Dissecting allele architecture of early onset IBD using high-density genotyping

Shervin Rabizadeh, Joshua Noe, Scott Snapper, Anthony Otley, Stanley Cohen, Maria Oliva-Hemker, Barbara Kirschner, Patel Ashish, David Ziring, Jonathan Evans, Susan Baker, David J. Cutler, Michael E. Zwick, David T. Okou, Sampath Prahalad, Thomas Walters, Stephen L. Guthery, Marla Dubinsky, Robert Baldassano, Wallace V. Crandall & 25 others Joel Rosh, James Markowitz, Michael Stephens, Richard Kellermayer, Marian Pfefferkorn, Melvin B. Heyman, Neal LeLeiko, David Mack, Dedrick Moulton, Michael D. Kappelman, Archana Kumar, Jarod Prince, Promita Bose, Kajari Mondal, Dhanya Ramachandran, John F. Bohnsack, Anne M. Griffiths, Yael Haberman, Jonah Essers, Susan D. Thompson, Bruce Aronow, David J. Keljo, Jeffrey S. Hyams, Lee A. Denson, Subra Kugathasan

Research output: Contribution to journalArticle

22 Citations (Scopus)

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.

Original languageEnglish (US)
Article numbere0128074
JournalPLoS One
Volume10
Issue number6
DOIs
StatePublished - Jun 22 2015

Fingerprint

inflammatory bowel disease
Inflammatory Bowel Diseases
genotyping
Alleles
alleles
Single Nucleotide Polymorphism
Crohn disease
colitis
Ulcerative Colitis
Crohn Disease
Pediatrics
loci
Genetic Loci
genetic disorders
Genetic Predisposition to Disease
Age of Onset
intestinal microorganisms
odds ratio
Population
Dissection

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Rabizadeh, S., Noe, J., Snapper, S., Otley, A., Cohen, S., Oliva-Hemker, M., ... Kugathasan, S. (2015). Dissecting allele architecture of early onset IBD using high-density genotyping. PLoS One, 10(6), [e0128074]. https://doi.org/10.1371/journal.pone.0128074

Dissecting allele architecture of early onset IBD using high-density genotyping. / Rabizadeh, Shervin; Noe, Joshua; Snapper, Scott; Otley, Anthony; Cohen, Stanley; Oliva-Hemker, Maria; Kirschner, Barbara; Ashish, Patel; Ziring, David; Evans, Jonathan; Baker, Susan; Cutler, David J.; Zwick, Michael E.; Okou, David T.; Prahalad, Sampath; Walters, Thomas; Guthery, Stephen L.; Dubinsky, Marla; Baldassano, Robert; Crandall, Wallace V.; Rosh, Joel; Markowitz, James; Stephens, Michael; Kellermayer, Richard; Pfefferkorn, Marian; Heyman, Melvin B.; LeLeiko, Neal; Mack, David; Moulton, Dedrick; 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; Keljo, David J.; Hyams, Jeffrey S.; Denson, Lee A.; Kugathasan, Subra.

In: PLoS One, Vol. 10, No. 6, e0128074, 22.06.2015.

