Identification of genetic risk loci and prioritization of genes and pathways for myasthenia gravis: a genome-wide association study

Chia, Ruth; Sáez-Atiénzar, Sara; Murphy, Natalie A.; Chiò, Adriano; Blauwendraat, Cornelis; Roda, Ricardo H.; Tienari, Pentti J.; Kaminski, Henry J.; Ricciardi, Rocco; Guida, Melania; Rosa, Anna De; Petrucci, Loredana; Evoli, Amelia; Provenzano, Carlo; Drachman, Daniel B.; Traynor, Bryan J.

doi:10.1073/pnas.2108672119

Cited by 59 publications

(46 citation statements)

References 41 publications

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“…The second protective trait is a higher proportion of CD4 + Tregs, which is in accordance with previous studies. Previous GWASs on MG have identified the correlations between variants in genes (e.g., CTLA4 and PTPN22) with MG risk, which directly modulates the proportion or function of CD4 + Tregs ( 9 , 11 ). Biological evidence from experimental autoimmune MG (EAMG) models has explained the potential mechanisms in which CD4 + Tregs suppressed the abnormal proliferation of T effector cells in response to MG-related antigens ( 31 , 32 ).…”

Section: Discussionmentioning

confidence: 99%

“…These T-cell traits included subtypes in the T-cell panel (double negative, double positive, CD4 + , CD8 + ), regulatory T (Treg) panel, maturation stages (central memory/effector memory/terminally differentiated), and cell marker expression levels on different T cells. As a primary analysis, the MG data were sourced from the currently largest meta-GWAS conducted in the US and Italy (1,873 patients versus 36,370 age/gender-matched controls) ( 11 ). Only anti-acetylcholine receptor antibody-positive (AChR+) MG patients were enrolled in this study, and patients with positive test results for antibodies to muscle-specific kinase (MuSK+) were excluded from the enrollment.…”

Section: Methodsmentioning

confidence: 99%

“…Mendelian randomization (MR) uses genetic variants as the exposure proxy of the exposure to examine the causal effect of that exposure on the outcome (8). The correlations between genetic variants and MG have been explored in several genomewide association studies (GWASs) and human leukocyte antigen (HLA) haplotype analysis, by which T-cell relevant genes, including CTLA4, TNFRSF11A, PTPN22, and the HLA haplotypes, have been implicated in the pathogenesis of MG (9)(10)(11)(12). With now available large data sets, MR analysis may be an elegant tool to explore the novel biomarkers from T cells with causal impacts on MG risk, which has rarely been performed in this field.…”

Section: Introductionmentioning

confidence: 99%

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Herpesvirus entry mediator on T cells as a protective factor for myasthenia gravis: A Mendelian randomization study

et al. 2022

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Background and objectivesMyasthenia gravis (MG) is a T cell-driven, autoantibody-mediated disorder affecting transmission in neuromuscular junctions. The associations between the peripheral T cells and MG have been extensively studied. However, they are mainly of observational nature, thus limiting our understanding of the effect of inflammatory biomarkers on MG risk. With large data sets now available, we used Mendelian randomization (MR) analysis to investigate whether the biomarkers on T cells are causally associated with MG and further validate the relationships.MethodsWe performed a two-sample MR analysis using genetic data from one genome-wide association study (GWAS) for 210 extensive T-cell traits in 3,757 general population individuals and the largest GWAS for MG currently available (1,873 patients versus 36,370 age/gender-matched controls) from US and Italy. Then the biomarkers of interest were validated separately in two GWASs for MG in FIN biobank (232 patients versus 217,056 controls) and UK biobank (152 patients versus 386,631 controls).ResultsIn the first analysis, three T-cell traits were identified to be causally protective for MG risk: 1) CD8 on terminally differentiated CD8+ T cells (OR [95% CI] = 0.71 [0.59, 0.86], P = 5.62e-04, adjusted P =2.81e-02); 2) CD4+ regulatory T proportion in T cells (OR [95% CI] = 0.44 [0.26, 0.72], P = 1.30e-03, adjusted P =2.81e-02); 3) HVEM expression on total T cells (OR [95% CI] = 0.67 [0.52, 0.86], P = 1.61e-03, adjusted P =2.81e-02) and other eight T-cell subtypes (e.g., naïve CD4+ T cells). In particular, HVEM is a novel immune checkpoint on T cells that has never been linked to MG before. The SNPs on the TNFRSF14 per se further support a more direct link between the HVEM and MG. The validation analysis replicated these results in both FIN and UK biobanks. Both datasets showed a concordant protective trend supporting the findings, albeit not significant.ConclusionThis study highlighted the role of HVEM on T cells as a novel molecular-modified factor for MG risk and validated the causality between T cells and MG. These findings may advance our understanding of MG’s immunopathology and facilitate the future development of predictive disease-relevant biomarkers.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Herpesvirus entry mediator on T cells as a protective factor for myasthenia gravis: A Mendelian randomization study

et al. 2022

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“…Recently, we have proposed a strategic framework that generalizes how to establish the link from genetic loci to modulated genes that can be further linked to drug targets ( 14 , 15 ). Our advocates of genetic target prioritization have driven this field of research ( 16 – 22 ). In this study, we extended this into genomics-led target prioritization (called ‘ END’ ) and demonstrated better performance than the status quo approaches ( Figure 1 ), with the aim of providing genomic evidence for endometriosis as an inflammatory systemic disease.…”

