More than 1,000 susceptibility loci have been identified through genome-wide association studies (GWAS) of common variants; however, the specific genes and full allelic spectrum of causal variants underlying these findings have not yet been defined. Here we used pooled next-generation sequencing to study 56 genes from regions associated with Crohn's disease in 350 cases and 350 controls. Through follow-up genotyping of 70 rare and low-frequency protein-altering variants in nine independent case-control series (16,054 Crohn's disease cases, 12,153 ulcerative colitis cases and 17,575 healthy controls), we identified four additional independent risk factors in NOD2, two additional protective variants in IL23R, a highly significant association with a protective splice variant in CARD9 (P < 1 × 10(-16), odds ratio ≈ 0.29) and additional associations with coding variants in IL18RAP, CUL2, C1orf106, PTPN22 and MUC19. We extend the results of successful GWAS by identifying new, rare and probably functional variants that could aid functional experiments and predictive models.
Pubmed ID: 21983784 RIS Download
Mesh terms: Case-Control Studies | Cell Line | Genetic Predisposition to Disease | Genome-Wide Association Study | Humans | Inflammatory Bowel Diseases | Nod2 Signaling Adaptor Protein | RNA Splicing | Receptors, Interleukin | Sequence Analysis, DNA
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The program of medical genome research is a large-scale biomedical research project which extends the national genome research net (NGFN) and will be funded by the federal ministry of education and research (BMBF) from 2008-2013. Currently the program includes two fields: * Research ** NGFN-Plus: With the aim on combating diseases that are central to health policy, several hundred researchers are systematically investigating the complex molecular interactions of the human body. They are organized in 26 Integrated Genome Research Networks. * Application ** NGFN-Transfer: The rapid transfer of results from medical genome research into medical and industrial application is the aim of the scientists from research institutes and biomedical enterprises that cooperate in eight Innovation Alliances. AREAS OF DISEASE * Cardiovascular disease * Cancer * Neuronal diseases * Infections and Inflammations * Environmental factors
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