A genome-wide scan of ashkenazi jewish crohn's disease suggests novel susceptibility loci

Eimear E. Kenny, Itsik Pe'er, Amir Karban, Laurie Ozelius, Adele A. Mitchell, Sok Meng Ng, Monica Erazo, Harry Ostrer, Clara Abraham, Maria T. Abreu, Gil Atzmon, Nir Barzilai, Steven R. Brant, Susan Bressman, Edward R. Burns, Yehuda Chowers, Lorraine N. Clark, Ariel Darvasi, Dana Doheny, Richard H. Duerr & 23 others Rami Eliakim, Nir Giladi, Peter K. Gregersen, Hakon Hakonarson, Michelle R. Jones, Karen Marder, Dermot P B McGovern, Jennifer Mulle, Avi Orr-Urtreger, Deborah D. Proctor, Ann Pulver, Jerome I. Rotter, Mark S. Silverberg, Thomas A. Ullman, Stephen T. Warren, Matti Waterman, Wei Zhang, Aviv Bergman, Lloyd Mayer, Seymour Katz, Robert J. Desnick, Judy H. Cho, Inga Peter

Research output: Contribution to journalArticle

85 Citations (Scopus)

Abstract

Crohn's disease (CD) is a complex disorder resulting from the interaction of intestinal microbiota with the host immune system in genetically susceptible individuals. The largest meta-analysis of genome-wide association to date identified 71 CD-susceptibility loci in individuals of European ancestry. An important epidemiological feature of CD is that it is 2-4 times more prevalent among individuals of Ashkenazi Jewish (AJ) descent compared to non-Jewish Europeans (NJ). To explore genetic variation associated with CD in AJs, we conducted a genome-wide association study (GWAS) by combining raw genotype data across 10 AJ cohorts consisting of 907 cases and 2,345 controls in the discovery stage, followed up by a replication study in 971 cases and 2,124 controls. We confirmed genome-wide significant associations of 9 known CD loci in AJs and replicated 3 additional loci with strong signal (p<5×10 -6). Novel signals detected among AJs were mapped to chromosomes 5q21.1 (rs7705924, combined p = 2×10 -8; combined odds ratio OR = 1.48), 2p15 (rs6545946, p = 7×10 -9; OR = 1.16), 8q21.11 (rs12677663, p = 2×10 -8; OR = 1.15), 10q26.3 (rs10734105, p = 3×10 -8; OR = 1.27), and 11q12.1 (rs11229030, p = 8×10 -9; OR = 1.15), implicating biologically plausible candidate genes, including RPL7, CPAMD8, PRG2, and PRG3. In all, the 16 replicated and newly discovered loci, in addition to the three coding NOD2 variants, accounted for 11.2% of the total genetic variance for CD risk in the AJ population. This study demonstrates the complementary value of genetic studies in the Ashkenazim.

Original languageEnglish (US)
Article numbere1002559
JournalPLoS Genetics
Volume8
Issue number3
DOIs
StatePublished - Mar 2012

Fingerprint

Crohn disease
Crohn Disease
genome
Genome
loci
Genome-Wide Association Study
Disease Susceptibility
meta-analysis
immune system
genetic variance
intestinal microorganisms
ancestry
odds ratio
disease resistance
Meta-Analysis
genetic variation
chromosome
Immune System
genotype
Chromosomes

ASJC Scopus subject areas

  • Genetics
  • Molecular Biology
  • Ecology, Evolution, Behavior and Systematics
  • Cancer Research
  • Genetics(clinical)

Cite this

Kenny, E. E., Pe'er, I., Karban, A., Ozelius, L., Mitchell, A. A., Ng, S. M., ... Peter, I. (2012). A genome-wide scan of ashkenazi jewish crohn's disease suggests novel susceptibility loci. PLoS Genetics, 8(3), [e1002559]. https://doi.org/10.1371/journal.pgen.1002559

