Identifying high-impact variants and genes in exomes of Ashkenazi Jewish inflammatory bowel disease patients

Yiming Wu; Kyle Gettler; Meltem Ece Kars; Mamta Giri; Dalin Li; Cigdem Sevim Bayrak; Peng Zhang; Aayushee Jain; Patrick Maffucci; Ksenija Sabic; Tielman Van Vleck; Girish Nadkarni; Lee A. Denson; Harry Ostrer; Adam P. Levine; Elena R. Schiff; Anthony W. Segal; Subra Kugathasan; Peter D. Stenson; David N. Cooper; L. Philip Schumm; Scott Snapper; Mark J. Daly; Talin Haritunians; Richard H. Duerr; Mark S. Silverberg; John D. Rioux; Steven R. Brant; Dermot P.B. McGovern; Judy H. Cho; Yuval Itan

doi:10.1038/s41467-023-37849-3

Identifying high-impact variants and genes in exomes of Ashkenazi Jewish inflammatory bowel disease patients

Yiming Wu, Kyle Gettler, Meltem Ece Kars, Mamta Giri, Dalin Li, Cigdem Sevim Bayrak, Peng Zhang, Aayushee Jain, Patrick Maffucci, Ksenija Sabic, Tielman Van Vleck, Girish Nadkarni, Lee A. Denson, Harry Ostrer, Adam P. Levine, Elena R. Schiff, Anthony W. Segal, Subra Kugathasan, Peter D. Stenson, David N. CooperL. Philip Schumm, Scott Snapper, Mark J. Daly, Talin Haritunians, Richard H. Duerr, Mark S. Silverberg, John D. Rioux, Steven R. Brant, Dermot P.B. McGovern, Judy H. Cho, Yuval Itan

Pathology

Research output: Contribution to journal › Article › peer-review

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Abstract

Inflammatory bowel disease (IBD) is a group of chronic digestive tract inflammatory conditions whose genetic etiology is still poorly understood. The incidence of IBD is particularly high among Ashkenazi Jews. Here, we identify 8 novel and plausible IBD-causing genes from the exomes of 4453 genetically identified Ashkenazi Jewish IBD cases (1734) and controls (2719). Various biological pathway analyses are performed, along with bulk and single-cell RNA sequencing, to demonstrate the likely physiological relatedness of the novel genes to IBD. Importantly, we demonstrate that the rare and high impact genetic architecture of Ashkenazi Jewish adult IBD displays significant overlap with very early onset-IBD genetics. Moreover, by performing biobank phenome-wide analyses, we find that IBD genes have pleiotropic effects that involve other immune responses. Finally, we show that polygenic risk score analyses based on genome-wide high impact variants have high power to predict IBD susceptibility.

Original language	English (US)
Article number	2256
Journal	Nature communications
Volume	14
Issue number	1
DOIs	https://doi.org/10.1038/s41467-023-37849-3
State	Published - Dec 2023

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

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Wu, Y., Gettler, K., Kars, M. E., Giri, M., Li, D., Bayrak, C. S., Zhang, P., Jain, A., Maffucci, P., Sabic, K., Van Vleck, T., Nadkarni, G., Denson, L. A., Ostrer, H., Levine, A. P., Schiff, E. R., Segal, A. W., Kugathasan, S., Stenson, P. D., ... Itan, Y. (2023). Identifying high-impact variants and genes in exomes of Ashkenazi Jewish inflammatory bowel disease patients. Nature communications, 14(1), Article 2256. https://doi.org/10.1038/s41467-023-37849-3

Wu, Y, Gettler, K, Kars, ME, Giri, M, Li, D, Bayrak, CS, Zhang, P, Jain, A, Maffucci, P, Sabic, K, Van Vleck, T, Nadkarni, G, Denson, LA, Ostrer, H, Levine, AP, Schiff, ER, Segal, AW, Kugathasan, S, Stenson, PD, Cooper, DN, Philip Schumm, L, Snapper, S, Daly, MJ, Haritunians, T, Duerr, RH, Silverberg, MS, Rioux, JD, Brant, SR, McGovern, DPB, Cho, JH & Itan, Y 2023, 'Identifying high-impact variants and genes in exomes of Ashkenazi Jewish inflammatory bowel disease patients', Nature communications, vol. 14, no. 1, 2256. https://doi.org/10.1038/s41467-023-37849-3

