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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.

SUBMITTER: Sazonovs A

PROVIDER: S-EPMC9700438 | biostudies-literature | 2022 Sep

REPOSITORIES: biostudies-literature

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

Sazonovs Aleksejs A Stevens Christine R CR Venkataraman Guhan R GR Yuan Kai K Avila Brandon B Abreu Maria T MT Ahmad Tariq T Allez Matthieu M Ananthakrishnan Ashwin N AN Atzmon Gil G Baras Aris A Barrett Jeffrey C JC Barzilai Nir N Beaugerie Laurent L Beecham Ashley A Bernstein Charles N CN Bitton Alain A Bokemeyer Bernd B Chan Andrew A Chung Daniel D Cleynen Isabelle I Cosnes Jacques J Cutler David J DJ Daly Allan A Damas Oriana M OM Datta Lisa W LW Dawany Noor N Devoto Marcella M Dodge Sheila S Ellinghaus Eva E Fachal Laura L Farkkila Martti M Faubion William W Ferreira Manuel M Franchimont Denis D Gabriel Stacey B SB Ge Tian T Georges Michel M Gettler Kyle K Giri Mamta M Glaser Benjamin B Goerg Siegfried S Goyette Philippe P Graham Daniel D Hämäläinen Eija E Haritunians Talin T Heap Graham A GA Hiltunen Mikko M Hoeppner Marc M Horowitz Julie E JE Irving Peter P Iyer Vivek V Jalas Chaim C Kelsen Judith J Khalili Hamed H Kirschner Barbara S BS Kontula Kimmo K Koskela Jukka T JT Kugathasan Subra S Kupcinskas Juozas J Lamb Christopher A CA Laudes Matthias M Lévesque Chloé C Levine Adam P AP Lewis James D JD Liefferinckx Claire C Loescher Britt-Sabina BS Louis Edouard E Mansfield John J May Sandra S McCauley Jacob L JL Mengesha Emebet E Mni Myriam M Moayyedi Paul P Moran Christopher J CJ Newberry Rodney D RD O'Charoen Sirimon S Okou David T DT Oldenburg Bas B Ostrer Harry H Palotie Aarno A Paquette Jean J Pekow Joel J Peter Inga I Pierik Marieke J MJ Ponsioen Cyriel Y CY Pontikos Nikolas N Prescott Natalie N Pulver Ann E AE Rahmouni Souad S Rice Daniel L DL Saavalainen Päivi P Sands Bruce B Sartor R Balfour RB Schiff Elena R ER Schreiber Stefan S Schumm L Philip LP Segal Anthony W AW Seksik Philippe P Shawky Rasha R Sheikh Shehzad Z SZ Silverberg Mark S MS Simmons Alison A Skeiceviciene Jurgita J Sokol Harry H Solomonson Matthew M Somineni Hari H Sun Dylan D Targan Stephan S Turner Dan D Uhlig Holm H HH van der Meulen Andrea E AE Vermeire Séverine S Verstockt Sare S Voskuil Michiel D MD Winter Harland S HS Young Justine J Duerr Richard H RH Franke Andre A Brant Steven R SR Cho Judy J Weersma Rinse K RK Parkes Miles M Xavier Ramnik J RJ Rivas Manuel A MA Rioux John D JD McGovern Dermot P B DPB Huang Hailiang H Anderson Carl A CA Daly Mark J MJ

Nature genetics 20220829 9

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 ...[more]

PMID: 36038634

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Dataset Information

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

Publications

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

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