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; 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 Ullman; Stephen T. Warren; Matti Waterman; Wei Zhang; Aviv Bergman; Lloyd Mayer; Seymour Katz; Robert J. Desnick; Judy H. Cho; Inga Peter

doi:10.1371/journal.pgen.1002559

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. DuerrRami 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 Ullman, Stephen T. Warren, Matti Waterman, Wei Zhang, Aviv Bergman, Lloyd Mayer, Seymour Katz, Robert J. Desnick, Judy H. Cho, Inga Peter

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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.

Original language	English (US)
Article number	e1002559
Journal	PLoS genetics
Volume	8
Issue number	3
DOIs	https://doi.org/10.1371/journal.pgen.1002559
State	Published - Mar 2012

ASJC Scopus subject areas

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

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This output contributes to the following UN Sustainable Development Goals (SDGs)

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Kenny, E. E., Pe'er, I., Karban, A., Ozelius, L., Mitchell, A. A., Ng, S. M., Erazo, M., Ostrer, H., Abraham, C., Abreu, M. T., Atzmon, G., Barzilai, N., Brant, S. R., Bressman, S., Burns, E. R., Chowers, Y., Clark, L. N., Darvasi, A., Doheny, D., ... Peter, I. (2012). A genome-wide scan of ashkenazi jewish crohn's disease suggests novel susceptibility loci. PLoS genetics, 8(3), Article e1002559. https://doi.org/10.1371/journal.pgen.1002559

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, T, 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

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

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.",

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

year = "2012",

month = mar,

doi = "10.1371/journal.pgen.1002559",

language = "English (US)",

volume = "8",

journal = "PLoS genetics",

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T1 - A genome-wide scan of ashkenazi jewish crohn's disease suggests novel susceptibility loci

AU - Kenny, Eimear E.

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

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.

AU - Peter, Inga

PY - 2012/3

Y1 - 2012/3

N2 - 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.

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

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