Pathway analysis of body mass index genome-wide association study highlights risk pathways in cardiovascular disease

Zhao, Xin; Gu, Jinxia; Li, Ming; Xi, Jie; Sun, Wenyu; Song, Guanhua; Liu, Guiyou

doi:10.1038/srep13025

Cited by 13 publications

(7 citation statements)

References 38 publications

(59 reference statements)

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“…The proteins encoded by the corresponding methylated genes were mainly associated with the cytoplasm, and were enriched in the molecular functions of phospholipid, protein and lipid binding activities. These results are highly consistent with data from a recent genome-wide systematic pathway analysis of body mass index, which provided insights into the genetics of CVD and its risk factors ( 43 ). The results of the present study revealed a significant enrichment to immune system processes in the ACS samples, which may be due to the altered maturation status and possible immune exhaustion of immune cells in the peripheral blood of patients with ACS ( 44 ).…”

Section: Discussionsupporting

confidence: 88%

Genome-wide DNA methylome alterations in acute coronary syndrome

Yan

Yuan

et al. 2017

Int J Mol Med

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Acute coronary syndrome (ACS) is a common disease with high mortality and morbidity rates. The methylation status of blood DNA may serve as a potential early diagnosis and prevention biomarker for numerous diseases. The present study was designed to explore novel genome-wide aberrant DNA methylation patterns associated with ACS. The Infinium HumanMethylation450 assay was used to examine genome-wide DNA methylation profiles in 3 pairs of ACS and control group samples. Epigenome-wide DNA methylation, genomic distribution, Gene Ontology (GO) term and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed. The results were confirmed using methylation-specific polymerase chain reaction (MSP) and Sequenom MassARRAY analyses in ACS, stable coronary artery disease (SCAD) and control samples. A total of 11,342 differentially methylated (DM) 5′-C-phosphate-G-3′ (CpG) sites were identified, including 8,865 hypomethylated and 2,477 hypermethylated CpG sites in the ACS group compared with the control samples. They varied in frequency across genomic compartments, but were particularly notable in gene bodies and shores. The results of GO term and KEGG pathway enrichment analyses revealed that the methylated genes were associated with certain biological processes and pathways. Despite the considerable variability in methylation data, the candidate selected possessed significant methylation alteration in mothers against decapentaplegic homolog 3 (SMAD3) transcription start site 155 (Chr1:67356838-Chr1:67356942). MSP analysis from 81 ACS samples, 74 SCAD samples and 53 healthy samples, and Sequenom MassARRAY analysis, confirmed that differential CpG methylation of SMAD3 was significantly corrected with the reference results of the HumanMethylation450 array. The data identified an ACS-specific DNA methylation profile with a large number of novel DM CpG sites, some of which may serve as candidate markers for the early diagnosis of ACS.

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Section: Discussionsupporting

confidence: 88%

Genome-wide DNA methylome alterations in acute coronary syndrome

Yan

Yuan

et al. 2017

Int J Mol Med

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“…Here, we selected the pathway resources from KEGG and GO databases, as provided in Web-based Gene Set Analysis Toolkit (WebGestalt version 2019) (Wang et al, 2017). To identify a potential OA risk pathway, the hypergeometric test was used to evaluate an overrepresentation of the OA risk genes among all the genes in the selected pathway, as did in previous studies (Bao et al, 2015; Zhao et al, 2015; Jiang et al, 2017; Liu et al, 2017; Wang et al, 2017). For a given pathway, the P value of observing more than K OA risk genes could be calculated by…”

Section: Methodsmentioning

confidence: 99%

Integrating Genome-Wide Association Studies With Pathway Analysis and Gene Expression Analysis Highlights Novel Osteoarthritis Risk Pathways and Genes

Gao¹,

Yu²,

Zhang³

et al. 2019

Front. Genet.

