Pathway analysis for genome-wide genetic variation data: Analytic principles, latest developments, and new opportunities

Silberstein, Micah; Nesbit, Nicholas; Cai, Jacquelyn; Lee, Phil H.

doi:10.1016/j.jgg.2021.01.007

Cited by 8 publications

(8 citation statements)

References 90 publications

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“…As we all know, most of the disease susceptibility SNPs found in GWAS are located in the non‐coding regions of genes, and the specific mechanisms of most of the SNPs have not been clarified due to the limitations of research methods. However, with the continuous efforts of scientists, many valuable databases have been established to help predict the possible mechanisms of genetic variation in non‐coding regions 36 . Through various prediction websites, such as HaploReg database, RegulomeDB, ENCODE, we found that the region where rs2853694 located contained a large number of regulatory elements, such as enhancer markers H3K27ac, H3K4me1, H3K27me3 and transcription factor binding sites.…”

Section: Discussionmentioning

confidence: 99%

Polymorphism of IL‐12/IL‐23 axis is associated with coronary heart disease

Dong,

Chen,

Xie

et al. 2024

J Cellular Molecular Medi

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IL12B encodes the shared p40 subunit (IL‐12p40) of IL‐12 and IL‐23, which have diverse immune functions and are closely related to the occurrence and development of atherosclerosis (AS). However, the exact role of IL12B in coronary heart disease (CHD) was still unknown. A case–control association analysis was performed between five single nucleotide polymorphisms (SNPs) of IL12B (rs1003199, rs3212219, rs2569254, rs2853694 and rs3212227) and CHD in Chinese Han population (1824 patients with CHD vs. 2784 controls). Logistic regression analyses were used to study the relationships between SNPs and CHD, while multiple linear regression analyses were used to test the association between the SNP and the severity of CHD. In addition, the plasma IL12B concentration of CHD patients were detected by ELISA. We detected a significant association between one of the SNPs, rs2853694−G and CHD (padj = 2.075 × 10−5, OR, 0.773 [95% CI, 0.686–0.870]). Stratified analysis showed that rs2853694 was associated with CHD in both male and female populations and was significantly associated with both early‐ and late‐onset CHD. In addition, rs2853694 is also related to the different types of CHD including clinical‐CHD and anatomical‐CHD. Moreover, there are significant differences in serum IL12B concentrations between rs2853694−TT carriers and rs2853694−GT carriers in CHD patients (p = 0.010). A common variant of IL12B was found significantly associated with CHD and its subgroups. As a shared subunit of IL‐12 and IL‐23, IL‐12p40 may play a key role in IL‐12/IL‐23 axis mediated AS, which is expected to be an effective therapeutic target for CHD.

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Section: Discussionmentioning

confidence: 99%

Polymorphism of IL‐12/IL‐23 axis is associated with coronary heart disease

Dong,

Chen,

Xie

et al. 2024

J Cellular Molecular Medi

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“…We identified all proteins identified by Brocca and colleagues, indicating robust replication of the physiological response to immobilization and validation of our SWATH methodology. The SWATH methodology unique to our study permitted not only a greater yield of differentially expressed proteins, but use of GSEA, and this is the first study to provide a more comprehensive description of the biological processes impacted by limb immobilization [ 30 ].…”

Section: Discussionmentioning

confidence: 99%

“…permitted not only a greater yield of differentially expressed proteins, but use of GSEA, and this is the first study to provide a more comprehensive description of the biological processes impacted by limb immobilization [30].…”

Section: Plos Onementioning

confidence: 99%

The muscle proteome reflects changes in mitochondrial function, cellular stress and proteolysis after 14 days of unilateral lower limb immobilization in active young men

