Large-scale sequencing identifies multiple genes and rare variants associated with Crohn's disease susceptibility

Aleksejs Sazonovs; Christine R Stevens; Guhan R Venkataraman; Kai Yuan; Brandon Avila; Maria T Abreu; Tariq Ahmad; Matthieu Allez; Ashwin N Ananthakrishnan; Gil Atzmon; Aris Baras; Jeffrey C Barrett; Nir Barzilai; Laurent Beaugerie; Ashley Beecham; Charles N Bernstein; Alain Bitton; Bernd Bokemeyer; Andrew Chan; Daniel Chung; Isabelle Cleynen; Jacques Cosnes; David J Cutler; Allan Daly; Oriana M Damas; Lisa W Datta; Noor Dawany; Marcella Devoto; Sheila Dodge; Eva Ellinghaus; Laura Fachal; Martti Farkkila; William Faubion; Manuel Ferreira; Denis Franchimont; Stacey B Gabriel; Tian Ge; Michel Georges; Kyle Gettler; Mamta Giri; Benjamin Glaser; Siegfried Goerg; Philippe Goyette; Daniel Graham; Eija Hämäläinen; Talin Haritunians; Graham A Heap; Mikko Hiltunen; Marc Hoeppner; Marieke J Pierik; Belgium IBD Consortium

doi:10.1038/s41588-022-01156-2

Large-scale sequencing identifies multiple genes and rare variants associated with Crohn's disease susceptibility

Aleksejs Sazonovs, Christine R Stevens, Guhan R Venkataraman, Kai Yuan, Brandon Avila, Maria T Abreu, Tariq Ahmad, Matthieu Allez, Ashwin N Ananthakrishnan, Gil Atzmon, Aris Baras, Jeffrey C Barrett, Nir Barzilai, Laurent Beaugerie, Ashley Beecham, Charles N Bernstein, Alain Bitton, Bernd Bokemeyer, Andrew Chan, Daniel ChungIsabelle Cleynen, Jacques Cosnes, David J Cutler, Allan Daly^*, Oriana M Damas, Lisa W Datta, Noor Dawany, Marcella Devoto, Sheila Dodge, Eva Ellinghaus, Laura Fachal, Martti Farkkila, William Faubion, Manuel Ferreira, Denis Franchimont, Stacey B Gabriel, Tian Ge, Michel Georges, Kyle Gettler, Mamta Giri, Benjamin Glaser, Siegfried Goerg, Philippe Goyette, Daniel Graham, Eija Hämäläinen, Talin Haritunians, Graham A Heap, Mikko Hiltunen, Marc Hoeppner, Marieke J Pierik, Belgium IBD Consortium

^*Corresponding author for this work

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

Abstract

Genome-wide association studies (GWASs) have identified hundreds of loci associated with Crohn's disease (CD). However, as with all complex diseases, robust identification of the genes dysregulated by noncoding variants typically driving GWAS discoveries has been challenging. Here, to complement GWASs and better define actionable biological targets, we analyzed sequence data from more than 30,000 patients with CD and 80,000 population controls. We directly implicate ten genes in general onset CD for the first time to our knowledge via association to coding variation, four of which lie within established CD GWAS loci. In nine instances, a single coding variant is significantly associated, and in the tenth, ATG4C, we see additionally a significantly increased burden of very rare coding variants in CD cases. In addition to reiterating the central role of innate and adaptive immune cells as well as autophagy in CD pathogenesis, these newly associated genes highlight the emerging role of mesenchymal cells in the development and maintenance of intestinal inflammation.

