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A Systematic Genome-Wide Association Analysis for Inflammatory Bowel Diseases (IBD)

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A Systematic Genome-Wide Association Analysis for Inflammatory Bowel Diseases (IBD) A systematic genome-wide association analysis for inflammatory bowel diseases (IBD) Dissertation zur Erlangung des Doktorgrades der Mathematisch-Naturwissenschaftlichen Fakultät der Christian-Albrechts-Universität zu Kiel vorgelegt von Dipl.-Biol. ANDRE FRANKE Kiel, im September 2006 Referent: Prof. Dr. Dr. h.c. Thomas C.G. Bosch Koreferent: Prof. Dr. Stefan Schreiber Tag der mündlichen Prüfung: Zum Druck genehmigt: der Dekan “After great pain a formal feeling comes.” (Emily Dickinson) To my wife and family ii Table of contents Abbreviations, units, symbols, and acronyms . vi List of figures . xiii List of tables . .xv 1 Introduction . .1 1.1 Inflammatory bowel diseases, a complex disorder . 1 1.1.1 Pathogenesis and pathophysiology. .2 1.2 Genetics basis of inflammatory bowel diseases . 6 1.2.1 Genetic evidence from family and twin studies . .6 1.2.2 Single nucleotide polymorphisms (SNPs) . .7 1.2.3 Linkage studies . .8 1.2.4 Association studies . 10 1.2.5 Known susceptibility genes . 12 1.2.5.1 CARD15. .12 1.2.5.2 CARD4. .15 1.2.5.3 TNF-α . .15 1.2.5.4 5q31 haplotype . .16 1.2.5.5 DLG5 . .17 1.2.5.6 TNFSF15 . .18 1.2.5.7 HLA/MHC on chromosome 6 . .19 1.2.5.8 Other proposed IBD susceptibility genes . .20 1.2.6 Animal models. 21 1.3 Aims of this study . 23 2 Methods . .24 2.1 Laboratory information management system (LIMS) . 24 2.2 Recruitment. 25 2.3 Sample preparation. 27 2.3.1 DNA extraction from blood. 27 2.3.2 Plate design . 28 2.4 Measurement of DNA concentration . 29 2.5 Whole genome amplification (WGA). 31 2.6 Agarose gel electrophoresis . 33 2.7 Mutation detection . 34 2.7.1 Primer design. 34 2.7.2 Polymerase chain reaction (PCR) . 35 2.7.3 DNA sequencing . 35 2.7.3.1 Sequence analysis . .38 iii 2.8 Genotyping . 39 2.8.1 TaqMan® . 39 2.8.2 SNPlex™ . 44 2.8.3 SNP selection . 48 2.8.4 Design of coding SNPlex™ pools by Applied Biosystems . 48 2.8.5 Affymetrix arrays . 49 2.8.6 Quality control. 53 2.9 Association analyses . 55 2.9.1 Linkage disequilibrium (LD). 56 2.9.2 Case-control single-point analyses . 58 2.9.2.1 Genotype-based case-control comparison (CCG) . .58 2.9.2.2 Allele-based case-control comparison (CCA) . .59 2.9.2.3 Odds ratio (OR) . .61 2.9.3 GENOMIZER - an analysis tool for genome-wide association studies . 63 2.9.4 Transmission disequilibrium test (TDT) . 65 2.9.5 Haplotype analysis . 67 2.9.5.1 Haplotype tagging SNPs . .69 2.9.6 Multivariate logistic regression . 70 2.9.7 Fisher’s exact test . 70 2.10 Functional experiments . 71 2.10.1 Gene expression experiments . 71 2.10.1.1 Stimulation of cell lines. .71 2.10.1.2 RNA extraction from cells. .72 2.10.1.3 cDNA synthesis . .73 2.10.1.4 Plate production . .73 2.10.1.5 Real-time PCR . .74 2.10.2 Isolation of primary epithelial cells (IECs). 75 2.10.3 RT-PCR . 75 2.10.4 Western Blot. 76 2.10.5 Immunohistochemistry. 76 2.11 Protein modeling . 77 3 Results . .80 3.1 Genome-wide screenings (GWS) . 80 3.1.1 Direct approach: cSNP experiment. 80 3.1.2 LD-based approach: 100k SNP array . 83 3.1.2.1 Randomization of the 100k dataset . .88 3.2 Replication of leads . 89 3.2.1 Replication of the ATG16L1 nsSNP in a UK panel . 89 3.2.2 Replication of the NELL1 and 5p13.1 lead SNPs in independent panels . 90 3.3 Mutation detection and fine mapping of.
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