Human Molecular Genetics, 2002, Vol. 11, No. 21 2599-2606
© 2002 Oxford University Press
Evidence for an inflammatory bowel disease locus on chromosome 3p26: linkage, transmission/disequilibrium and partitioning of linkage
1Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, 2Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania, 3Department of Gastroenterology, The Cleveland Clinic Foundation, Cleveland, Ohio, 4The Martin Boyer Laboratories, Section of Gastroenterology, Department of Medicine, The University of Chicago Hospitals, Chicago, Illinois, 5Harvey M. and Lyn P. Meyerhoff Inflammatory Bowel Disease Center, Johns Hopkins University School of Medicine, Baltimore, Maryland and 6The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania
Received May 29, 2002; Revised July 17, 2002; Accepted July 27, 2002
Crohn's disease and ulcerative colitis, the two major forms of idiopathic inflammatory bowel disease (IBD), are heritable, complex traits that appear to share some but not all susceptibility loci. We report that transmission/disequilibrium test analysis of a Crohn's disease genome scan dataset has detected an inflammatory bowel disease locus on chromosome 3p26 (nominal P=0.000052 and genome-wide corrected P=0.039 at D3S1297). An allele sharing method shows significant linkage (multipoint lod=3.69) in a larger, independent sample of inflammatory bowel disease-affected sibling pairs. A survey of 16 chromosome 3p26 short tandem repeat polymorphisms in a combined sample of 234 independent nuclear families with 324 IBD-affected sibling pairs shows significant linkage to chromosome 3p26 (multipoint lod=3.78) and significant transmission/disequilibrium test results at two adjacent markers (nominal P values in two different transmission/disequilibrium analysis methods=0.00011 and 0.0011 for the first marker, and 0.00071 and 0.00013 for the second marker). There is highly significant under-transmission of a common allele and modest over-transmission of other alleles at both markers. Families with no transmission to affected individuals of the under-transmitted alleles show significant linkage (multipoint lod=4.50) that is significantly greater in four simulation studies (P=0.0001, 0.0000625, 0.0000625 and 0.0000625, respectively) than the linkage evidence in families with transmission of the under-transmitted alleles (multipoint lod=0.12). Thus, the existence of an inflammatory bowel disease locus on chromosome 3p26 is supported by significant linkage, transmission/disequilibrium and partitioning of linkage evidence.
* To whom correspondence should be addressed at: S724 Biomedical Science Tower, 3500 Terrace Street, Pittsburgh, PA 15261. Tel: 4126481897, Fax: 4123838753; Email: duerr{at}msx.dept-med.pitt.edu
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