<i>C1orf106</i>
            is a colitis risk gene that regulates stability of epithelial adherens junctions

Mohanan, Vishnu; Nakata, Toru; Desch, A. Nicole; Lévesque, Chloé; Boroughs, Angela C.; Guzman, Gaelen; Cao, Zhiwei; Creasey, Elizabeth A.; Yao, Junmei; Boucher, Gabrielle; Charron, Guy; Bhan, Atul K.; Schenone, Monica; Carr, Steven A.; Reinecker, Hans–Christian; Daly, Mark J.; Rioux, John D.; Lassen, Kara G.; Xavier, Ramnik J.

doi:10.1126/science.aan0814

Cited by 101 publications

(96 citation statements)

References 30 publications

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“…Deficiency of C1orf106 compromised barrier function under certain proinflammatory conditions and led to increased fecal water content and diarrhea. During the preparation of this article, an independent study also demonstrated a role for C1ORF106 in regulating epithelial adherens junctions (13). The additional data provided in this study support that C1orf106 deficiency may have synergic effects with other proinflammatory stimuli such as TNF-a, a clinically validated therapeutic target, for IBD disease pathogenesis.…”

Section: Discussionsupporting

confidence: 63%

“…Two additional cytohesin adherens junction scaffold proteins, FRMD4A and FRMD4B, share sequence homology with C1ORF106 and have also been shown to contain DUF3338 domains (14). Similar interaction between C1ORF106 and cytohesins was also revealed by an independent mass spectrometry-based approach (13). These data suggest that DUF3338 is a novel cytohesin interaction domain and mediates C1ORF106 interaction with cytohesins.…”

Section: Resultsmentioning

confidence: 64%

“…A recent study revealed a reduction of C1orf106 protein expression with a rare Tyr-.Phe coding variant (rs41313912, minor allele frequency ,1%), which is associated with increased risk of IBD (13). However, the role of the common noncoding risk variant rs7554511 in regulation of C1orf106 is still unclear.…”

Section: Resultsmentioning

confidence: 99%

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Inflammatory Bowel Disease Susceptibility Gene C1ORF106 Regulates Intestinal Epithelial Permeability

Manzanillo¹,

Mouchess²,

Ota³

et al. 2018

ImmunoHorizons

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Intestinal epithelial cells form a physical barrier that is tightly regulated to control intestinal permeability. Proinflammatory cytokines, such as TNF-α, increase epithelial permeability through disruption of epithelial junctions. The regulation of the epithelial barrier in inflammatory gastrointestinal disease remains to be fully characterized. In this article, we show that the human inflammatory bowel disease genetic susceptibility gene C1ORF106 plays a key role in regulating gut epithelial permeability. C1ORF106 directly interacts with cytohesins to maintain functional epithelial cell junctions. C1orf106-deficient mice are hypersensitive to TNF-α–induced increase in epithelial permeability, and this is associated with increased diarrhea. This study identifies C1ORF106 as an epithelial cell junction protein, and the loss of C1ORF106 augments TNF-α–induced intestinal epithelial leakage and diarrhea that may play a critical role in the development of inflammatory bowel disease.

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Section: Discussionsupporting

confidence: 63%

Section: Resultsmentioning

confidence: 64%

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Inflammatory Bowel Disease Susceptibility Gene C1ORF106 Regulates Intestinal Epithelial Permeability

Manzanillo¹,

Mouchess²,

Ota³

et al. 2018

ImmunoHorizons

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“…However, a small population effect size does not exclude the possibility of a substantially larger effect on molecular phenotypes nor does it preclude the utility of association regions in understanding biology or having a clinical impact. Efforts following up GWAS results to date have demonstrated the value of these findings in pointing to genes that can aid in understanding the underlying biology of the trait(Claussnitzer et al, 2015; Mohanan et al, 2018; Sekar et al, 2016). Further, there is a clear relationship between GWAS results of a phenotype and gene targets of drugs that treat that phenotype pointing to the potential for improved therapeutic understanding(Nelson et al, 2015; Ruderfer et al, 2016).…”

Section: Discussionmentioning

confidence: 99%

Genomic Dissection of Bipolar Disorder and Schizophrenia, Including 28 Subphenotypes

