Improved Detection Of Variants Associated With Crohn's Disease And Ulcerative Colitis Using The CFDR Method

Genome-wide association studies(GWAS)have been widely applied to identify single nucleotide polymorphisms(SNPs)associated with inflammatory bowel disease(IBD).The IBD related GWAS mainly includes those researches identifying SNPs associated with Ulcerative colitis(UC)or Crohn's disease(CD)or both.So far,GWAS have identified more than 200 genes associated with the two diseases.However,these genes explain only a small part of the estimated heritability,cost-effective analytical methods are needed to better and more efficiently utilize the existing data to identify more loci associated with the diseases for helping us understand the pathogenic mechanism of the diseases.Objectives To identify more genetic loci associated with UC and CD by using efficient statistical analysis methods for secondary mining of the IBD related GWAS summary data.Methods The IBD related GWAS meta summary data sets were downloaded from the official website of the International Inflammatory Bowel Disease Genetics Consortium(the UC related GWAS meta summary data including 20,464 controls and 6,968 cases,and the CD related GWAS meta summary data involving 14,927 controls and 5,956 cases).Firstly,We used the stratified conditional Quantile-Quantile(Q-Q)Plots and the corresponding conditional true discovery rate(TDR)plots to assess the degree of the pleiotropic enrichment between these two diseases.Then,the cFDR and ccFDR corresponding to each SNP were calculated by using the conditional false discovery rate(cFDR)method.Finally,we used gene function annotation and path ways analysis to determine in which functional groups and metabolic pathways the identified genes were enriched.Results 1.The stratified conditional Q-Q plots and conditional TDR plots showed a strong pleiotropic enrichment between UC and CD.2.A total of 130 SNPs for UC and 174 SNPs for CD were identified with a significance threshold of cFDR < 0.01,and respectively 43 novel loci are associated with UC;86 novel loci for CD.3.Conjunction cFDR(ccFDR)analysis identified 75 independent pleiotropic SNPs for both UC and CD(ccFDR < 0.01),including 22 novel loci.Conclusions The cFDR method successfully identified some novel SNPs associated with UC and CD as well as some novel SNPs associated with the both,indicating a strong pleiotropic enrichment between UC and CD,and revealing that some potential common pathogenic mechanism exist between the two diseases.These results provide us novel insights into the etiology of UC and CD and deepen our understanding of the common mechanisms between these two diseases.