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

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

doi:10.1038/s41588-022-01156-2

Cited by 69 publications

(22 citation statements)

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“…5A and Table S7 ). Examples of newly prioritised genes included the well-characterised immune genes IL1R1, IL1R2, NFKB1, TNFSF8 and TYK2 , the latter recently found to harbour rare CD-associated coding variants 64 . In contrast, multiCOGS did not prioritise JAK2 (multiCOGS score = 0.01, COGS score ~1), due to the shift of the fine-mapped signal from the promoter to a region ~20 kb upstream of it without detectable promoter contacts in multivariate fine-mapping.…”

Section: Resultsmentioning

confidence: 99%

“…Datasets used to compare the COGS prioritised genes with previously functionally validated genes were: OpenTargets 64 L2G gene prioritisation score > 0.5 for five CD studies 48,[127][128][129][130] , the IBDDB database of functionally validated targets 65 , a functional screen of IBD genes 66 , experimentally validated IDB and CD genes from DisGeNET 67 that had evidence "AlteredExpression", "Biomarker", "Posttranslationalmodification", or "Therapeutic" or CD-containing exonic variants in a recent IBD exome study 62 .…”

Section: Sources Of Prior Mechanistic Evidence For CD Genesmentioning

confidence: 99%

“…Finally, we searched for prior evidence of association of the prioritised genes with CD or IBD using curated gene-to-disease databases, functional studies and a recent exome sequencing study of CD patients (see Methods) 62,[64][65][66][67] . We found that over half of multiCOGS-prioritised genes in ILC3s (56/99) were not previously implicated in these diseases (Table S8).…”

Section: Multivariate Fine-mapping Improves the Prioritisation Of Cd-...mentioning

confidence: 99%

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High-resolution promoter interaction analysis in Type 3 Innate Lymphoid Cells implicates Batten Disease geneCLN3in Crohn’s Disease aetiology

Malysheva

Ray-Jones

Cazares

et al. 2022

Preprint

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Innate lymphoid cells (ILCs) are rare tissue-resident “helper” lymphocytes that do not express diversified antigen receptors. Type 3 ILCs (ILC3s) are an important class of these cells enriched in the respiratory and intestinal mucosa, where they regulate inflammation and mucosal homeostasis. To gain insight into the cis-regulatory circuitries underlying ILC3 function, we used high-resolution Capture Hi-C to profile promoter-anchored chromosomal contacts in human primary ILC3s. Combining significant interaction detection with the Activity-By-Contact approach adapted to Capture Hi-C, we reveal a multitude of contacts between promoters and distal regulatory elements and obtain evidence for distinct regulatory wiring of alternative promoters. We find that promoter-interacting regions in ILC3s are enriched for genetic variants associated with multiple immune diseases. Focusing on Crohn’s disease (CD), in which ILC3s are established mediators, we used a Bayesian approach that incorporates multivariate fine-mapping to link CD-associated genetic variants with putative target genes. We identify known and previously unimplicated genes in conferring genetic risk of CD through activity in ILC3s. This includes the CLN3gene that is mutated in the neurodegenerative disorder Batten disease. UsingCln3mutant mice, we show thatCLN3is a putative negative regulator of IL-17 production in an inflammatory subset of ILC3s. This finding suggests a functional role forCLN3in ILC3 biology, with mechanistic implications for both Crohn’s and Batten diseases.

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Section: Resultsmentioning

confidence: 99%

Section: Sources Of Prior Mechanistic Evidence For CD Genesmentioning

confidence: 99%

Section: Multivariate Fine-mapping Improves the Prioritisation Of Cd-...mentioning

confidence: 99%

See 1 more Smart Citation

High-resolution promoter interaction analysis in Type 3 Innate Lymphoid Cells implicates Batten Disease geneCLN3in Crohn’s Disease aetiology

Malysheva

Ray-Jones

Cazares

et al. 2022

Preprint

View full text Add to dashboard Cite

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“…Hence, the exploration of immunopathogenesis is one of the most important therapeutic targets in IBD. Within the context of large-scale sequencing analysis, the identification of novel genes reiterates the central roles of innate and adaptive immune cells as well as autophagy in IBD pathogenesis ( Sazonovs et al, 2022 ). Autophagy is implicated in diverse biological processes of IBD.…”

Section: Introductionmentioning

confidence: 99%

Deciphering the role of autophagy in the immunopathogenesis of inflammatory bowel disease

Law

2022

Front. Pharmacol.