Section: Introductionmentioning

confidence: 99%

Genomic Evidence Supports the Recognition of Endometriosis as an Inflammatory Systemic Disease and Reveals Disease-Specific Therapeutic Potentials of Targeting Neutrophil Degranulation

2022

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BackgroundEndometriosis, classically viewed as a localized disease, is increasingly recognized as a systemic disease with multi-organ effects. This disease is highlighted by systemic inflammation in affected organs and by high comorbidity with immune-mediated diseases.ResultsWe provide genomic evidence to support the recognition of endometriosis as an inflammatory systemic disease. This was achieved through our genomics-led target prioritization, called ‘END’, that leverages the value of multi-layered genomic datasets (including genome-wide associations in disease, regulatory genomics, and protein interactome). Our prioritization recovered existing proof-of-concept therapeutic targeting in endometriosis and outperformed competing prioritization approaches (Open Targets and Naïve prioritization). Target genes at the leading prioritization revealed molecular hallmarks (and possibly the cellular basis as well) that are consistent with systemic disease manifestations. Pathway crosstalk-based attack analysis identified the critical gene AKT1. In the context of this gene, we further identified genes that are already targeted by licensed medications in other diseases, such as ESR1. Such analysis was supported by current interests targeting the PI3K/AKT/mTOR pathway in endometriosis and by the fact that therapeutic agents targeting ESR1 are now under active clinical trials in disease. The construction of cross-disease prioritization map enabled the identification of shared and distinct targets between endometriosis and immune-mediated diseases. Shared target genes identified opportunities for repurposing existing immunomodulators, particularly disease-modifying anti-rheumatic drugs (such as TNF, IL6 and IL6R blockades, and JAK inhibitors). Genes highly prioritized only in endometriosis revealed disease-specific therapeutic potentials of targeting neutrophil degranulation – the exocytosis that can facilitate metastasis-like spread to distant organs causing inflammatory-like microenvironments.ConclusionImproved target prioritization, along with an atlas of in silico predicted targets and repurposed drugs (available at https://23verse.github.io/end), provides genomic insights into endometriosis, reveals disease-specific therapeutic potentials, and expands the existing theories on the origin of disease.

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“…Priority index or Pi, a genetics-led target prioritisation approach ( 5 ), has already supported specific applications for a wide range of diseases, including but not limited to: Alzheimer's disease ( 15 ), Dupuytren's disease ( 16 ), endometriosis ( 17 ), kidney stone disease ( 18 ), myasthenia gravis ( 19 ) and type 1 diabetes ( 20 ). The Pi approach is unique in three ways.…”

Section: Introductionmentioning

confidence: 99%

PiER: web-based facilities tailored for genetic target prioritisation harnessing human disease genetics, functional genomics and protein interactions

Fang

2022

Nucleic Acids Research

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Integrative prioritisation promotes translational use of disease genetic findings in target discovery. I report ‘PiER’ (http://www.genetictargets.com/PiER), web-based facilities that support ab initio and real-time genetic target prioritisation through integrative use of human disease genetics, functional genomics and protein interactions. By design, the PiER features two facilities: elementary and combinatory. The elementary facility is designed to perform specific tasks, including three online tools: eV2CG, utilising functional genomics to link disease-associated variants (particularly located at the non-coding genome) to core genes likely responsible for genetic associations in disease; eCG2PG, using knowledge of protein interactions to ‘network’ core genes and additional peripheral genes, producing a ranked list of core and peripheral genes; and eCrosstalk, exploiting the information of pathway-derived interactions to identify highly-ranked genes mediating crosstalk between molecular pathways. Each of elementary tasks giving results is sequentially piped to the next one. By chaining together elementary tasks, the combinatory facility automates genetics-led and network-based integrative prioritisation for genetic targets at the gene level (cTGene) and at the crosstalk level (cTCrosstalk). Together with a tutorial-like booklet describing instructions on how to use, the PiER facilities meet multi-tasking needs to accelerate computational translational medicine that leverages human disease genetics and genomics for early-stage target discovery and drug repurposing.

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Identification of genetic risk loci and prioritization of genes and pathways for myasthenia gravis: a genome-wide association study

Cited by 59 publications

References 41 publications

Herpesvirus entry mediator on T cells as a protective factor for myasthenia gravis: A Mendelian randomization study

Herpesvirus entry mediator on T cells as a protective factor for myasthenia gravis: A Mendelian randomization study

Genomic Evidence Supports the Recognition of Endometriosis as an Inflammatory Systemic Disease and Reveals Disease-Specific Therapeutic Potentials of Targeting Neutrophil Degranulation

PiER: web-based facilities tailored for genetic target prioritisation harnessing human disease genetics, functional genomics and protein interactions

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