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title = "Identifying high-impact variants and genes in exomes of Ashkenazi Jewish inflammatory bowel disease patients",

abstract = "Inflammatory bowel disease (IBD) is a group of chronic digestive tract inflammatory conditions whose genetic etiology is still poorly understood. The incidence of IBD is particularly high among Ashkenazi Jews. Here, we identify 8 novel and plausible IBD-causing genes from the exomes of 4453 genetically identified Ashkenazi Jewish IBD cases (1734) and controls (2719). Various biological pathway analyses are performed, along with bulk and single-cell RNA sequencing, to demonstrate the likely physiological relatedness of the novel genes to IBD. Importantly, we demonstrate that the rare and high impact genetic architecture of Ashkenazi Jewish adult IBD displays significant overlap with very early onset-IBD genetics. Moreover, by performing biobank phenome-wide analyses, we find that IBD genes have pleiotropic effects that involve other immune responses. Finally, we show that polygenic risk score analyses based on genome-wide high impact variants have high power to predict IBD susceptibility.",

author = "Yiming Wu and Kyle Gettler and Kars, {Meltem Ece} and Mamta Giri and Dalin Li and Bayrak, {Cigdem Sevim} and Peng Zhang and Aayushee Jain and Patrick Maffucci and Ksenija Sabic and {Van Vleck}, Tielman and Girish Nadkarni and Denson, {Lee A.} and Harry Ostrer and Levine, {Adam P.} and Schiff, {Elena R.} and Segal, {Anthony W.} and Subra Kugathasan and Stenson, {Peter D.} and Cooper, {David N.} and {Philip Schumm}, L. and Scott Snapper and Daly, {Mark J.} and Talin Haritunians and Duerr, {Richard H.} and Silverberg, {Mark S.} and Rioux, {John D.} and Brant, {Steven R.} and McGovern, {Dermot P.B.} and Cho, {Judy H.} and Yuval Itan",

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doi = "10.1038/s41467-023-37849-3",

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AU - Wu, Yiming

AU - Gettler, Kyle

AU - Kars, Meltem Ece

AU - Giri, Mamta

AU - Li, Dalin

AU - Bayrak, Cigdem Sevim

AU - Zhang, Peng

AU - Jain, Aayushee

AU - Maffucci, Patrick

AU - Sabic, Ksenija

AU - Van Vleck, Tielman

AU - Nadkarni, Girish

AU - Denson, Lee A.

AU - Ostrer, Harry

AU - Levine, Adam P.

AU - Schiff, Elena R.

AU - Segal, Anthony W.

AU - Kugathasan, Subra

AU - Stenson, Peter D.

AU - Cooper, David N.

AU - Philip Schumm, L.

AU - Snapper, Scott

AU - Daly, Mark J.

AU - Haritunians, Talin

AU - Duerr, Richard H.

AU - Silverberg, Mark S.

AU - Rioux, John D.

AU - Brant, Steven R.

AU - McGovern, Dermot P.B.

AU - Cho, Judy H.

AU - Itan, Yuval

PY - 2023/12

Y1 - 2023/12

N2 - Inflammatory bowel disease (IBD) is a group of chronic digestive tract inflammatory conditions whose genetic etiology is still poorly understood. The incidence of IBD is particularly high among Ashkenazi Jews. Here, we identify 8 novel and plausible IBD-causing genes from the exomes of 4453 genetically identified Ashkenazi Jewish IBD cases (1734) and controls (2719). Various biological pathway analyses are performed, along with bulk and single-cell RNA sequencing, to demonstrate the likely physiological relatedness of the novel genes to IBD. Importantly, we demonstrate that the rare and high impact genetic architecture of Ashkenazi Jewish adult IBD displays significant overlap with very early onset-IBD genetics. Moreover, by performing biobank phenome-wide analyses, we find that IBD genes have pleiotropic effects that involve other immune responses. Finally, we show that polygenic risk score analyses based on genome-wide high impact variants have high power to predict IBD susceptibility.

AB - Inflammatory bowel disease (IBD) is a group of chronic digestive tract inflammatory conditions whose genetic etiology is still poorly understood. The incidence of IBD is particularly high among Ashkenazi Jews. Here, we identify 8 novel and plausible IBD-causing genes from the exomes of 4453 genetically identified Ashkenazi Jewish IBD cases (1734) and controls (2719). Various biological pathway analyses are performed, along with bulk and single-cell RNA sequencing, to demonstrate the likely physiological relatedness of the novel genes to IBD. Importantly, we demonstrate that the rare and high impact genetic architecture of Ashkenazi Jewish adult IBD displays significant overlap with very early onset-IBD genetics. Moreover, by performing biobank phenome-wide analyses, we find that IBD genes have pleiotropic effects that involve other immune responses. Finally, we show that polygenic risk score analyses based on genome-wide high impact variants have high power to predict IBD susceptibility.

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Identifying high-impact variants and genes in exomes of Ashkenazi Jewish inflammatory bowel disease patients

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