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; Julie E Horowitz; Peter Irving; Vivek Iyer; Chaim Jalas; Judith Kelsen; Hamed Khalili; Barbara S Kirschner; Kimmo Kontula; Jukka T Koskela; Subra Kugathasan; Juozas Kupcinskas; Christopher A Lamb; Matthias Laudes; Chloé Lévesque; Adam P Levine; James D Lewis; Claire Liefferinckx; Britt-Sabina Loescher; Edouard Louis; John Mansfield; Sandra May; Jacob L McCauley; Emebet Mengesha; Myriam Mni; Paul Moayyedi; Christopher J Moran; Rodney D Newberry; Sirimon O'Charoen; David T Okou; Bas Oldenburg; Harry Ostrer; Aarno Palotie; Jean Paquette; Joel Pekow; Inga Peter; Marieke J Pierik; Cyriel Y Ponsioen; Nikolas Pontikos; Natalie Prescott; Ann E Pulver; Souad Rahmouni; Daniel L Rice; Päivi Saavalainen; Bruce Sands; R Balfour Sartor; Elena R Schiff; Stefan Schreiber; L Philip Schumm; Anthony W Segal; Philippe Seksik; Rasha Shawky; Shehzad Z Sheikh; Mark S Silverberg; Alison Simmons; Jurgita Skeiceviciene; Harry Sokol; Matthew Solomonson; Hari Somineni; Dylan Sun; Stephan Targan; Dan Turner; Holm H Uhlig; Andrea E van der Meulen; Séverine Vermeire; Sare Verstockt; Michiel D Voskuil; Harland S Winter; Justine Young; Richard H Duerr; Andre Franke; Steven R Brant; Judy Cho; Rinse K Weersma; Miles Parkes; Ramnik J Xavier; Manuel A Rivas; John D Rioux; Dermot P B McGovern; Hailiang Huang; Carl A Anderson; Mark J Daly; 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, Julie E Horowitz, Peter Irving, Vivek Iyer, Chaim Jalas, Judith Kelsen, Hamed Khalili, Barbara S Kirschner, Kimmo Kontula, Jukka T Koskela, Subra Kugathasan, Juozas Kupcinskas, Christopher A Lamb, Matthias Laudes, Chloé Lévesque, Adam P Levine, James D Lewis, Claire Liefferinckx, Britt-Sabina Loescher, Edouard Louis, John Mansfield, Sandra May, Jacob L McCauley, Emebet Mengesha, Myriam Mni, Paul Moayyedi, Christopher J Moran, Rodney D Newberry, Sirimon O'Charoen, David T Okou, Bas Oldenburg, Harry Ostrer, Aarno Palotie, Jean Paquette, Joel Pekow, Inga Peter, Marieke J Pierik, Cyriel Y Ponsioen, Nikolas Pontikos, Natalie Prescott, Ann E Pulver, Souad Rahmouni, Daniel L Rice, Päivi Saavalainen, Bruce Sands, R Balfour Sartor, Elena R Schiff, Stefan Schreiber, L Philip Schumm, Anthony W Segal, Philippe Seksik, Rasha Shawky, Shehzad Z Sheikh, Mark S Silverberg, Alison Simmons, Jurgita Skeiceviciene, Harry Sokol, Matthew Solomonson, Hari Somineni, Dylan Sun, Stephan Targan, Dan Turner, Holm H Uhlig, Andrea E van der Meulen, Séverine Vermeire, Sare Verstockt, Michiel D Voskuil, Harland S Winter, Justine Young, Richard H Duerr, Andre Franke, Steven R Brant, Judy Cho, Rinse K Weersma, Miles Parkes, Ramnik J Xavier, Manuel A Rivas, John D Rioux, Dermot P B McGovern, Hailiang Huang, Carl A Anderson, Mark J Daly, Belgium IBD Consortium

Research output: Contribution to journal › Journal article › Research › peer-review

