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

Cutler DJ, Zwick ME, Okou DT, Prahalad S, Walters T, Guthery SL, Dubinsky M, Baldassano R, Crandall WV, Rosh J, Markowitz J, Stephens M, Kellermayer R, Pfefferkorn M, Heyman MB, LeLeiko N, Mack D, Moulton D, Kappelman MD, Kumar A, Prince J, Bose P, Mondal K, Ramachandran D, Bohnsack JF, Griffiths AM, Haberman Y, Essers J, Thompson SD, Aronow B, Keljo DJ, Hyams JS, Denson LA, PRO-KIIDS Research GroupKugathasan S - PLoS ONE (2015)

Bottom Line: Earlier genetic studies performed in mostly adult population of European descent identified 163 loci affecting IBD risk, but most have relatively modest effect sizes, and altogether explain only ~20% of the genetic susceptibility.This immunochip genotyping study failed to identify additional common variants that may explain the distinct phenotype that characterize early onset IBD.A comprehensive dissection of genetic loci is necessary to further characterize the genetic architecture of early onset IBD.

View Article: PubMed Central - PubMed

Affiliation: Department of Human Genetics, Emory University, Atlanta, Georgia, United States of America.

ABSTRACT

Background: The inflammatory bowel diseases (IBD) are common, complex disorders in which genetic and environmental factors are believed to interact leading to chronic inflammatory responses against the gut microbiota. Earlier genetic studies performed in mostly adult population of European descent identified 163 loci affecting IBD risk, but most have relatively modest effect sizes, and altogether explain only ~20% of the genetic susceptibility. Pediatric onset represents about 25% of overall incident cases in IBD, characterized by distinct disease physiology, course and risks. The goal of this study is to compare the allelic architecture of early onset IBD with adult onset in population of European descent.

Methods: We performed a fine mapping association study of early onset IBD using high-density Immunochip genotyping on 1008 pediatric-onset IBD cases (801 Crohn's disease; 121 ulcerative colitis and 86 IBD undetermined) and 1633 healthy controls. Of the 158 SNP genotypes obtained (out of the 163 identified in adult onset), this study replicated 4% (5 SNPs out of 136) of the SNPs identified in the Crohn's disease (CD) cases and 0.8% (1 SNP out of 128) in the ulcerative colitis (UC) cases. Replicated SNPs implicated the well known NOD2 and IL23R. The point estimate for the odds ratio (ORs) for NOD2 was above and outside the confidence intervals reported in adult onset. A polygenic liability score weakly predicted the age of onset for a larger collection of CD cases (p< 0.03, R2= 0.007), but not for the smaller number of UC cases.

Conclusions: The allelic architecture of common susceptibility variants for early onset IBD is similar to that of adult onset. This immunochip genotyping study failed to identify additional common variants that may explain the distinct phenotype that characterize early onset IBD. A comprehensive dissection of genetic loci is necessary to further characterize the genetic architecture of early onset IBD.

No MeSH data available.


Related in: MedlinePlus

Manhattan plot of SNP association p-values result for CD vs controls within pediatric onset IBD.The horizontal black line represent the thresholds of P = 3.57 x 10–7 for Bonferroni significance
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pone.0128074.g001: Manhattan plot of SNP association p-values result for CD vs controls within pediatric onset IBD.The horizontal black line represent the thresholds of P = 3.57 x 10–7 for Bonferroni significance

Mentions: We performed a genome-wide scan of our collection of early-onset CD cases vs controls (S1 Table) and early-onset UC vs controls (S2 Table). Fig 1 shows the results of CD cases vs controls for the ~140,000 SNPs that passed QC procedures. Highly conservative Bonferroni correction for multiple testing suggests any SNP p-value below 0.05/140000 = 3.57 x 10–7 is experiment-wide significant, which corresponds to a-log10(p) of approximately 6.5. Some of the most significant loci are labeled for the CD vs controls analysis and are shown in Fig 1. None of the loci in the remaining cases (IBDminusCD) vs controls analysis exceeded our conservative experiment-wide threshold for statistical significance, which reflects the limited sample size of this portion of our study (S1 Fig).


