Shared Genetics of Multiple System Atrophy and Inflammatory Bowel Disease

Shadrin, Alexey; Mucha, Sören; Ellinghaus, David; Makarious, Mary B.; Blauwendraat, Cornelis; Sreelatha, Ashwin Ashok Kumar; Heras‐Garvin, Antonio; Ding, Jinhui; Hammer, Monia; Foubert‐Samier, Alexandra; Meissner, Wassilios G.; Rascol, Olivier; Traon, Anne Pavy‐Le; Frei, Oleksandr; O’Connell, Kevin; Bahrami, Shahram; Schreiber, Stefan; Lieb, Wolfgang; Müller‐Nurasyid, Martina; Schminke, Ulf; Homuth, Georg; Schmidt, Carsten Oliver; Nöthen, Markus M.; Hoffmann, Per; Gieger, Christian; Wenning, Gregor K.; Gibbs, J. Raphael; Franke, André; Hardy, John; Stefanova, Nadia; Gasser, Thomas; Singleton, Andrew B.; Houlden, Henry; Scholz, Sonja W.; Andreassen, Ole A.; Sharma, Manu

doi:10.1002/mds.28338

Cited by 20 publications

(7 citation statements)

References 59 publications

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“…And down-regulation of FOXO1 leads to over-production of Th17 cells and increased inflammatory responses 86 . DENND1B has been previously reported as one of the susceptibility gene regions that are associated with IBD(rs12740041) 87 especially CD and PBC((rs2488393)) 88 . However, our results found that DENND1B expression was significantly reduced in UC at the transcriptomic level.…”

Section: Discussionmentioning

confidence: 99%

Rare Comorbidity between Inflammatory Bowel Disease and Primary Biliary Cholangitis: Evidence from Causality, Shared Genetic Architecture and Transcriptomics

Huang

Jiang²,

Zeng

et al. 2023

Preprint

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BackgroundClinical studies have found comorbidity between Inflammatory Bowel Disease (IBD) and primary sclerosing cholangitis (PSC). Primary biliary cholangitis (PBC) is another autoimmune liver disease but the coexistence of IBD and PBC is rare. Whether there exists comorbidity between IBD and PBC and potential mechanism remains unclear.MethodsWe assessed the casual effect between PBC and IBD, i.e., Crohn Disease (CD) and Ulcerative Colitis (UC) independently based on genome-wide association studies (GWAS) summary statistics. By leveraging data from GWAS data, Bulk tissue RNA sequencing (bulk RNA-seq) data, and Single-cell RNA sequencing (scRNA-seq) dataset, we investigated the shared genetic architecture between IBDs and PBC. The transcriptomic expressions of shared genes were explored in patients with IBD (intestinal biopsies) and PBC (peripheral CD4+T cells).ResultWe found a bidirectional causal relationship for PBC and IBDs using Mendelian randomization. The IBDs had been considered as the protective factors on PBC (0.87[95% confidence interval (CI): 0.81-0.93],P= 8.72e-5, vice versa (0.91[95% CI: 0.81-0.93],P= 2.65e-09). We find a consistent negative genetic correlation between PBC and IBD (LDSC:rg= -0.2245,P= 2.89e-5). Cross-trait analysis yielded 9 shared risk SNPs and 7 nearest genes. In transcriptome analysis, we observed significant (P< 0.05) differences expression in intestinal biopsies (PGAP3andDENND1B) and in peripheral CD4+T cells (PTPN11andPNMT). We identified shared tissue-specific heritability enrichment for PBC and IBD (including CD not UC) in lung, spleen and cells EBV-transformed lymphocytes and identified shared cell type-level enrichment for IBD, CD and PBC in type 1 dendritic cells, natural killer cells, CD8+cytotoxic T lymphocytes in lung and activated CD8+T cell in spleen.ConclusionOur study indicates that IBD and PBC are protective factors for each other and shared genetic architecture may contribute to the negative genetic correlation. These findings may explain the rare comorbidity between IBD and PBC.

