Title Page
ABSTRACT
Contents
ABBREVIATIONS 9
1. INTRODUCTION 10
2. MATERIALS AND METHODS 11
2.1. Study subjects 11
2.2. Quality control and imputation 11
2.3. Association analysis comparing CD with UC 14
2.4. CC-GWAS analysis using summary statistics of Europeans or East Asians 15
2.5. Expression quantitative trait loci (eQTL) analysis 15
2.6. Gene annotation 15
2.7. Polygenic risk scores 16
3. RESULTS 17
3.1. Differentiating genetic contribution to CD and UC 17
3.2. Two novel loci with divergent effects on CD and UC 28
3.3. Replications of loci with divergent effects on CD and UC 32
3.4. Polygenic risk score analysis 32
4. DISCUSSION 39
Web resources 43
References 44
국문요약 49
Table 1. Clinical characteristics of Korean patients with CD and UC. 13
Table 2. Lead SNPs in the 10 loci with P meta 〈1.00 x 10⁻⁷ from fixed-effects meta-analysis.[이미지참조] 20
Table 3. Combined analysis of 2 novel loci with divergent effects on CD and UC in Koreans. 21
Table 4. Combined analysis of the 8q21 locus using cohort IV. 22
Table 5. Associations of the 9 loci after adjustment for age and sex. 24
Table 6. Nine loci with divergent effects on CD and UC in Koreans. 25
Table 7. List of SNPs in the 95% credible set of 9 identified loci. 27
Table 8. eQTLs in the 9 loci with divergent effects on CD and UC in Koreans. 30
Table 9. Associations of the 9 loci from the CC-GWAS analysis in East Asians and Europeans. 34
Table 10. Significant loci from the CC-GWAS analysis in East Asians and Europeans (CC-GWASOLS P 〈5 x 10⁻⁸ and CC-GWASexact P 〈10⁻⁴).[이미지참조] 35
Table 11. Variance explained in CD-UC status by PRS. 40
Table 12. Genetic correlation between Koreans and Europeans using LDSC. 42
Figure 1. Study design to identify genetic loci with divergent effects on Crohn's disease (CD) and ulcerative colitis (UC). 12
Figure 2. Quantile-quantile plot for meta-analysis of the 3 GWAS datasets. 18
Figure 3. Manhattan plot for the 9 identified loci with divergent effects in CD and UC. 19
Figure 4. Conditional association signals for 2 novel loci. 23
Figure 5. Comparison of OR values in CD and UC for the 9 identified loci with divergent effects. 26
Figure 6. Regional association plots for two novel loci: (A) rs885026 at 12q24 and (B) rs9842650 at 3q13. 29
Figure 7. Replication of the loci with divergent effects on CD and UC in other populations using a case-case GWAS (CC-GWAS). 33
Figure 8. PRS analysis of patients with CD and UC. 36
Figure 9. Normal distributions of the PRS for cohort III based on cohorts I and II. 37
Figure 10. Receiver operating characteristic (ROC) curve to predict accuracy in correctly classifying patients with CD and UC (738 CD/ 601 UC cases). 38