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Inflammatory bowel disease (IBD) is a typical immune-mediated chronic inflammatory disorder. Following the industrialization and changes in lifestyle, the incidence of IBD in the world is rising, which makes health concerns and heavy burdens all over the world. However, the pathogenesis of IBD remains unclear, and the current understanding of the pathogenesis involves dysregulation of mucosal immunity, gut microbiome dysbiosis, and gut barrier defect based on genetic susceptibility and environmental triggers. In recent years, autophagy has emerged as a key mechanism in IBD development and progression because Genome-Wide Association Study revealed the complex interactions of autophagy in IBD, especially immunopathogenesis. Besides, autophagy markers are also suggested to be potential biomarkers and target treatment in IBD. This review summarizes the autophagy-related genes regulating immune response in IBD. Furthermore, we explore the evolving evidence that autophagy interacts with intestinal epithelial and immune cells to contribute to the inflammatory changes in IBD. Finally, we discuss how novel discovery could further advance our understanding of the role of autophagy and inform novel therapeutic strategies in IBD.

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“…The genomic intervals identified by GWAS contain multiple genes and few SNVs are likely to be functional. To extend association analysis, whole genome sequencing has been applied to identify rare and/or causal variants within expression quantitative trait loci (eQTL) [9][10][11]. After sequencing 100 candidate genes in 6600 CD patients and 5500 controls, Momozawa et al [10] concluded that > 10-fold greater sample sizes would be required to demonstrate causality.…”

Section: Introductionmentioning

confidence: 99%

The association between transcriptional regulation of macrophage differentiation and activation and genetic susceptibility to inflammatory bowel disease

O’Brien

Summers

Martin

et al. 2022

Preprint

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The abundant macrophage population of the intestinal lamina propria turns over rapidly and is replaced by blood monocytes. The differentiation and survival of resident intestinal macrophages depends upon signals from the macrophage colony-stimulating factor receptor (CSF1R). The response of human monocyte-derived macrophages (MDM) grown in macrophage colony-stimulating factor (CSF1) to bacterial lipopolysaccharide (LPS) has been proposed as a model for the differentiation and adaptation of monocytes entering the intestinal lamina propria. We hypothesized that dysregulation of this response leads to susceptibility to chronic inflammatory bowel disease (IBD). To address this hypothesis we analyzed transcriptomic variation in MDM from affected and unaffected sib pairs/trios from 22 IBD families and 6 healthy controls. There was no overall or inter-sib distinction between affected and unaffected individuals in basal gene expression or the stereotypical time course of the response to LPS. However, the basal or LPS-inducible expression of individual genes including inflammatory cytokines and many associated with IBD susceptibility in genome-wide association studies (GWAS) varied by as much as 100-fold between subjects. Extreme independent variation in the expression of pairs of HLA-associated transcripts (HLA-B/C, HLA-A/F and HLA-DRB1/DRB5) was associated with HLA genotype providing a novel explanation for the HLA association with disease susceptibility. The relationship between single nucleotide variant (SNV) genotype and gene expression at other loci was weaker and inconsistent suggesting that much of the variation arises from the integration of multiple trans-acting effects. For example, expression of IL1B at 2 hrs of LPS treatment was significantly associated with local SNV genotype and with peak expression of IL23A at 7 hrs. By contrast, there was no evidence of association between peak IL6 mRNA at 7hrs, IL6-associated SNV genotype or IL1B at 2 hrs. Our results support the view that gene-specific dysregulation in macrophage adaptation to the intestinal milieu provides a plausible explanation for genetic susceptibility to IBD. The analysis also suggests that the molecular basis of susceptibility is unique to each individual which may contribution to variation in the precise environmental trigger, the consequent pathology and response to treatment.

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

Cited by 69 publications

References 100 publications

High-resolution promoter interaction analysis in Type 3 Innate Lymphoid Cells implicates Batten Disease geneCLN3in Crohn’s Disease aetiology

High-resolution promoter interaction analysis in Type 3 Innate Lymphoid Cells implicates Batten Disease geneCLN3in Crohn’s Disease aetiology

Deciphering the role of autophagy in the immunopathogenesis of inflammatory bowel disease

The association between transcriptional regulation of macrophage differentiation and activation and genetic susceptibility to inflammatory bowel disease

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