPort |
- Gendler, S.J. & Spicer, A.P. Epithelial mucin genes. Annu. Rev. Physiol. 57, 607−634 (1995). | Article | PubMed | ISI | ChemPort |
- Tysk, C., Riedesel, H., Lindberg, E., Panzini, B. & Podolsky, D. Colonic glycoproteins in inflammatory bowel disease. Gastroenterol. 100, 419−423 (1991). | ISI | ChemPort |
- Ohta, M. et al. The FHIT gene, spanning the chromosome 3p14.2 fragile site and renal carcinoma-associated t(3;8) breakpoint, is abnormal in digestive tract cancers. Cell 84, 587−597 (1996). | PubMed | ISI | ChemPort |
- Connell, W.R. et al. Clinico-pathological characteristics of coiorectal carcinoma complicating ulcerative colitis. Gut 35, 1419−1423 (1994). | PubMed | ISI | ChemPort |
- Satsangi, J., Marshall, J., Roskell, D. & Jewell, D.R. Ulcerative colitis complicated by renal cell carcinoma: a series of three cases. Gut 38, 148−150 (1996). | PubMed | ISI | ChemPort |
- Rudolph, U. et al. Ulcerative colitis and adenocarcinoma of the colon in G
 l2-deficientmice. Nature Genet. 10, 143−149 (1995). | Article | PubMed | ISI | ChemPort |
- Futami, S. et al. HLA-DRB1 *1502 allele, subtype of DR15, is associated with susceptibility to ulcerative colitis and its progression. Digest Dis. Sci. 40, 814−818 (1995). | PubMed | ISI | ChemPort |
- Satsangi, J. et al. Contribution of genes of the major histocompatibility complex to susceptibility and disease phenotype in inflammatory bowel disease. Lancet 347, 1212−1217 (1996). | Article | PubMed | ISI | ChemPort |
- Toyoda, H. et al. Distinct association of HLA Class II genes with inflammatory bowel disease. Gastroenterology 104, 741−748 (1993). | PubMed | ISI | ChemPort |
- Reinshagen, M. et al. HLA Class II gene frequencies in Crohn's disease: a population based analysis in Germany. Gut 38, 538−542 (1996). | PubMed | ISI | ChemPort |
- Hugot, J.P. et al. Linkage analyses of chromsome 6 loci, including HLA, in familial aggregations of Crohn's disease. Am. J. Med. Genet. 52, 207−214 (1994). | PubMed | ISI | ChemPort |
- Todd, J.A. Genetic analysis of type 1 diabetes using whole genome approaches. Proc. Natl. Acad. Sci. USA 92, 8560−8565 (1995). | PubMed | ChemPort |
- Satsangi, J., Grootscholten, C., Holt, H. & Jewell, D.R. Clinical patterns of familial inflammatory bowel disease. Gut 38, 738−741 (1996). | PubMed | ISI | ChemPort |
- Reed, P.W. et al. Chromosome-specific microsatellite sets for fluorescence-based semi-automated genome mapping. Nature Genet. 7, 390−395 (1994). | PubMed | ISI | ChemPort |
- Dib, C. et al. A comprehensive genetic map of the human genome based on 5,264 microsatellites. Nature 380, 152−154 (1996). | Article | PubMed | ISI | ChemPort |
- Hyer, R.N. et al. High resolution linkage mapping for susceptibility genes in human polygenic disease: Insulin-dependent diabetes mellitus and chromosome 11 q. Am. J. Hum. Genet. 48, 243−257 (1991). | PubMed | ISI | ChemPort |
- Knapp, M., Seuchter, S.A. & Baur, M.P. Linkage analysis in nuclear families. 2: Relationship between affected sib-pair tests and lod score analysis. Hum. Hered. 44, 44−51 (1994). | PubMed | ISI | ChemPort |
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