Abstract for presentation at 11th International Congress of Human Genetics

A genome-wide direct association study of Crohn’s disease with 19,772 putative functional coding SNPs

  • Francisco De La Vega, Applied Biosystems, Foster City, CA, USA., United States
  • Jochen Hampe, Institute of Clinical Molecular Biology, University of Kiel, Germany, Germany
  • Andre Franke, Institute of Clinical Molecular Biology, University of Kiel, Germany, Germany
  • Tanja Henke, Institute of Clinical Molecular Biology, University of Kiel, Germany, Germany
  • Birthe Petersen, Institute of Clinical Molecular Biology, University of Kiel, Germany, Germany
  • Simone Guenther, Applied Biosystems, Germany, Germany
  • Dennis Gilbert, Applied Biosystems, Foster City, CA, USA., United States
  • Stefan Schreiber, Institute of Clinical Molecular Biology, University of Kiel, Germany, Germany

    • Genetic association studies of complex disease can be carried out by: indirect association, in which surrogate markers assumed to be in linkage disequilibrium with the disease allele are tested for trait association; or direct association, in which a list of putatively functional SNPs are tested for their disease relevance directly. A genome scan with putative functional SNPs (pfSNP) may require typing only the tens of thousands common causative variants implicated in human complex disease. We pursued such a strategy in an association study of Chron’s disease, a complex inflammatory disease of the gastrointestinal tract. Previous studies, that have identified a pair of loci associated with susceptibility for this disease, point to a polygenic etiology. A sample of 735 Crohn’s disease patients and 368 controls from northern Germany was genotyped with 19,772 non-synonymous coding SNPs utilizing the SNPlex(TM) Genotyping System, a multiplexed oligonucleotide ligation assay utilizing capillary electrophoresis as the readout. These SNPs were selected from a database of over 70,000 candidate pfSNPs filtered on their measured or expected heterozygosity in populations of European and African descent. The top 100 significant hits (p<0.05), alongside with tagging SNPs selected for 5 genes and one region, were submitted for replication in a cohort of 1096 controls, 1153 cases, and 479 trios from northern Germany, and 343 controls and 359 cases from Italy. The analysis of the replication sample resulted in a dozen of significantly associated SNPs within a previously unidentified gene (p<0.05 Chi2 and TDT tests), including one putative functional variant for which a plausible functional hypothesis can be formulated and is currently under investigation. These results demonstrate the feasibility of direct genome-wide association scans with a relatively small number of putative functional variants as an effective strategy for performing association studies of complex disease.

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