Ruderfer¹,

Ripke²,

McQuillin³

et al. 2018

Cell

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625

254

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Schizophrenia and bipolar disorder are two distinct diagnoses that share symptomology. Understanding the genetic factors contributing to the shared and disorder-specific symptoms will be crucial for improving diagnosis and treatment. In genetic data consisting of 53,555 cases (20,129 bipolar disorder [BD], 33,426 schizophrenia [SCZ]) and 54,065 controls, we identified 114 genome-wide significant loci implicating synaptic and neuronal pathways shared between disorders. Comparing SCZ to BD (23,585 SCZ, 15,270 BD) identified four genomic regions including one with disorder-independent causal variants and potassium ion response genes as contributing to differences in biology between the disorders. Polygenic risk score (PRS) analyses identified several significant correlations within case-only phenotypes including SCZ PRS with psychotic features and age of onset in BD. For the first time, we discover specific loci that distinguish between BD and SCZ and identify polygenic components underlying multiple symptom dimensions. These results point to the utility of genetics to inform symptomology and potential treatment.

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“…As genotyping technologies and accompanying analytical capabilities have continued to improve, genome-wide association studies (GWAS) have identified tens of thousands of variants associated with numerous human diseases and traits. Despite these advances, our ability to discern the underlying biological mechanisms for the vast majority of such robust associations has remained limited, with a few exceptions (Claussnitzer et al, 2015;Gupta et al, 2017;Mohanan et al, 2018;Musunuru et al, 2010;Sankaran et al, 2008;Smemo et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

Gene-centric functional dissection of human genetic variation uncovers regulators of hematopoiesis

Nandakumar

McFarland

Mateyka

et al. 2018

Preprint

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Genome-wide association studies (GWAS) have identified thousands of variants associated with human diseases and traits. However, the majority of GWAS-implicated variants are in noncoding regions of the genome and require in depth follow-up to identify target genes and decipher biological mechanisms. Here, rather than focusing on causal variants, we have undertaken a pooled loss-of-function screen in primary hematopoietic cells to interrogate 389 candidate genes contained in 75 loci associated with red blood cell traits. Using this approach, we identify 77 genes at 38 GWAS loci, with most loci harboring 1-2 candidate genes.Importantly, the hit set was strongly enriched for genes validated through orthogonal genetic approaches. Genes identified by this approach are enriched in specific and relevant biological pathways, allowing regulators of human erythropoiesis and modifiers of blood diseases to be defined. More generally, this functional screen provides a paradigm for gene-centric follow up of GWAS for a variety of human diseases and traits.We applied a gene-centric loss-of-function screening approach to GWAS of RBC traits. We focused on 75 loci associated with RBC traits that were identified by a GWAS performed in up to 135,000 individuals (van der Harst et al., 2012) spanning 6 RBC traits ( Figure S1A). Importantly, these 75 loci have been robustly replicated and show large effect sizes in more recently reported association studies performed on larger cohorts and thus represent ideal targets for perturbation studies (Astle et al., 2016;Lareau et al., 2018). We endeavored to select all genes that could potentially underlie these 75 GWAS signals. To do this, each of the 75 sentinel SNPs was first expanded to a linkage disequilibrium (LD) block including all SNPs in high LD (r 2 > 0.8, Figure 1A, Figure S1B), then further to the nearest genomic recombination hotspot. Based upon insights from previous expression quantitative trait locus (eQTL) studies (Montgomery and Dermitzakis, 2011; Rossin et al., 2011;Veyrieras et al., 2008), each gene annotated in the genome was expanded to include a wingspan encompassing 110 kb upstream and 40 kb downstream of the transcriptional start and end sites, respectively, to also capture potential functional regulatory elements. This resulted in selection of 389 genes overlapping or in the vicinity of the LD blocks to be tested in the pooled loss-of-function screen. These were distributed at a median of 4 genes per loci ( Figure S1C).Since the majority of common genetic variation underlying RBC traits appears to act in a cellintrinsic manner within the erythroid lineage, we decided to perturb the candidate genes during the process of human erythropoiesis Sankaran et al., 2012;Sankaran et al., 2008;Ulirsch et al., 2016). We chose a pooled short hairpin RNA (shRNA) based loss-of-

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C1orf106 is a colitis risk gene that regulates stability of epithelial adherens junctions

Cited by 101 publications

References 30 publications

Inflammatory Bowel Disease Susceptibility Gene C1ORF106 Regulates Intestinal Epithelial Permeability

Inflammatory Bowel Disease Susceptibility Gene C1ORF106 Regulates Intestinal Epithelial Permeability

Genomic Dissection of Bipolar Disorder and Schizophrenia, Including 28 Subphenotypes

Gene-centric functional dissection of human genetic variation uncovers regulators of hematopoiesis

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