80 Citations (Scopus)

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
Journal	Nature Genetics
Volume	54
Issue number	9
Pages (from-to)	1275-1283
Number of pages	9
ISSN	1061-4036
DOIs	https://doi.org/10.1038/s41588-022-01156-2
Publication status	Published - Sept 2022
Externally published	Yes

Bibliographical note

Keywords

Crohn Disease/genetics
Genetic Predisposition to Disease
Genome-Wide Association Study
Humans
Polymorphism, Single Nucleotide/genetics

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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

@article{34f18c981831419995840e7fa59b1b13,

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.",

keywords = "Crohn Disease/genetics, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Polymorphism, Single Nucleotide/genetics",

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 Horowitz, {Julie E} and Peter Irving and Vivek Iyer and Chaim Jalas and Judith Kelsen and Hamed Khalili and Kirschner, {Barbara S} and Kimmo Kontula and Koskela, {Jukka T} and Subra Kugathasan and Juozas Kupcinskas and Lamb, {Christopher A} and Matthias Laudes and Chlo{\'e} L{\'e}vesque and Levine, {Adam P} and Lewis, {James D} and Claire Liefferinckx and Britt-Sabina Loescher and Edouard Louis and John Mansfield and Sandra May and McCauley, {Jacob L} and Emebet Mengesha and Myriam Mni and Paul Moayyedi and Moran, {Christopher J} and Newberry, {Rodney D} and Sirimon O'Charoen and Okou, {David T} and Bas Oldenburg and Harry Ostrer and Aarno Palotie and Jean Paquette and Joel Pekow and Inga Peter and Pierik, {Marieke J} and Ponsioen, {Cyriel Y} and Nikolas Pontikos and Natalie Prescott and Pulver, {Ann E} and Souad Rahmouni and Rice, {Daniel L} and P{\"a}ivi Saavalainen and Bruce Sands and Sartor, {R Balfour} and Schiff, {Elena R} and Stefan Schreiber and Schumm, {L Philip} and Segal, {Anthony W} and Philippe Seksik and Rasha Shawky and Sheikh, {Shehzad Z} and Silverberg, {Mark S} and Alison Simmons and Jurgita Skeiceviciene and Harry Sokol and Matthew Solomonson and Hari Somineni and Dylan Sun and Stephan Targan and Dan Turner and Uhlig, {Holm H} and {van der Meulen}, {Andrea E} and S{\'e}verine Vermeire and Sare Verstockt and Voskuil, {Michiel D} and Winter, {Harland S} and Justine Young and Duerr, {Richard H} and Andre Franke and Brant, {Steven R} and Judy Cho and Weersma, {Rinse K} and Miles Parkes and Xavier, {Ramnik J} and Rivas, {Manuel A} and Rioux, {John D} and McGovern, {Dermot P B} and Hailiang Huang and Anderson, {Carl A} and Daly, {Mark J} and {Belgium IBD Consortium}",

note = "{\textcopyright} 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.",

year = "2022",

month = sep,

doi = "10.1038/s41588-022-01156-2",

language = "English",

volume = "54",

pages = "1275--1283",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Research",

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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, Horowitz, JE, Irving, P, Iyer, V, Jalas, C, Kelsen, J, Khalili, H, Kirschner, BS, Kontula, K, Koskela, JT, Kugathasan, S, Kupcinskas, J, Lamb, CA, Laudes, M, Lévesque, C, Levine, AP, Lewis, JD, Liefferinckx, C, Loescher, B-S, Louis, E, Mansfield, J, May, S, McCauley, JL, Mengesha, E, Mni, M, Moayyedi, P, Moran, CJ, Newberry, RD, O'Charoen, S, Okou, DT, Oldenburg, B, Ostrer, H, Palotie, A, Paquette, J, Pekow, J, Peter, I, Pierik, MJ, Ponsioen, CY, Pontikos, N, Prescott, N, Pulver, AE, Rahmouni, S, Rice, DL, Saavalainen, P, Sands, B, Sartor, RB, Schiff, ER, Schreiber, S, Schumm, LP, Segal, AW, Seksik, P, Shawky, R, Sheikh, SZ, Silverberg, MS, Simmons, A, Skeiceviciene, J, Sokol, H, Solomonson, M, Somineni, H, Sun, D, Targan, S, Turner, D, Uhlig, HH, van der Meulen, AE, Vermeire, S, Verstockt, S, Voskuil, MD, Winter, HS, Young, J, Duerr, RH, Franke, A, Brant, SR, Cho, J, Weersma, RK, Parkes, M, Xavier, RJ, Rivas, MA, Rioux, JD, McGovern, DPB, Huang, H, Anderson, CA, Daly, 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