A genome-wide scan of ashkenazi jewish crohn's disease suggests novel susceptibility loci. / Kenny, Eimear E.; Pe'er, Itsik; Karban, Amir; Ozelius, Laurie; Mitchell, Adele A.; Ng, Sok Meng; Erazo, Monica; Ostrer, Harry; Abraham, Clara; Abreu, Maria T.; Atzmon, Gil; Barzilai, Nir; Brant, Steven R.; Bressman, Susan; Burns, Edward R.; Chowers, Yehuda; Clark, Lorraine N.; Darvasi, Ariel; Doheny, Dana; Duerr, Richard H.; Eliakim, Rami; Giladi, Nir; Gregersen, Peter K.; Hakonarson, Hakon; Jones, Michelle R.; Marder, Karen; McGovern, Dermot P B; Mulle, Jennifer; Orr-Urtreger, Avi; Proctor, Deborah D.; Pulver, Ann; Rotter, Jerome I.; Silverberg, Mark S.; Ullman, Thomas A.; Warren, Stephen T.; Waterman, Matti; Zhang, Wei; Bergman, Aviv; Mayer, Lloyd; Katz, Seymour; Desnick, Robert J.; Cho, Judy H.; Peter, Inga.

In: PLoS Genetics, Vol. 8, No. 3, e1002559, 03.2012.

Research output: Contribution to journalArticle

Kenny, EE, Pe'er, I, Karban, A, Ozelius, L, Mitchell, AA, Ng, SM, Erazo, M, Ostrer, H, Abraham, C, Abreu, MT, Atzmon, G, Barzilai, N, Brant, SR, Bressman, S, Burns, ER, Chowers, Y, Clark, LN, Darvasi, A, Doheny, D, Duerr, RH, Eliakim, R, Giladi, N, Gregersen, PK, Hakonarson, H, Jones, MR, Marder, K, McGovern, DPB, Mulle, J, Orr-Urtreger, A, Proctor, DD, Pulver, A, Rotter, JI, Silverberg, MS, Ullman, TA, Warren, ST, Waterman, M, Zhang, W, Bergman, A, Mayer, L, Katz, S, Desnick, RJ, Cho, JH & Peter, I 2012, 'A genome-wide scan of ashkenazi jewish crohn's disease suggests novel susceptibility loci', PLoS Genetics, vol. 8, no. 3, e1002559. https://doi.org/10.1371/journal.pgen.1002559
Kenny, Eimear E. ; Pe'er, Itsik ; Karban, Amir ; Ozelius, Laurie ; Mitchell, Adele A. ; Ng, Sok Meng ; Erazo, Monica ; Ostrer, Harry ; Abraham, Clara ; Abreu, Maria T. ; Atzmon, Gil ; Barzilai, Nir ; Brant, Steven R. ; Bressman, Susan ; Burns, Edward R. ; Chowers, Yehuda ; Clark, Lorraine N. ; Darvasi, Ariel ; Doheny, Dana ; Duerr, Richard H. ; Eliakim, Rami ; Giladi, Nir ; Gregersen, Peter K. ; Hakonarson, Hakon ; Jones, Michelle R. ; Marder, Karen ; McGovern, Dermot P B ; Mulle, Jennifer ; Orr-Urtreger, Avi ; Proctor, Deborah D. ; Pulver, Ann ; Rotter, Jerome I. ; Silverberg, Mark S. ; Ullman, Thomas A. ; Warren, Stephen T. ; Waterman, Matti ; Zhang, Wei ; Bergman, Aviv ; Mayer, Lloyd ; Katz, Seymour ; Desnick, Robert J. ; Cho, Judy H. ; Peter, Inga. / A genome-wide scan of ashkenazi jewish crohn's disease suggests novel susceptibility loci. In: PLoS Genetics. 2012 ; Vol. 8, No. 3.
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abstract = "Crohn's disease (CD) is a complex disorder resulting from the interaction of intestinal microbiota with the host immune system in genetically susceptible individuals. The largest meta-analysis of genome-wide association to date identified 71 CD-susceptibility loci in individuals of European ancestry. An important epidemiological feature of CD is that it is 2-4 times more prevalent among individuals of Ashkenazi Jewish (AJ) descent compared to non-Jewish Europeans (NJ). To explore genetic variation associated with CD in AJs, we conducted a genome-wide association study (GWAS) by combining raw genotype data across 10 AJ cohorts consisting of 907 cases and 2,345 controls in the discovery stage, followed up by a replication study in 971 cases and 2,124 controls. We confirmed genome-wide significant associations of 9 known CD loci in AJs and replicated 3 additional loci with strong signal (p<5×10 -6). Novel signals detected among AJs were mapped to chromosomes 5q21.1 (rs7705924, combined p = 2×10 -8; combined odds ratio OR = 1.48), 2p15 (rs6545946, p = 7×10 -9; OR = 1.16), 8q21.11 (rs12677663, p = 2×10 -8; OR = 1.15), 10q26.3 (rs10734105, p = 3×10 -8; OR = 1.27), and 11q12.1 (rs11229030, p = 8×10 -9; OR = 1.15), implicating biologically plausible candidate genes, including RPL7, CPAMD8, PRG2, and PRG3. In all, the 16 replicated and newly discovered loci, in addition to the three coding NOD2 variants, accounted for 11.2{\%} of the total genetic variance for CD risk in the AJ population. This study demonstrates the complementary value of genetic studies in the Ashkenazim.",
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AU - Pe'er, Itsik

