Integrating genome-wide association studies and gene expression data highlights dysregulated multiple sclerosis risk pathways

Liu, Guiyou; Zhang, Fang; Jiang, Yixiang; Hu, Yang; Gong, Zhongying; Liu, Shoufeng; Chen, Xiuju; Jiang, Qinghua; Hao, Junwei

doi:10.1177/1352458516649038

Cited by 43 publications

(31 citation statements)

References 23 publications

(50 reference statements)

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“…However, these risk variants only explain a small proportion of osteoporosis genetic risk, and most genetic risk is largely unknown (Wei et al, 2016). Considering the limitations of GWAS on single genetic variant level, some improved method named pathway analysis of GWAS dataset or gene set analysis has been proposed and widely used in multiple human complex diseases (Eleftherohorinou et al, 2009;Hong et al, 2010;Liu et al, 2012;Holmans et al, 2013;Liu et al, 2013;Liu et al, 2014;Quan et al, 2015;Jiang et al, 2017;Liu et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

Analyzing Genome-Wide Association Study Dataset Highlights Immune Pathways in Lip Bone Mineral Density

et al. 2020

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Osteoporosis is a common complex human disease. Until now, large-scale genomewide association studies (GWAS) using single genetic variant have reported some novel osteoporosis susceptibility variants. However, these risk variants only explain a small proportion of osteoporosis genetic risk, and most genetic risk is largely unknown. Interestingly, the pathway analysis method has been used in investigation of osteoporosis mechanisms and reported some novel pathways. Until now, it remains unclear whether there are other risk pathways involved in BMD. Here, we selected a lip BMD GWAS with 301,019 SNPs in 5,858 Europeans, and conducted a gene-based analysis (SET SCREEN TEST) and a pathway-based analysis (WebGestalt). On the gene level, BMD susceptibility genes reported by previous GWAS were identified to be the top 10 significant signals. On the pathway level, we identified 27 significant KEGG pathways. Three immune pathways including T cell receptor signaling pathway (hsa04660), complement and coagulation cascades (hsa04610), and intestinal immune network for IgA production (hsa04672) are ranked the top three significant signals. Evidence from the PubMed and Google Scholar databases further supports our findings. In summary, our findings provide complementary information to these nine risk pathways.

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Section: Introductionmentioning

confidence: 99%

Analyzing Genome-Wide Association Study Dataset Highlights Immune Pathways in Lip Bone Mineral Density

et al. 2020

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“…Also, these studies have introduced biomarkers or drug targets through bioinformatics [10][11][12][13]. Also, these studies have introduced biomarkers or drug targets through bioinformatics [10][11][12][13].…”

Section: Introductionmentioning

confidence: 99%

“…Their results revealed that one of the peptides belonged to a region of an Epstein-Barr virus nuclear antigen 1 (EBNA1) protein and was homologous to alphacrystallin B chain in humans [10]. Furthermore, two pathways related to infectious diseases, including toxoplasmosis and Staphylococcus aureus infection, were found [11]. In addition to three pathways reported in a previous study [Janus kinase/signal transducers and activators of transcription (JAK-STAT) signalling pathway, acute myeloid leukaemia and T cell receptor signalling pathway] [14], several other pathways were also identified (e.g.…”

Section: Introductionmentioning

confidence: 99%

“…In recent years, several studies have evaluated the autoantibody repertoires in MS patients and examined proteomic and transcriptomic alterations during DMT. Also, these studies have introduced biomarkers or drug targets through bioinformatics [10][11][12][13]. In this regard, Hecker et al [10] investigated the autoantibody repertoires in serum and CSF samples of patients with RR-MS or primary progressive MS (PP-MS) via high density-peptide microarray representing the protein sequences of 45 MS autoantigens.…”

Section: Introductionmentioning

confidence: 99%

“…antigen processing and presentation, focal adhesion and mechanistic target of rapamycin signalling pathway). Furthermore, two pathways related to infectious diseases, including toxoplasmosis and Staphylococcus aureus infection, were found [11].…”

Section: Introductionmentioning

confidence: 99%

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A systems medicine approach reveals disordered immune system and lipid metabolism in multiple sclerosis patients

Pazhouhandeh

Sahraian

Siadat

et al. 2018

Clinical and Experimental Immunology

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Identification of autoimmune processes and introduction of new autoantigens involved in the pathogenesis of multiple sclerosis (MS) can be helpful in the design of new drugs to prevent unresponsiveness and side effects in patients. To find significant changes, we evaluated the autoantibody repertoires in newly diagnosed relapsing-remitting MS patients (NDP) and those receiving disease-modifying therapy (RP). Through a random peptide phage library, a panel of NDP- and RP-specific peptides was identified, producing two protein data sets visualized using Gephi, based on protein--protein interactions in the STRING database. The top modules of NDP and RP networks were assessed using Enrichr. Based on the findings, a set of proteins, including ATP binding cassette subfamily C member 1 (ABCC1), neurogenic locus notch homologue protein 1 (NOTCH1), hepatocyte growth factor receptor (MET), RAF proto-oncogene serine/threonine-protein kinase (RAF1) and proto-oncogene vav (VAV1) was found in NDP and was involved in over-represented terms correlated with cell-mediated immunity and cancer. In contrast, transcription factor RelB (RELB), histone acetyltransferase p300 (EP300), acetyl-CoA carboxylase 2 (ACACB), adiponectin (ADIPOQ) and phosphoenolpyruvate carboxykinase 2 mitochondrial (PCK2) had major contributions to viral infections and lipid metabolism as significant events in RP. According to these findings, further research is required to demonstrate the pathogenic roles of such proteins and autoantibodies targeting them in MS and to develop therapeutic agents which can ameliorate disease severity.

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Rs4878104 contributes to Alzheimer’s disease risk and regulates DAPK1 gene expression

Liang

Zhang

et al. 2017

Neurol Sci

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In 2006, a candidate gene study reported death-associated protein kinase 1 (DAPK1) rs4878104 variant to be significantly associated with Alzheimer's disease (AD) risk. However, the following studies showed inconsistent association results. Here, we conducted an updated analysis to investigate the potential association between rs4878104 and AD using a total of 60,751 samples (20,161 AD cases and 40,590 controls). In the pooled population, the results based on the allele and genotype genetic models show that rs4878104 variant is not significantly associated with AD risk. Interestingly, we identified rs4878104 variant to be significantly associated with AD risk in American population and Chinese population in subgroup analysis. Using multiple large-scale expression quantitative trait loci datasets, we further found that rs4878104 T allele could significantly regulate increased DAPK1 expression in European population. These findings suggest that rs4878104 may contribute AD susceptibility by modifying DAPK1 expression in European population.

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Integrating genome-wide association studies and gene expression data highlights dysregulated multiple sclerosis risk pathways

Abstract: We report shared genetic pathways in different MS-GWAS datasets and highlight some new MS risk pathways. Our findings provide new insights on the genetic determinants of MS.

Cited by 43 publications

References 23 publications

Analyzing Genome-Wide Association Study Dataset Highlights Immune Pathways in Lip Bone Mineral Density

Analyzing Genome-Wide Association Study Dataset Highlights Immune Pathways in Lip Bone Mineral Density

A systems medicine approach reveals disordered immune system and lipid metabolism in multiple sclerosis patients

Rs4878104 contributes to Alzheimer’s disease risk and regulates DAPK1 gene expression

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