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Bayesian analysis of genome-wide inflammatory bowel disease data sets reveals new risk loci.

ABSTRACT: Genome-wide association studies (GWAS) have identified and validated 200 risk loci for inflammatory bowel disease (IBD) to date, including risk loci for both Crohn's disease and ulcerative colitis. Previously studies mainly used single SNP testing methods and only reported the most significant association within each locus. Advanced methods are needed to detect additional joint effects of multiple SNPs and fine map causal variants in presence of strong linkage disequilibrium. In this study, we applied a powerful Bayesian method to analyze an existing Immunochip data sets for IBD from the international inflammatory bowel disease genetics consortium. The method jointly tested single and set-based SNPs in a unified framework and filtered indirect associations due to linkage disequilibrium, thereby fine-mapping the most likely IBD variants. Using an independent collection of individuals from 11 IBD GWAS as validation, our approach discovered and validated 9 completely new IBD loci and 5 independent signals (excluding the major histocompatibility complex) near known IBD loci reaching genome-wide significance. Several of the replicated new loci implicated functionally more interpretable genes than previous reports. The epigenetic marks at our detected IBD signals demonstrated significant activation signatures in blood cell types and correspondingly substantial repression in stem cells, suggesting regulatory links between genetic variants and IBD. Our analysis of the currently largest IBD datasets therefore added new insights that will be integral to the ongoing efforts in IBD genetics.

SUBMITTER: Zhang Y

PROVIDER: S-EPMC5838995 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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Bayesian analysis of genome-wide inflammatory bowel disease data sets reveals new risk loci.

Zhang Yu Y Tian Lifeng L Sleiman Patrick P Ghosh Soumitra S Hakonarson Hakon H

European journal of human genetics : EJHG 20171204 2

Genome-wide association studies (GWAS) have identified and validated 200 risk loci for inflammatory bowel disease (IBD) to date, including risk loci for both Crohn's disease and ulcerative colitis. Previously studies mainly used single SNP testing methods and only reported the most significant association within each locus. Advanced methods are needed to detect additional joint effects of multiple SNPs and fine map causal variants in presence of strong linkage disequilibrium. In this study, we a ...[more]

PMID: 29203833

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Project description:Background & aimsThe inflammatory bowel diseases (IBD) ulcerative colitis (UC) and Crohn's disease (CD) cause significant morbidity and are increasing in prevalence among all populations, including African Americans. More than 200 susceptibility loci have been identified in populations of predominantly European ancestry, but few loci have been associated with IBD in other ethnicities.MethodsWe performed 2 high-density, genome-wide scans comprising 2345 cases of African Americans with IBD (1646 with CD, 583 with UC, and 116 inflammatory bowel disease unclassified) and 5002 individuals without IBD (controls, identified from the Health Retirement Study and Kaiser Permanente database). Single-nucleotide polymorphisms (SNPs) associated at P < 5.0 × 10-8 in meta-analysis with a nominal evidence (P < .05) in each scan were considered to have genome-wide significance.ResultsWe detected SNPs at HLA-DRB1, and African-specific SNPs at ZNF649 and LSAMP, with associations of genome-wide significance for UC. We detected SNPs at USP25 with associations of genome-wide significance for IBD. No associations of genome-wide significance were detected for CD. In addition, 9 genes previously associated with IBD contained SNPs with significant evidence for replication (P < 1.6 × 10-6): ADCY3, CXCR6, HLA-DRB1 to HLA-DQA1 (genome-wide significance on conditioning), IL12B,PTGER4, and TNC for IBD; IL23R, PTGER4, and SNX20 (in strong linkage disequilibrium with NOD2) for CD; and KCNQ2 (near TNFRSF6B) for UC. Several of these genes, such as TNC (near TNFSF15), CXCR6, and genes associated with IBD at the HLA locus, contained SNPs with unique association patterns with African-specific alleles.ConclusionsWe performed a genome-wide association study of African Americans with IBD and identified loci associated with UC in only this population; we also replicated IBD, CD, and UC loci identified in European populations. The detection of variants associated with IBD risk in only people of African descent demonstrates the importance of studying the genetics of IBD and other complex diseases in populations beyond those of European ancestry.

Project description:Entamoeba histolytica is the etiologic agent of amebic dysentery, though clinical manifestation of infection is highly variable ranging from subclinical colonization to invasive disease. We hypothesize that host genetics contribute to the variable outcomes of E. histolytica infection; thus, we conducted a genome-wide association study (GWAS) in two independent birth cohorts of Bangladeshi infants monitored for susceptibility to E. histolytica disease in the first year of life. Children with at least one diarrheal episode positive for E. histolytica (cases) were compared to children with no detectable E. histolytica infection in the same time frame (controls). Meta-analyses under a fixed-effect inverse variance weighting model identified multiple variants in a region of chromosome 10 containing loci associated with symptomatic E. histolytica infection. An intergenic insertion between CREM and CCNY (rs58000832) achieved genome-wide significance (P value from meta-analysis [Pmeta] = 6.05 × 10-9), and each additional risk allele of rs58000832 conferred 2.42 increased odds of a diarrhea-associated E. histolytica infection. The most strongly associated single nucleotide polymorphism (SNP) within a gene was in an intron of CREM (rs58468612; Pmeta = 8.94 × 10-8), which has been implicated as a susceptibility locus for inflammatory bowel disease (IBD). Gene expression resources suggest associated loci are related to the lower expression of CREM Increased CREM expression is also observed in early E. histolytica infection. Further, CREM-/- mice were more susceptible to E. histolytica amebic colitis. These genetic associations reinforce the pathological similarities observed in gut inflammation between E. histolytica infection and IBD.IMPORTANCE Diarrhea is the second leading cause of death for children globally, causing 760,000 deaths each year in children less than 5 years old. Amebic dysentery contributes significantly to this burden, especially in developing countries. The identification of host factors that control or enable enteric pathogens has the potential to transform our understanding of disease predisposition, outcomes, and treatments. Our discovery of the transcriptional regulator cAMP-responsive element modulator (CREM) as a genetic modifier of susceptibility to amebic disease has implications for understanding the pathogenesis of other diarrheal infections. Further, emerging evidence for CREM in IBD susceptibility suggests that CREM is a critical regulator of enteric inflammation and may have broad therapeutic potential as a drug target across intestinal inflammatory diseases.

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Bayesian analysis of genome-wide inflammatory bowel disease data sets reveals new risk loci.

Publications

Bayesian analysis of genome-wide inflammatory bowel disease data sets reveals new risk loci.

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