et al. 2022

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Skeletal muscle unloading due to joint immobilization induces muscle atrophy, which has primarily been attributed to reductions in protein synthesis in humans. However, no study has evaluated the skeletal muscle proteome response to limb immobilization using SWATH proteomic methods. This study characterized the shifts in individual muscle protein abundance and corresponding gene sets after 3 and 14 d of unilateral lower limb immobilization in otherwise healthy young men. Eighteen male participants (25.4 ±5.5 y, 81.2 ±11.6 kg) underwent 14 d of unilateral knee-brace immobilization with dietary provision and following four-weeks of training to standardise acute training history. Participant phenotype was characterized before and after 14 days of immobilization, and muscle biopsies were obtained from the vastus lateralis at baseline (pre-immobilization) and at 3 and 14 d of immobilization for analysis by SWATH-MS and subsequent gene-set enrichment analysis (GSEA). Immobilization reduced vastus group cross sectional area (-9.6 ±4.6%, P <0.0001), immobilized leg lean mass (-3.3 ±3.9%, P = 0.002), unilateral 3-repetition maximum leg press (-15.6 ±9.2%, P <0.0001), and maximal oxygen uptake (-2.9 ±5.2%, P = 0.044). SWATH analyses consistently identified 2281 proteins. Compared to baseline, two and 99 proteins were differentially expressed (FDR <0.05) after 3 and 14 d of immobilization, respectively. After 14 d of immobilization, 322 biological processes were different to baseline (FDR <0.05, P <0.001). Most (77%) biological processes were positively enriched and characterized by cellular stress, targeted proteolysis, and protein-DNA complex modifications. In contrast, mitochondrial organization and energy metabolism were negatively enriched processes. This study is the first to use data independent proteomics and GSEA to show that unilateral lower limb immobilization evokes mitochondrial dysfunction, cellular stress, and proteolysis. Through GSEA and network mapping, we identify 27 hub proteins as potential protein/gene candidates for further exploration.

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“…The technique in use to assess an individual's susceptibility to a particular physical or mental illness is the PRS, which relies on determining the set of the SNPs that were known as risky from other studies including GWAS. However, polygenicity is a significant problem for this technique, as many phenotypic traits are affected by too many genes, making it hard to calculate PRS [2], [3], [4], [5], [6], [11], [12], [13], [14], [15], [16], [17], [18]. Another difficulty of the PRS is the requirement of knowledge about the weighted effect of each variant on the phenotype.…”

Section: Discussionmentioning

confidence: 99%

“…Besides, there is no consensus on which of the various methods used to calculate PRS is the most appropriate. In particular, the necessity of finding new strategies to overcome the polygenicity problem is emphasized [6], [11], [12], [13], [14], [15], [16], [17], [18].…”

Section: Introductionmentioning

confidence: 99%

Gene Teams are on the Field: Evaluation of Variants in Gene-Networks Using High Dimensional Modelling

Tuna

Güleç

Yücesan

et al. 2022

Preprint

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Variation is a key concept in every biological aspect, particularly in medical genetics. In this field, each genetic variant is evaluated mostly as an independent entity in respect to its clinical importance. This approach may be sufficient to detect the pathogenic variants in single-gene disorders. However, in most of the complex diseases, the combination of the variants in specific gene networks, rather than the presence of a certain single variant predominates. Therefore, while considering a complex disease, the disease status can be evaluated as the success of a team composed of certain variants. To apply this approach, we tested the efficiency of high-dimensional modelling of gene-network restricted variants in distinguishing a disease status. To evaluate the proposed method, we select two gene networks, mTOR and TGF-β. For each pathway, we generate 400 control and 400 patient group samples. The considered mTOR and TGF-β pathways contain 31 and 93 genes of varying sizes, respectively. We performed Chaos Game Representation to each gene sequence to obtain 2-D binary patterns. Produced patterns are ordered successively, and a 3-D tensor structure is achieved for each gene network. Features for each data sample are acquired by exploiting Enhanced Multivariance Products Representation to 3-D data. The features are split as training and testing vectors. The training vectors are employed to train a Support Vector Machines classification model. We manage to achieve more than 96% and 99% classification accuracies for mTOR and TGF-β networks, respectively, using a limited amount of training samples.

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Pathway analysis for genome-wide genetic variation data: Analytic principles, latest developments, and new opportunities

Cited by 8 publications

References 90 publications

Polymorphism of IL‐12/IL‐23 axis is associated with coronary heart disease

Polymorphism of IL‐12/IL‐23 axis is associated with coronary heart disease

The muscle proteome reflects changes in mitochondrial function, cellular stress and proteolysis after 14 days of unilateral lower limb immobilization in active young men

Gene Teams are on the Field: Evaluation of Variants in Gene-Networks Using High Dimensional Modelling

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