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

Cutler DJ, Zwick ME, Okou DT, Prahalad S, Walters T, Guthery SL, Dubinsky M, Baldassano R, Crandall WV, Rosh J, Markowitz J, Stephens M, Kellermayer R, Pfefferkorn M, Heyman MB, LeLeiko N, Mack D, Moulton D, Kappelman MD, Kumar A, Prince J, Bose P, Mondal K, Ramachandran D, Bohnsack JF, Griffiths AM, Haberman Y, Essers J, Thompson SD, Aronow B, Keljo DJ, Hyams JS, Denson LA, PRO-KIIDS Research GroupKugathasan S - PLoS ONE (2015)

Manhattan plot of SNP association p-values result for CD vs controls within pediatric onset IBD.The horizontal black line represent the thresholds of P = 3.57 x 10–7 for Bonferroni significance
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4476779&req=5

pone.0128074.g001: Manhattan plot of SNP association p-values result for CD vs controls within pediatric onset IBD.The horizontal black line represent the thresholds of P = 3.57 x 10–7 for Bonferroni significance
Mentions: We performed a genome-wide scan of our collection of early-onset CD cases vs controls (S1 Table) and early-onset UC vs controls (S2 Table). Fig 1 shows the results of CD cases vs controls for the ~140,000 SNPs that passed QC procedures. Highly conservative Bonferroni correction for multiple testing suggests any SNP p-value below 0.05/140000 = 3.57 x 10–7 is experiment-wide significant, which corresponds to a-log10(p) of approximately 6.5. Some of the most significant loci are labeled for the CD vs controls analysis and are shown in Fig 1. None of the loci in the remaining cases (IBDminusCD) vs controls analysis exceeded our conservative experiment-wide threshold for statistical significance, which reflects the limited sample size of this portion of our study (S1 Fig).

Bottom Line: Earlier genetic studies performed in mostly adult population of European descent identified 163 loci affecting IBD risk, but most have relatively modest effect sizes, and altogether explain only ~20% of the genetic susceptibility.This immunochip genotyping study failed to identify additional common variants that may explain the distinct phenotype that characterize early onset IBD.A comprehensive dissection of genetic loci is necessary to further characterize the genetic architecture of early onset IBD.

View Article: PubMed Central - PubMed

Affiliation: Department of Human Genetics, Emory University, Atlanta, Georgia, United States of America.

ABSTRACT

Background: The inflammatory bowel diseases (IBD) are common, complex disorders in which genetic and environmental factors are believed to interact leading to chronic inflammatory responses against the gut microbiota. Earlier genetic studies performed in mostly adult population of European descent identified 163 loci affecting IBD risk, but most have relatively modest effect sizes, and altogether explain only ~20% of the genetic susceptibility. Pediatric onset represents about 25% of overall incident cases in IBD, characterized by distinct disease physiology, course and risks. The goal of this study is to compare the allelic architecture of early onset IBD with adult onset in population of European descent.

Methods: We performed a fine mapping association study of early onset IBD using high-density Immunochip genotyping on 1008 pediatric-onset IBD cases (801 Crohn's disease; 121 ulcerative colitis and 86 IBD undetermined) and 1633 healthy controls. Of the 158 SNP genotypes obtained (out of the 163 identified in adult onset), this study replicated 4% (5 SNPs out of 136) of the SNPs identified in the Crohn's disease (CD) cases and 0.8% (1 SNP out of 128) in the ulcerative colitis (UC) cases. Replicated SNPs implicated the well known NOD2 and IL23R. The point estimate for the odds ratio (ORs) for NOD2 was above and outside the confidence intervals reported in adult onset. A polygenic liability score weakly predicted the age of onset for a larger collection of CD cases (p< 0.03, R2= 0.007), but not for the smaller number of UC cases.

Conclusions: The allelic architecture of common susceptibility variants for early onset IBD is similar to that of adult onset. This immunochip genotyping study failed to identify additional common variants that may explain the distinct phenotype that characterize early onset IBD. A comprehensive dissection of genetic loci is necessary to further characterize the genetic architecture of early onset IBD.

No MeSH data available.


Related in: MedlinePlus