Original language	English
Pages (from-to)	1275-1283
Number of pages	22
Journal	Nature Genetics
Volume	54
Issue number	9
Early online date	29 Aug 2022
DOIs	https://doi.org/10.1038/s41588-022-01156-2
Publication status	Published - Sept 2022

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10.1038/s41588-022-01156-2

Cite this

Sazonovs, A., Stevens, C. R., Venkataraman, G. R., Yuan, K., Avila, B., Abreu, M. T., Ahmad, T., Allez, M., Ananthakrishnan, A. N., Atzmon, G., Baras, A., Barrett, J. C., Barzilai, N., Beaugerie, L., Beecham, A., Bernstein, C. N., Bitton, A., Bokemeyer, B., Chan, A., ... Belgium IBD Consortium (2022). Large-scale sequencing identifies multiple genes and rare variants associated with Crohn's disease susceptibility. Nature Genetics, 54(9), 1275-1283. https://doi.org/10.1038/s41588-022-01156-2

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title = "Large-scale sequencing identifies multiple genes and rare variants associated with Crohn's disease susceptibility",

abstract = "Genome-wide association studies (GWASs) have identified hundreds of loci associated with Crohn's disease (CD). However, as with all complex diseases, robust identification of the genes dysregulated by noncoding variants typically driving GWAS discoveries has been challenging. Here, to complement GWASs and better define actionable biological targets, we analyzed sequence data from more than 30,000 patients with CD and 80,000 population controls. We directly implicate ten genes in general onset CD for the first time to our knowledge via association to coding variation, four of which lie within established CD GWAS loci. In nine instances, a single coding variant is significantly associated, and in the tenth, ATG4C, we see additionally a significantly increased burden of very rare coding variants in CD cases. In addition to reiterating the central role of innate and adaptive immune cells as well as autophagy in CD pathogenesis, these newly associated genes highlight the emerging role of mesenchymal cells in the development and maintenance of intestinal inflammation.",

author = "Aleksejs Sazonovs and Stevens, {Christine R} and Venkataraman, {Guhan R} and Kai Yuan and Brandon Avila and Abreu, {Maria T} and Tariq Ahmad and Matthieu Allez and Ananthakrishnan, {Ashwin N} and Gil Atzmon and Aris Baras and Barrett, {Jeffrey C} and Nir Barzilai and Laurent Beaugerie and Ashley Beecham and Bernstein, {Charles N} and Alain Bitton and Bernd Bokemeyer and Andrew Chan and Daniel Chung and Isabelle Cleynen and Jacques Cosnes and Cutler, {David J} and Allan Daly and Damas, {Oriana M} and Datta, {Lisa W} and Noor Dawany and Marcella Devoto and Sheila Dodge and Eva Ellinghaus and Laura Fachal and Martti Farkkila and William Faubion and Manuel Ferreira and Denis Franchimont and Gabriel, {Stacey B} and Tian Ge and Michel Georges and Kyle Gettler and Mamta Giri and Benjamin Glaser and Siegfried Goerg and Philippe Goyette and Daniel Graham and Eija H{\"a}m{\"a}l{\"a}inen and Talin Haritunians and Heap, {Graham A} and Mikko Hiltunen and Marc Hoeppner and Pierik, {Marieke J} and {Belgium IBD Consortium}",

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Sazonovs, A, Stevens, CR, Venkataraman, GR, Yuan, K, Avila, B, Abreu, MT, Ahmad, T, Allez, M, Ananthakrishnan, AN, Atzmon, G, Baras, A, Barrett, JC, Barzilai, N, Beaugerie, L, Beecham, A, Bernstein, CN, Bitton, A, Bokemeyer, B, Chan, A, Chung, D, Cleynen, I, Cosnes, J, Cutler, DJ, Daly, A, Damas, OM, Datta, LW, Dawany, N, Devoto, M, Dodge, S, Ellinghaus, E, Fachal, L, Farkkila, M, Faubion, W, Ferreira, M, Franchimont, D, Gabriel, SB, Ge, T, Georges, M, Gettler, K, Giri, M, Glaser, B, Goerg, S, Goyette, P, Graham, D, Hämäläinen, E, Haritunians, T, Heap, GA, Hiltunen, M, Hoeppner, M, Pierik, MJ & Belgium IBD Consortium 2022, 'Large-scale sequencing identifies multiple genes and rare variants associated with Crohn's disease susceptibility', Nature Genetics, vol. 54, no. 9, pp. 1275-1283. https://doi.org/10.1038/s41588-022-01156-2