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Osteoarthritis (OA) is the most common degenerative joint disorder worldwide. To identify more genetic signals, genome-wide association study (GWAS) has been widely used and elucidated some OA susceptibility genes. However, these susceptibility genes could only explain only a small part of heritability of OA. It is suggested that the identification of disease-related pathways may contribute to understand the genomic etiology of OA. Here, we integrated the GWAS into pathway analysis to identify novel OA risk pathways. In this study, we first selected 187 independent genetic variants identified by GWAS (P < 1.00E−05) and found that most of these genetic variants are noncoding mutations. We then conducted an expression quantitative trait loci analysis and found that 165 of these 187 genetic variants could significantly regulate the expression of nearby genes. Third, we identified OA susceptibility genes corresponding to these genetic variants, conducted a pathway analysis, and identified novel OA-related KEGG pathways, GO biological processes, GO molecular functions, and GO cellular components. In KEGG database, transforming growth factor β signaling pathway is the most significant signal (P = 5.98E−05) and is the only pathway after the BH multiple-test adjustment with false discovery rate (FDR) = 0.02. In GO database, we identified 24 statistically significant GO biological processes, one statistically significant GO molecular function, and five statistically significant GO cellular components (FDR < 0.05). These signals are related with chondrocyte differentiation and development, which are all known biological pathways associated with OA. Finally, we conducted an OA case–control gene expression analysis to evaluate the differential expression of these OA risk genes. Using an OA case–control gene expression analysis, we showed that 44 risk genes were suggestively differentially expressed in OA cases compared with controls (P < 0.05). Three genes, WWP2, COG5, and MAPT, were statistically differentially expressed in OA cases compared with controls (P < 0.05/122 = 4.10E−04). Hence, our findings may contribute to understanding the genomic etiology of OA.

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“…For instance, this approach has been successfully applied to identify novel regulatory pathways in different phenotypes such as body mass index [6], colorectal cancer [7] or outcome of breast cancer [8]. …”

Section: Introductionmentioning

confidence: 99%

Genomic Contributors to Rhythm Outcome of Atrial Fibrillation Catheter Ablation – Pathway Enrichment Analysis of GWAS Data

Husser¹,

Büttner²,

Ueberham³

et al. 2016

PLoS ONE

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BackgroundLeft atrial enlargement and persistent atrial fibrillation (AF) are well-known predictors for arrhythmia recurrence after AF catheter ablation (LRAF). In this study, by using pathway enrichment analysis of GWAS data, we tested the hypothesis that genetic pathways associated with these phenotypes are also associated with LRAF.MethodsSamples from 660 patients with paroxysmal (n = 370) or persistent AF (n = 290) undergoing de-novo AF catheter ablation were genotyped for ~1,000,000 SNPs. SNPs found to be significantly associated with left atrial diameter (LAD) or AF type were used for gene-based association tests in a systematic biological Knowledge-based mining system for Genome-wide Genetic studies (KGG). Associated genes were tested for pathway enrichment using WEB-based Gene SeT AnaLysis Toolkit (WebGestalt), the Gene Annotation Tool to Help Explain Relationships (GATHER) and the databases provided by Kyoto Encyclopedia of Genes and Genomes (KEGG). In a second step, the association of consistently enriched pathways and LRAF was tested.ResultsBy using sequential 7-day Holter ECGs, LRAF between 3 and 12 months was observed in 48% and was associated with LAD (B = 1.801, 95% CI 0.760–2.841, p = 1.0E-3) and persistent AF (OR = 2.1; 95% CI 1.567–2.931, p = 2.0E-6). WebGestalt (adj. p = 2.7E-22) and GATHER (adj. p = 5.2E-3) identified the calcium signaling pathway (hsa04020) as the only consistently enriched pathway for LAD, while the extracellular matrix (ECM) -receptor interaction pathway (hsa04512) was the only consistently enriched pathway for AF type (adj. p = 2.1E-15 in WebGestalt; adj. p = 9.3E-4 in GATHER). Both calcium signaling (adj. p = 2.2E-17 in WebGestalt; adj. p = 2.9E-2 in GATHER) and ECM-receptor interaction (adj. p = 1.2E-10 in WebGestalt; adj. p = 2.9E-2 in GATHER) were significantly associated with LRAF.ConclusionsCalcium signaling and ECM-receptor interaction pathways are associated with LAD and AF type and, in turn, with LRAF. Future and larger studies are necessary to replicate and apply these findings.

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Pathway analysis of body mass index genome-wide association study highlights risk pathways in cardiovascular disease

Cited by 13 publications

References 38 publications

Genome-wide DNA methylome alterations in acute coronary syndrome

Genome-wide DNA methylome alterations in acute coronary syndrome

Integrating Genome-Wide Association Studies With Pathway Analysis and Gene Expression Analysis Highlights Novel Osteoarthritis Risk Pathways and Genes

Genomic Contributors to Rhythm Outcome of Atrial Fibrillation Catheter Ablation – Pathway Enrichment Analysis of GWAS Data

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