New Approaches to Gene Hunting in IBD

Without a doubt, one of the greatest promises of the human genome project has been the expectation that its completion will rapidly accelerate the discovery of the heritable components of complex disease. Such discoveries will educate us as to the underlying causes of disease and hold out great promise for medicine in the future by potentially enabling the prediction of individual risk, the selection of therapy based on genetic profile, and a more rational approach to designing drugs. Unfortunately, discovering these genetic components of complex disease has been much more difficult than initially hoped and, to date, very few positive results have been conclusively confirmed. We review here approaches to tackling the problem of gene finding in complex disease with an emphasis on new approaches that may complement and supplement existing methods that have been making only slow progress toward the elucidation of the genetic architecture of disease. Along the way we highlight the successful work by many groups in studying the genetics of IBD, where significant successes have arrived earlier than in most other complex human diseases.

[1]  International Human Genome Sequencing Consortium Initial sequencing and analysis of the human genome , 2001, Nature.

[2]  Judy H. Cho,et al.  A frameshift mutation in NOD2 associated with susceptibility to Crohn's disease , 2001, Nature.

[3]  E S Lander,et al.  The common PPARgamma Pro12Ala polymorphism is associated with decreased risk of type 2 diabetes. , 2000, Nature genetics.

[4]  Jean Weissenbach,et al.  Mapping of a susceptibility locus for Crohn's disease on chromosome 16 , 1996, Nature.

[5]  D. Slonim From patterns to pathways: gene expression data analysis comes of age , 2002, Nature Genetics.

[6]  S. Fisher,et al.  Association between insertion mutation in NOD2 gene and Crohn's disease in German and British populations , 2001, The Lancet.

[7]  W. Wong,et al.  Transitive functional annotation by shortest-path analysis of gene expression data , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[8]  N. O’Callaghan,et al.  CARD15/NOD2 Risk Alleles in the Development of Crohn's Disease in the Australian Population , 2003, Annals of human genetics.

[9]  S. Fisher,et al.  Genetic evidence for interaction of the 5q31 cytokine locus and the CARD15 gene in Crohn disease. , 2003, American journal of human genetics.

[10]  Eric S. Lander,et al.  Identification of a gene causing human cytochrome c oxidase deficiency by integrative genomics , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[11]  S. O’Brien,et al.  Markers for mapping by admixture linkage disequilibrium in African American and Hispanic populations. , 2001, American journal of human genetics.

[12]  M. Pericak-Vance,et al.  Apolipoprotein E: high-avidity binding to beta-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer disease. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[13]  M. Daly,et al.  CARD15 genetic variation in a Quebec population: prevalence, genotype-phenotype relationship, and haplotype structure. , 2002, American journal of human genetics.

[14]  J. Cavanaugh,et al.  International collaboration provides convincing linkage replication in complex disease through analysis of a large pooled data set: Crohn disease and chromosome 16. , 2001, American journal of human genetics.

[15]  K. Sullivan,et al.  Inflammatory bowel disease in African-American children living in Georgia. , 1998, The Journal of pediatrics.

[16]  J. Stephens,et al.  Significant admixture linkage disequilibrium across 30 cM around the FY locus in African Americans. , 2000, American journal of human genetics.

[17]  Ash A. Alizadeh,et al.  Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling , 2000, Nature.

[18]  D. Jewell,et al.  Genotype-phenotype analysis of the Crohn’s disease susceptibility haplotype on chromosome 5q31 , 2003, Gut.

[19]  Mourad Sahbatou,et al.  Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn's disease , 2001, Nature.

[20]  D. Allison,et al.  Estimating African American admixture proportions by use of population-specific alleles. , 1998, American journal of human genetics.

[21]  M. Daly,et al.  High-resolution haplotype structure in the human genome , 2001, Nature Genetics.

[22]  L. Cardon,et al.  Analysis of the IBD5 locus and potential gene-gene interactions in Crohn’s disease , 2003, Gut.

[23]  J. Kirsner,et al.  An epidemiologic and demographic study of inflammatory bowel disease in black patients , 1974, The American Journal of Digestive Diseases.

[24]  D. Goldstein,et al.  Consistent long-range linkage disequilibrium generated by admixture in a Bantu-Semitic hybrid population. , 2000, American journal of human genetics.

[25]  R. Mann,et al.  Inflammatory bowel disease in rural sub-Saharan Africa: rarity of diagnosis in patients attending mission hospitals. , 1989, Digestion.

[26]  L. Kruglyak Prospects for whole-genome linkage disequilibrium mapping of common disease genes , 1999, Nature Genetics.

[27]  T. Ahmad,et al.  The molecular classification of the clinical manifestations of Crohn's disease. , 2002, Gastroenterology.

[28]  K. Weiss,et al.  Admixture as a tool for finding linked genes and detecting that difference from allelic association between loci. , 1988, Proceedings of the National Academy of Sciences of the United States of America.

[29]  H. Stefánsson,et al.  Neuregulin 1 and susceptibility to schizophrenia. , 2002, American journal of human genetics.

[30]  Luc J. Smink,et al.  Association of the T-cell regulatory gene CTLA4 with susceptibility to autoimmune disease , 2003, Nature.

[31]  Kevin J. Tracey,et al.  Nicotinic acetylcholine receptor α7 subunit is an essential regulator of inflammation , 2002, Nature.

[32]  M. Daly,et al.  IBD5 is a general risk factor for inflammatory bowel disease: replication of association with Crohn disease and identification of a novel association with ulcerative colitis. , 2003, American journal of human genetics.

[33]  M. Daly,et al.  Guilt by association , 2000, Nature Genetics.

[34]  Sinead B. O'Leary,et al.  Genetic variation in the 5q31 cytokine gene cluster confers susceptibility to Crohn disease , 2001, Nature Genetics.