AU - Karban, Amir

AU - Ozelius, Laurie

AU - Mitchell, Adele A.

AU - Ng, Sok Meng

AU - Erazo, Monica

AU - Ostrer, Harry

AU - Abraham, Clara

AU - Abreu, Maria T.

AU - Atzmon, Gil

AU - Barzilai, Nir

AU - Brant, Steven R.

AU - Bressman, Susan

AU - Burns, Edward R.

AU - Chowers, Yehuda

AU - Clark, Lorraine N.

AU - Darvasi, Ariel

AU - Doheny, Dana

AU - Duerr, Richard H.

AU - Eliakim, Rami

AU - Giladi, Nir

AU - Gregersen, Peter K.

AU - Hakonarson, Hakon

AU - Jones, Michelle R.

AU - Marder, Karen

AU - McGovern, Dermot P B

AU - Mulle, Jennifer

AU - Orr-Urtreger, Avi

AU - Proctor, Deborah D.

AU - Pulver, Ann

AU - Rotter, Jerome I.

AU - Silverberg, Mark S.

AU - Ullman, Thomas A.

AU - Warren, Stephen T.

AU - Waterman, Matti

AU - Zhang, Wei

AU - Bergman, Aviv

AU - Mayer, Lloyd

AU - Katz, Seymour

AU - Desnick, Robert J.

AU - Cho, Judy H.

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AB - Crohn's disease (CD) is a complex disorder resulting from the interaction of intestinal microbiota with the host immune system in genetically susceptible individuals. The largest meta-analysis of genome-wide association to date identified 71 CD-susceptibility loci in individuals of European ancestry. An important epidemiological feature of CD is that it is 2-4 times more prevalent among individuals of Ashkenazi Jewish (AJ) descent compared to non-Jewish Europeans (NJ). To explore genetic variation associated with CD in AJs, we conducted a genome-wide association study (GWAS) by combining raw genotype data across 10 AJ cohorts consisting of 907 cases and 2,345 controls in the discovery stage, followed up by a replication study in 971 cases and 2,124 controls. We confirmed genome-wide significant associations of 9 known CD loci in AJs and replicated 3 additional loci with strong signal (p<5×10 -6). Novel signals detected among AJs were mapped to chromosomes 5q21.1 (rs7705924, combined p = 2×10 -8; combined odds ratio OR = 1.48), 2p15 (rs6545946, p = 7×10 -9; OR = 1.16), 8q21.11 (rs12677663, p = 2×10 -8; OR = 1.15), 10q26.3 (rs10734105, p = 3×10 -8; OR = 1.27), and 11q12.1 (rs11229030, p = 8×10 -9; OR = 1.15), implicating biologically plausible candidate genes, including RPL7, CPAMD8, PRG2, and PRG3. In all, the 16 replicated and newly discovered loci, in addition to the three coding NOD2 variants, accounted for 11.2% of the total genetic variance for CD risk in the AJ population. This study demonstrates the complementary value of genetic studies in the Ashkenazim.

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