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Section: Discussionmentioning

confidence: 99%

Rare Comorbidity between Inflammatory Bowel Disease and Primary Biliary Cholangitis: Evidence from Causality, Shared Genetic Architecture and Transcriptomics

Huang

Jiang²,

Zeng

et al. 2023

Preprint

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“…Furthermore, [11C]PBR28 positron emission tomography (PET), which visualizes the translocator protein expressed in glial cells, revealed a significant increase in the accumulation of lentiform nuclei and cerebellar white matter in MSA compared with PD, and both diseases could be differentiated with 83% sensitivity and 100% specificity [ 5 ]. Conversely, a genome-wide association study revealed a multifactorial overlap between MSA and inflammatory bowel disease, identifying three shared loci with reading variants upstream of the DENND1B and RSP04 genes and in an intron of the C7 gene, which has been implicated in various neuroinflammatory conditions [ 6 ].…”

Section: Advances In Understanding the Pathophysiologymentioning

confidence: 99%

Multiple System Atrophy: Advances in Diagnosis and Therapy

Watanabe

Shima

Mizutani

et al. 2023

JMD

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This review summarizes improvements in understanding the pathophysiology and early clinical symptoms of multiple system atrophy (MSA) and advancements in diagnostic methods and disease-modifying therapies for the condition. In 2022, the Movement Disorder Society proposed new diagnostic criteria to develop disease-modifying therapies and promote clinical trials of MSA since the second consensus was proposed in 2008. Regarding pathogenesis, cutting-edge findings have accumulated on the interactions of α-synuclein, neuroinflammation, and oligodendroglia with neurons. In neuroimaging, introducing artificial intelligence, machine learning, and deep learning has notably improved diagnostic accuracy and individual analyses. Advancements in treatment have also been achieved, including immunotherapy therapy against α-synuclein and serotonin-targeted and mesenchymal stem cell therapies, which are thought to affect several aspects of the disease, including neuroinflammation. The accelerated progress in clarifying the pathogenesis of MSA over the past few years and the development of diagnostic techniques for detecting early-stage MSA are expected to facilitate the development of disease-modifying therapies for one of the most intractable neurodegenerative diseases.

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“…Genome wide association studies (GWAS) identified several potentially interesting gene loci, including the FBXO47, ELOVL7, EDN1, and MAPT, but no association of SNCA and COQ2 variants with MSA [50]. Importantly, MSA and inflammatory bowel disease have been reported to share common genetics including common variants of the C7 gene supporting immune dysfunction in both disorders [51]. The current understanding is that certain genetic background may predispose to MSA.…”

Section: Evidence On the Cause Of Msa So Far -The Possible Interplay ...mentioning

confidence: 99%

A Mouse Model of Multiple System Atrophy: Bench to Bedside

Stefanova

2023

Neurotherapeutics

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Multiple system atrophy (MSA) is a rare neurodegenerative disorder with unclear etiology, currently difficult and delayed diagnosis, and rapid progression, leading to disability and lethality within 6 to 9 years after symptom onset. The neuropathology of MSA classifies the disease in the group of a-synucleinopathies together with Parkinson’s disease and other Lewy body disorders, but features specific oligodendroglial inclusions, which are pathognomonic for MSA. MSA has no efficient therapy to date. Development of experimental models is crucial to elucidate the disease mechanisms in progression and to provide a tool for preclinical screening of putative therapies for MSA. In vitro and in vivo models, based on selective neurotoxicity, a-synuclein oligodendroglial overexpression, and strain-specific propagation of a-synuclein fibrils, have been developed, reflecting various facets of MSA pathology. Over the years, the continuous exchange from bench to bedside and backward has been crucial for the advancing of MSA modelling, elucidating MSA pathogenic pathways, and understanding the existing translational gap to successful clinical trials in MSA. The review discusses specifically advantages and limitations of the PLP-a-syn mouse model of MSA, which recapitulates motor and non-motor features of the human disease with underlying striatonigral degeneration, degeneration of autonomic centers, and sensitized olivopontocerebellar system, strikingly mirroring human MSA pathology.

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Shared Genetics of Multiple System Atrophy and Inflammatory Bowel Disease

Abstract: This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Cited by 20 publications

References 59 publications

Rare Comorbidity between Inflammatory Bowel Disease and Primary Biliary Cholangitis: Evidence from Causality, Shared Genetic Architecture and Transcriptomics

Rare Comorbidity between Inflammatory Bowel Disease and Primary Biliary Cholangitis: Evidence from Causality, Shared Genetic Architecture and Transcriptomics

Multiple System Atrophy: Advances in Diagnosis and Therapy

A Mouse Model of Multiple System Atrophy: Bench to Bedside

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