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AU - Sazonovs, Aleksejs

AU - Stevens, Christine R

AU - Venkataraman, Guhan R

AU - Yuan, Kai

AU - Avila, Brandon

AU - Abreu, Maria T

AU - Ahmad, Tariq

AU - Allez, Matthieu

AU - Ananthakrishnan, Ashwin N

AU - Atzmon, Gil

AU - Baras, Aris

AU - Barrett, Jeffrey C

AU - Barzilai, Nir

AU - Beaugerie, Laurent

AU - Beecham, Ashley

AU - Bernstein, Charles N

AU - Bitton, Alain

AU - Bokemeyer, Bernd

AU - Chan, Andrew

AU - Chung, Daniel

AU - Cleynen, Isabelle

AU - Cosnes, Jacques

AU - Cutler, David J

AU - Daly, Allan

AU - Damas, Oriana M

AU - Datta, Lisa W

AU - Dawany, Noor

AU - Devoto, Marcella

AU - Dodge, Sheila

AU - Ellinghaus, Eva

AU - Fachal, Laura

AU - Farkkila, Martti

AU - Faubion, William

AU - Ferreira, Manuel

AU - Franchimont, Denis

AU - Gabriel, Stacey B

AU - Ge, Tian

AU - Georges, Michel

AU - Gettler, Kyle

AU - Giri, Mamta

AU - Glaser, Benjamin

AU - Goerg, Siegfried

AU - Goyette, Philippe

AU - Graham, Daniel

AU - Hämäläinen, Eija

AU - Haritunians, Talin

AU - Heap, Graham A

AU - Hiltunen, Mikko

AU - Hoeppner, Marc

AU - Pierik, Marieke J

AU - Belgium IBD Consortium

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N2 - Genome-wide association studies (GWASs) have identified hundreds of loci associated with Crohn's disease (CD). However, as with all complex diseases, robust identification of the genes dysregulated by noncoding variants typically driving GWAS discoveries has been challenging. Here, to complement GWASs and better define actionable biological targets, we analyzed sequence data from more than 30,000 patients with CD and 80,000 population controls. We directly implicate ten genes in general onset CD for the first time to our knowledge via association to coding variation, four of which lie within established CD GWAS loci. In nine instances, a single coding variant is significantly associated, and in the tenth, ATG4C, we see additionally a significantly increased burden of very rare coding variants in CD cases. In addition to reiterating the central role of innate and adaptive immune cells as well as autophagy in CD pathogenesis, these newly associated genes highlight the emerging role of mesenchymal cells in the development and maintenance of intestinal inflammation.

AB - Genome-wide association studies (GWASs) have identified hundreds of loci associated with Crohn's disease (CD). However, as with all complex diseases, robust identification of the genes dysregulated by noncoding variants typically driving GWAS discoveries has been challenging. Here, to complement GWASs and better define actionable biological targets, we analyzed sequence data from more than 30,000 patients with CD and 80,000 population controls. We directly implicate ten genes in general onset CD for the first time to our knowledge via association to coding variation, four of which lie within established CD GWAS loci. In nine instances, a single coding variant is significantly associated, and in the tenth, ATG4C, we see additionally a significantly increased burden of very rare coding variants in CD cases. In addition to reiterating the central role of innate and adaptive immune cells as well as autophagy in CD pathogenesis, these newly associated genes highlight the emerging role of mesenchymal cells in the development and maintenance of intestinal inflammation.

U2 - 10.1038/s41588-022-01156-2

DO - 10.1038/s41588-022-01156-2

M3 - Article

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SN - 1061-4036

VL - 54

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EP - 1283

JO - Nature Genetics

JF - Nature Genetics

IS - 9

ER -