snpXplorer: a web application to explore human SNP-associations and annotate SNP-sets

Tesi, Niccolò; Lee, Sven J. van der; Hulsman, Marc; Holstege, Henne; Reinders, Marcel J. T.

doi:10.1093/nar/gkab410

Cited by 15 publications

(14 citation statements)

References 61 publications

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“…Variant-gene annotation and gene-set enrichment analyses were performed through the web-server that is freely accessible at https://snpxplorer.net. (Tesi et al, 2021).…”

Section: Methodsmentioning

confidence: 99%

The Effect of Alzheimer’s Disease-Associated Genetic Variants on Longevity

Tesi¹,

Hulsman²,

Lee³

et al. 2021

Front. Genet.

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Human longevity is influenced by the genetic risk of age-related diseases. As Alzheimer’s disease (AD) represents a common condition at old age, an interplay between genetic factors affecting AD and longevity is expected. We explored this interplay by studying the prevalence of AD-associated single-nucleotide-polymorphisms (SNPs) in cognitively healthy centenarians, and replicated findings in a parental-longevity GWAS. We found that 28/38 SNPs that increased AD-risk also associated with lower odds of longevity. For each SNP, we express the imbalance between AD- and longevity-risk as an effect-size distribution. Based on these distributions, we grouped the SNPs in three groups: 17 SNPs increased AD-risk more than they decreased longevity-risk, and were enriched for β-amyloid metabolism and immune signaling; 11 variants reported a larger longevity-effect compared to their AD-effect, were enriched for endocytosis/immune-signaling, and were previously associated with other age-related diseases. Unexpectedly, 10 variants associated with an increased risk of AD and higher odds of longevity. Altogether, we show that different AD-associated SNPs have different effects on longevity, including SNPs that may confer general neuro-protective functions against AD and other age-related diseases.

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“…Variant-gene annotation and gene-set enrichment analyses were performed through the web-server that is freely accessible at https://snpxplorer.net. (Tesi et al, 2021).…”

Section: Methodsmentioning

confidence: 99%

The Effect of Alzheimer’s Disease-Associated Genetic Variants on Longevity

Tesi¹,

Hulsman²,

Lee³

et al. 2021

Front. Genet.

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“…SnpXplorer was used to analyze SNP-sets for gene ontology, annotation, and relation to GWAS traits (24).…”

Section: Gene Ontology Analysismentioning

confidence: 99%

Complicated Common Variable Immunodeficiency is Driven by Aberrant IL-10/IL-21 Signaling and Predisposed Polygenic Risk

Khan

Acar²,

Stephens³

et al. 2022

Preprint

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Background: The inborn errors of immunity (IEI) that include defective antibody responses are clinically heterogenous, especially the common variable immunodeficiency (CVID) phenotype that includes low immunoglobulin levels and impaired humoral responses to antigens. Beyond recurrent infections, many with the CVID phenotype develop non-infectious complications (NICs), including autoimmunity and lymphoproliferation, that confer a high rate of morbidity and mortality. At present, it is unknown what genetic and functional factors predispose patients to NICs. Objective: We aimed to discover the pathobiology underlying complicated CVID (CVIDc). Methods: In a heterogenous group of 12 CVIDc patients, we conducted whole exome sequencing and high-throughput signaling assays by multiplexed phospho-mass cytometry. The immune deficiency and dysregulation activity (IDDA) score was used to determine the burden of NICs in individual patients. We integrated polygenic risk scores to determine the role of common background variants in the pathogenesis of CVIDc. Results: In CVID patients with high IDDA scores, there was aberrant increased phosphorylation of STAT1 and STAT3 upon stimulation with IL-10 or IL-21. Furthermore, common variants related to high eosinophil count and allergy/eczema confer a higher likelihood of autoimmunity in CVID. Conclusion: Variants in loci related to high eosinophil count/function and over-reactive IL-10 signaling are associated with the development of autoimmune disease and NICs in CVID. Clinical implications: It may be possible to manage CVIDc through modulating IL-10 and IL-21 signaling pathways. Polygenic risk scoring may predict the development of autoimmune complications in CVID patients.

