Dissecting Allele Architecture of Early Onset IBD Using High-Density Genotyping

Rabizadeh, Shervin; Noe, Joshua D.; Snapper, Scott B.; Otley, Anthony; Cohen, Stanley A.; Oliva-Hemker, Maria; Kirschner, Barbara S.; Patel, Ashish; Ziring, David; Evans, Jonathan; Baker, Susan S.; Cutler, David J.; Zwick, Michael E.; Okou, David T.; Prahalad, Sampath; Walters, Thomas D.; Guthery, Stephen L.; Dubinsky, Marla; Baldassano, Robert N.; Crandall, Wallace; Rosh, Joel R.; Markowitz, James; Stephens, Michael C.; Kellermayer, Richárd; Pfefferkorn, Marian D.; Heyman, Melvin B.; LeLeiko, Neal S.; Mack, David R.; Moulton, Dedrick E.; Kappelman, Michael D.; Kumar, Archana; Prince, Jarod; Bose, Promita; Mondal, Kajari; Ramachandran, Dhanya; Bohnsack, John F.; Griffiths, Anne M.; Haberman, Yael; Essers, Jonah; Thompson, Susan D.; Aronow, Bruce J.; Keljo, David J.; Hyams, Jeffrey S.; Denson, Lee A.; Kugathasan, Subra

doi:10.1371/journal.pone.0128074

Cited by 35 publications

(23 citation statements)

References 51 publications

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“…GWASs have limited utility in identifying low frequency and rare variants with greater penetrance and true causal genetic variants associated with VEO IBD19. To further search for potential differences in the genetic architecture of VEO and adult-onset IBD, we performed WES analysis for 21 and 22 children diagnosed with CD and UC, respectively, at less than 6 years of age (age range 1–5; median −3) and 23 and 22 patients diagnosed with CD and UC, respectively, after 40 years of age (age range 41–60; median −48.5).…”

Section: Resultsmentioning

confidence: 99%

Genetic architecture differences between pediatric and adult-onset inflammatory bowel diseases in the Polish population

Ostrowski

Paziewska

Łazowska

et al. 2016

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Most inflammatory bowel diseases (IBDs) are classic complex disorders represented by common alleles. Here we aimed to define the genetic architecture of pediatric and adult-onset IBDs for the Polish population. A total of 1495 patients were recruited, including 761 patients with Crohn’s disease (CD; 424 pediatric), 734 patients with ulcerative colitis (UC; 390 pediatric), and 934 healthy controls. Allelotyping employed a pooled-DNA genome-wide association study (GWAS) and was validated by individual genotyping. Whole exome sequencing (WES) was performed on 44 IBD patients diagnosed before 6 years of age, 45 patients diagnosed after 40 years of age, and 18 healthy controls. Altogether, out of 88 selected SNPs, 31 SNPs were replicated for association with IBD. A novel BRD2 (rs1049526) association reached significance of P = 5.2 × 10−11 and odds ratio (OR) = 2.43. Twenty SNPs were shared between pediatric and adult patients; 1 and 7 were unique to adult-onset and pediatric-onset IBD, respectively. WES identified numerous rare and potentially deleterious variants in IBD-associated or innate immunity-associated genes. Deleterious alleles in both groups were over-represented among rare variants in affected children. Our GWAS revealed differences in the polygenic architecture of pediatric- and adult-onset IBD. A significant accumulation of rare and deleterious variants in affected children suggests a contribution by yet unexplained genetic components.

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Section: Resultsmentioning

confidence: 99%

Genetic architecture differences between pediatric and adult-onset inflammatory bowel diseases in the Polish population

Ostrowski

Paziewska

Łazowska

et al. 2016

Sci Rep

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“…9 Granulocyte–macrophage colony-stimulating factor (GM-CSF) autoantibodies were measured at Cincinnati Children’s Hospital Medical Center (OH, USA). 10 NOD2 genotypes (rs2066844, rs2066845, and rs2066847) were extracted from previously published data 11 or determined with TaqMan (Thermo Fisher Scientific, Waltham, MA, USA) single nucleotide polymorphism genotyping assays. We used the score routine available in PLINK to generate a weighted genetic risk score on the basis of Immunochip data 11 for 137 single nucleotide polymorphisms associated with Crohn’s disease and inflammatory bowel disease.…”