TY - JOUR

T1 - Large-scale sequencing identifies multiple genes and rare variants associated with Crohn's disease susceptibility

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 - Horowitz, Julie E

AU - Irving, Peter

AU - Iyer, Vivek

AU - Jalas, Chaim

AU - Kelsen, Judith

AU - Khalili, Hamed

AU - Kirschner, Barbara S

AU - Kontula, Kimmo

AU - Koskela, Jukka T

AU - Kugathasan, Subra

AU - Kupcinskas, Juozas

AU - Lamb, Christopher A

AU - Laudes, Matthias

AU - Lévesque, Chloé

AU - Levine, Adam P

AU - Lewis, James D

AU - Liefferinckx, Claire

AU - Loescher, Britt-Sabina

AU - Louis, Edouard

AU - Mansfield, John

AU - May, Sandra

AU - McCauley, Jacob L

AU - Mengesha, Emebet

AU - Mni, Myriam

AU - Moayyedi, Paul

AU - Moran, Christopher J

AU - Newberry, Rodney D

AU - O'Charoen, Sirimon

AU - Okou, David T

AU - Oldenburg, Bas

AU - Ostrer, Harry

AU - Palotie, Aarno

AU - Paquette, Jean

AU - Pekow, Joel

AU - Peter, Inga

AU - Pierik, Marieke J

AU - Ponsioen, Cyriel Y

AU - Pontikos, Nikolas

AU - Prescott, Natalie

AU - Pulver, Ann E

AU - Rahmouni, Souad

AU - Rice, Daniel L

AU - Saavalainen, Päivi

AU - Sands, Bruce

AU - Sartor, R Balfour

AU - Schiff, Elena R

AU - Schreiber, Stefan

AU - Schumm, L Philip

AU - Segal, Anthony W

AU - Seksik, Philippe

AU - Shawky, Rasha

AU - Sheikh, Shehzad Z

AU - Silverberg, Mark S

AU - Simmons, Alison

AU - Skeiceviciene, Jurgita

AU - Sokol, Harry

AU - Solomonson, Matthew

AU - Somineni, Hari

AU - Sun, Dylan

AU - Targan, Stephan

AU - Turner, Dan

AU - Uhlig, Holm H

AU - van der Meulen, Andrea E

AU - Vermeire, Séverine

AU - Verstockt, Sare

AU - Voskuil, Michiel D

AU - Winter, Harland S

AU - Young, Justine

AU - Duerr, Richard H

AU - Franke, Andre

AU - Brant, Steven R

AU - Cho, Judy

AU - Weersma, Rinse K

AU - Parkes, Miles

AU - Xavier, Ramnik J

AU - Rivas, Manuel A

AU - Rioux, John D

AU - McGovern, Dermot P B

AU - Huang, Hailiang

AU - Anderson, Carl A

AU - Daly, Mark J

AU - Belgium IBD Consortium

PY - 2022/9

Y1 - 2022/9

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.

KW - Crohn Disease/genetics

KW - Genetic Predisposition to Disease

KW - Genome-Wide Association Study

KW - Humans

KW - Polymorphism, Single Nucleotide/genetics

U2 - 10.1038/s41588-022-01156-2

DO - 10.1038/s41588-022-01156-2

M3 - Journal article

C2 - 36038634

SN - 1061-4036

VL - 54

SP - 1275

EP - 1283

JO - Nature Genetics

JF - Nature Genetics

IS - 9

ER -

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

Abstract

Bibliographical note

Keywords

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