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“…2) and a dynamic cut tree algorithm for term-based clustering (Supplementary Fig. 3) 23 . The plug-in GeneMANIA in Cytoscape was used as an analytical method to provide an association network integration to predict gene function and gene-gene interaction out of the SNPs associated gene in this study 25,26 .…”

Section: Snp-gene Annotation and Pathway Enrichment Analysismentioning

confidence: 99%

“…The SNPs used in Gene-set Enrichment Analysis were obtained from GWAS catalog with the trait label "abdominal aortic aneurysm" (EFO_0004214) and from other literature whose allele frequency in AAA is 3% more than in controls. The obtained SNPs were annotated using snpXplorer AnnotateMe tool 23 with the following settings: SNP-gene annotation or Gene-set Enrichment Analysis, GRCh38, GTEx tissue: [Whole_Blood, Artery_Aorta, Artery_Coronary], GO:BP. For each SNP input, SNP-gene annotation gave back the following information: chromosomal position; minor allele frequency (MAF); CADD-annotation based pathogenicity score (CADD v1.6), variant consequence, & affected gene; GTEx based eQTL (expression quantitative-trait-loci) and sQTL (splicing quantitative-trait-loci); closest affected gene.…”

Section: Snp-gene Annotation and Pathway Enrichment Analysismentioning

confidence: 99%

Linking single nucleotide polymorphisms to metabolic risk and matrix remodeling in abdominal aortic aneurysms

Lim

Pratama

Silvestro

et al. 2022

Preprint

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Introduction: Genetic hereditary predisposes to AAA. However, the pathobiological relevance of single nucleotide polymorphisms (SNPs) to the development of AAA is not fully elucidated. The present study investigated 86 AAA SNPs from GWAS and clinical cohort studies to determine their phenotypical vulnerabilities in AAA. Methods SNPs from GWAS catalog and available clinical cohort were collected in this study. The SNPs were annotated using snpXplorer AnnotateMe tool to identify its chromosomal position, minor allele frequency (MAF), CADD (Combined Annotation Dependent Depletion)-annotation based pathogenicity score, variant consequence, & their affected gene. Gene enrichment analysis was performed on AAA-related genes using Gene Ontology (GO) terms and clustered using REVIGO. The plug-in GeneMANIA in Cytoscape was applied to reveal an association network integration of the SNPs with associated genes and functions. Results 15 SNPs affecting 20 genes with a CADD pathogenicity score above 10 were identified. AAA SNPs were predominantly located on chromosome 3 and 9. Stop-gained rs5516 KLK1 obtained high frequency in AAA (17.8%) and was associated with proinflammatory and vascular remodeling phenotypes. Our clinical cohort identified significant positive association of the SNPs presence with aortic diameter (P = 2.003e− 05), hypertension (P = 0.013), dyslipidemia (P = 0.042), and smoking history (P = 0.037) in AAA groups. Gene-ontology and Network association analysis showed that AAA SNPs and their associated genes could regulate signaling pathways including lipid metabolism, extracellular matrix organization, smooth muscle cell proliferation, and oxidative stress, suggesting that these AAA traits could be inheritable. Conclusion We show a library of inborn SNPs and associated genes that manifest in the presence of risk factors and uncovered their pathological signaling traits that are likely transmitted through familial lineage culminating in AAA development.

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snpXplorer: a web application to explore human SNP-associations and annotate SNP-sets

Cited by 15 publications

References 61 publications

The Effect of Alzheimer’s Disease-Associated Genetic Variants on Longevity

The Effect of Alzheimer’s Disease-Associated Genetic Variants on Longevity

Complicated Common Variable Immunodeficiency is Driven by Aberrant IL-10/IL-21 Signaling and Predisposed Polygenic Risk

Linking single nucleotide polymorphisms to metabolic risk and matrix remodeling in abdominal aortic aneurysms

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