Section: Methodsmentioning

confidence: 99%

Prediction of complicated disease course for children newly diagnosed with Crohn's disease: a multicentre inception cohort study

et al. 2017

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Summary Background Stricturing and penetrating complications account for substantial morbidity and health-care costs in paediatric and adult onset Crohn’s disease. Validated models to predict risk for complications are not available, and the effect of treatment on risk is unknown. Methods We did a prospective inception cohort study of paediatric patients with newly diagnosed Crohn’s disease at 28 sites in the USA and Canada. Genotypes, antimicrobial serologies, ileal gene expression, and ileal, rectal, and faecal microbiota were assessed. A competing-risk model for disease complications was derived and validated in independent groups. Propensity-score matching tested the effect of anti-tumour necrosis factor α (TNFα) therapy exposure within 90 days of diagnosis on complication risk. Findings Between Nov 1, 2008, and June 30, 2012, we enrolled 913 patients, 78 (9%) of whom experienced Crohn’s disease complications. The validated competing-risk model included age, race, disease location, and antimicrobial serologies and provided a sensitivity of 66% (95% CI 51–82) and specificity of 63% (55–71), with a negative predictive value of 95% (94–97). Patients who received early anti-TNFα therapy were less likely to have penetrating complications (hazard ratio [HR] 0·30, 95% CI 0·10–0·89; p=0·0296) but not stricturing complication (1·13, 0·51–2·51; 0·76) than were those who did not receive early anti-TNFα therapy. Ruminococcus was implicated in stricturing complications and Veillonella in penetrating complications. Ileal genes controlling extracellular matrix production were upregulated at diagnosis, and this gene signature was associated with stricturing in the risk model (HR 1·70, 95% CI 1·12–2·57; p=0·0120). When this gene signature was included, the model’s specificity improved to 71%. Interpretation Our findings support the usefulness of risk stratification of paediatric patients with Crohn’s disease at diagnosis, and selection of anti-TNFα therapy. Funding Crohn’s and Colitis Foundation of America, Cincinnati Children’s Hospital Research Foundation Digestive Health Center.

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“…Control AA subjects of GWAS1 (n=1678) were derived from the dbGaP Health and Retirement Study (HRS), a longitudinal panel study sponsored by the National Institute on Aging. Samples with IBD from GWAS2 (n=1087 IBD cases [803 CD, 215 UC, 69 IBD-U]) were obtained by Emory University from the GENESIS study (an ancillary study of the NIDDK IBDGC, coordinated by Emory University with recruitment of IBD cases and matched controls from 12 of their collaborating IBD centers and the RISK study, a large pediatric CD inception cohort with recruitment of IBD cases from 29 IBD centers 13 ). The GWAS2 AA control subjects (n=3324) were obtained from the Kaiser RPGEH study (a research program at Kaiser Permanente in California with the goal of discovering which genes and environmental factors linked to specific diseases).…”

Section: Methodsmentioning

confidence: 99%

Genome-Wide Association Study Identifies African-Specific Susceptibility Loci in African Americans With Inflammatory Bowel Disease

et al. 2017

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Background & Aims The 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. Methods We 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 [IBD-U]) 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. Results We 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 associations 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. Conclusions We performed a genome-wide association study of African Americans with IBD and identified loci associated with CD and UC in only this population; we also replicated 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.

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Dissecting Allele Architecture of Early Onset IBD Using High-Density Genotyping

Cited by 35 publications

References 51 publications

Genetic architecture differences between pediatric and adult-onset inflammatory bowel diseases in the Polish population

Genetic architecture differences between pediatric and adult-onset inflammatory bowel diseases in the Polish population

Prediction of complicated disease course for children newly diagnosed with Crohn's disease: a multicentre inception cohort study

Genome-Wide Association Study Identifies African-Specific Susceptibility Loci in African Americans With Inflammatory Bowel Disease

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