Research output: Contribution to journalArticle

Rabizadeh, S, Noe, J, Snapper, S, Otley, A, Cohen, S, Oliva-Hemker, M, Kirschner, B, Ashish, P, Ziring, D, Evans, J, Baker, S, 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 & Kugathasan, S 2015, 'Dissecting allele architecture of early onset IBD using high-density genotyping', PLoS One, vol. 10, no. 6, e0128074. https://doi.org/10.1371/journal.pone.0128074
Rabizadeh S, Noe J, Snapper S, Otley A, Cohen S, Oliva-Hemker M et al. Dissecting allele architecture of early onset IBD using high-density genotyping. PLoS One. 2015 Jun 22;10(6). e0128074. https://doi.org/10.1371/journal.pone.0128074
Rabizadeh, Shervin ; Noe, Joshua ; Snapper, Scott ; Otley, Anthony ; Cohen, Stanley ; Oliva-Hemker, Maria ; Kirschner, Barbara ; Ashish, Patel ; Ziring, David ; Evans, Jonathan ; Baker, Susan ; Cutler, David J. ; Zwick, Michael E. ; Okou, David T. ; Prahalad, Sampath ; Walters, Thomas ; Guthery, Stephen L. ; Dubinsky, Marla ; Baldassano, Robert ; Crandall, Wallace V. ; Rosh, Joel ; Markowitz, James ; Stephens, Michael ; Kellermayer, Richard ; Pfefferkorn, Marian ; Heyman, Melvin B. ; LeLeiko, Neal ; Mack, David ; Moulton, Dedrick ; 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 ; Keljo, David J. ; Hyams, Jeffrey S. ; Denson, Lee A. ; Kugathasan, Subra. / Dissecting allele architecture of early onset IBD using high-density genotyping. In: PLoS One. 2015 ; Vol. 10, No. 6.
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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.",
author = "Shervin Rabizadeh and Joshua Noe and Scott Snapper and Anthony Otley and Stanley Cohen and Maria Oliva-Hemker and Barbara Kirschner and Patel Ashish and David Ziring and Jonathan Evans and Susan Baker and Cutler, {David J.} and Zwick, {Michael E.} and Okou, {David T.} and Sampath Prahalad and Thomas Walters and Guthery, {Stephen L.} and Marla Dubinsky and Robert Baldassano and Crandall, {Wallace V.} and Joel Rosh and James Markowitz and Michael Stephens and Richard Kellermayer and Marian Pfefferkorn and Heyman, {Melvin B.} and Neal LeLeiko and David Mack and Dedrick Moulton and Kappelman, {Michael D.} and Archana Kumar and Jarod Prince and Promita Bose and Kajari Mondal and Dhanya Ramachandran and Bohnsack, {John F.} and Griffiths, {Anne M.} and Yael Haberman and Jonah Essers and Thompson, {Susan D.} and Bruce Aronow and Keljo, {David J.} and Hyams, {Jeffrey S.} and Denson, {Lee A.} and Subra Kugathasan",
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T1 - Dissecting allele architecture of early onset IBD using high-density genotyping

AU - Rabizadeh, Shervin

AU - Noe, Joshua

AU - Snapper, Scott

AU - Otley, Anthony

AU - Cohen, Stanley

AU - Oliva-Hemker, Maria

AU - Kirschner, Barbara

AU - Ashish, Patel

AU - Ziring, David

AU - Evans, Jonathan

AU - Baker, Susan

AU - Cutler, David J.

AU - Zwick, Michael E.

AU - Okou, David T.

AU - Prahalad, Sampath

AU - Walters, Thomas

AU - Guthery, Stephen L.

AU - Dubinsky, Marla

AU - Baldassano, Robert

AU - Crandall, Wallace V.

AU - Rosh, Joel

AU - Markowitz, James

AU - Stephens, Michael

AU - Kellermayer, Richard

AU - Pfefferkorn, Marian

AU - Heyman, Melvin B.

AU - LeLeiko, Neal

AU - Mack, David

AU - Moulton, Dedrick

AU - Kappelman, Michael D.

AU - Kumar, Archana

AU - Prince, Jarod

AU - Bose, Promita

AU - Mondal, Kajari

AU - Ramachandran, Dhanya

AU - Bohnsack, John F.

AU - Griffiths, Anne M.

AU - Haberman, Yael

AU - Essers, Jonah

AU - Thompson, Susan D.

AU - Aronow, Bruce

AU - Keljo, David J.

AU - Hyams, Jeffrey S.

AU - Denson, Lee A.

AU - Kugathasan, Subra

PY - 2015/6/22

Y1 - 2015/6/22

N2 - 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.

AB - 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.

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