JS PD KB

20240722_184317

6 min read

Pathway Analysis — comparison

concentrations of proteins in the same complex are less noisy compared with proteins that are not within one complex 31

Gene-disease phenotype associationPATHway analysis
Varelect,ReactomeKegg (Kyoto Encyclopedia of Genes and Genomes) pathwayWikiPathwaysGENE Ontologygene set enrichment analysis)(QIAGEN) Ingenuity Pathway Analysis (IPA)MetaCore (Clarivate Analytics)CytoscapeR/BioconductorSTRING
Web toolve.genecards.orghttps://www.genome.jp/kegg/tool/map_pathway2.htmlEnrichRIPA, 으로부터 app을 이미 download 받아놓았으니, 내 desktop에서 그 앱을 찾아 open 하면 됨. jae-won.lee@takeda.com Annafreud521https://taketda-tks.com/resources/
이 데도 scroll down 이번 나옴!		open source softwarehttps://string-db.org/, log in with Google account!
Input - Gene names ) that were derived from differential gene expression analysis (RNA-Seq)
- Phenotype keyword: ("Parkinson's Disease" and either "mitochondria" or "lysosome" 		RNA-Seq결과를 다음 format 으로 input,
467 green
1185 green

Cf) 467은 NCBI gene ID 임 (ATF3),
Green: fold change <0
Coral: fold change >0
output내가 input 한 gene 들을 내가 input 한 phenotype 을 일으키는 정도별로 rank order 해 보여줌.(Kegg signaling network/diagram thumbnail — figure with mixed cell text; kept as evidence in body_r02_c01) [significant pathways in order]
Y axis: negative log of p-value (base 10): the taller bar, the less p-value (ie more significant)
P value 0.05 = negative log of the p-value is 1.3.

[direction of pathway -color coding]
Orange bar: ↑activity (색이 짙으면, z score 가 크다는 의미이고, ↓의 부분/염려 없이 확실히 ↑라는 의미)
Blue bar: ↓ activity,
Whitel bar: nor ↑ or ↓
Based on z score: if z score≥2, then statiscally significant 		Proteomics data:
Gene IDProein IDratiop value (Q value)
특정 프로테인을 중심으로 해서 그 프로테인을 중심으로 관계성이 가까운 것을 prioritize 하시고 싶으신…
Eg.Carling 2020(Carling 2020
•
•		 •
Eg) (Bellenguez, 2020 #1300) Carling 2020
resource(Stelzer et al., 2016)https://bioinformaticsandme.tistory.com/210Kuleshov, M.V., 2016. Enrichr: a comprehensive gene set enrichment analysis web server 2016 update. Nucleic Acids Res. 44, W90-97.

Example of Pathway Analysis

  • Carling 2020
Mito-sPDLyso-sPD
in skin fibroblasts of 100 sPD patients and 50 age-matched controls
DefinitionThe five sPD patients with the most marked reduction in ATP levelsthe five patients with the most marked increase in the number of lysosomes
DEGs from RNA-Seq84 genes were differentially expressed (vs age-mated controls)342 genes were differentially expressed (vs age-mated controls)
liv) 이 complete list가 Supplmentary table 3, or 4에 있다는데 그런 file 찾을 수 없네.
lv) There was no overlap in differentially expressed genes (DEG) between the two subgroups*
VarElect results Table 4
Top 10 results for unadjusted mitochondrial-dysfunctional DEGs from VarElect. Investigation of DEGs using online tool VarElect with the terms "Mitochondria" and "Parkinson's Disease" in mito-sPD compared to controls indicates a number of genes score highly for association with these terms, including well-established PD genes. Gene symbol represents official HGNC symbol. Matched Phenotypes indicates the terms inputted into VarElect which have been associated with each gene. Results are ranked by VarElect score.
Gene SymbolGene NameMatched PhenotypesVarElect Score
SNCASynuclein AlphaParkinson's Disease, Mitochondria318.70
PLA2G6Phospholipase A2 Group VIParkinson's Disease, Mitochondria99.07
RPS27ARibosomal Protein S27aParkinson's Disease, Mitochondria63.08
PODXLPodocalyxin LikeParkinson's Disease, Mitochondria53.55
NDUFS2NADH:Ubiquinone Oxidoreductase Core Subunit S2Parkinson's Disease, Mitochondria52.91
GCH1GTP Cyclohydrolase 1Parkinson's Disease, Mitochondria52.80
APPAmyloid Beta Precursor ProteinParkinson's Disease, Mitochondria49.75
PANK2Pantothenate Kinase 2Parkinson's Disease, Mitochondria49.62
NDUFS1NADH:Ubiquinone Oxidoreductase Core Subunit S1Parkinson's Disease, Mitochondria48.41
NDUFAF5NADH:Ubiquinone Oxidoreductase Complex Assembly Factor 5Parkinson's Disease, Mitochondria43.05
 Table 1
Top 10 results for lysosomal-dysfunctional DEGs from VarElect. Investigation of DEGs using online tool VarElect with the terms "Lysosome" and "Parkinson's Disease" indicates a number of genes score highly for association with these terms, including well-established PD genes. Gene symbol represents official HGNC symbol. Matched Phenotypes indicates the terms inputted into VarElect which have been associated with each gene. Results are ranked by the VarElect score.
Gene SymbolGene NameMatched PhenotypesVarElect Score
CTSDCathepsin DParkinson's Disease, Lysosome59.51
SMPD1Sphingomyelin Phosphodiesterase 1Parkinson's Disease, Lysosome56.85
FUCA1Alpha-L-Fucosidase 1Parkinson's Disease, Lysosome45.44
NPC1NPC Intracellular Cholesterol Transporter 1Parkinson's Disease, Lysosome42.31
MAPK3Mitogen-Activated Protein Kinase 3Parkinson's Disease, Lysosome34.54
RAB7ARAB7A, Member RAS Oncogene FamilyParkinson's Disease, Lysosome29.89
IGF2Insulin Like Growth Factor 2Parkinson's Disease, Lysosome23.58
ALDH1A1Aldehyde Dehydrogenase 1 Family Member A1Parkinson's Disease21.85
MSX1Msh Homeobox 1Parkinson's Disease19.67
SORT1Sortilin 1Parkinson's Disease, Lysosome18.29
Kegg pathway results the 84 DEGs associated with mito-sPD did not enrich for any functions or pathways and therefore failed to identify any pathways associated with mitochondrial dysfunction. (위 VarElect analysis 도 84 gene 으로 한 것이 아니라, p VALUE 를 relax 해서 unadjuisted p value <0.05 했더니 나온 1659 gene 을 VAReLECT 에 넣어 나온 결과임.)
  • lvi) mito기능이 분명히 망가진 환자들인데 pathway enrichment in RNA levlel가 없네! → This suggests that i) the observed mitochondrial dysfunction is not due to transcriptionally regulated pathways, ii) the reduced ATP production doesn't result in compensatory changes at the transcriptional level.
 Top 5 most enriched KEGG pathways for lysosome-dysfunctional DEGs. Results indicate an enrichment of signalling pathways as well as "Lysosome". Overlap indicates number of genes in input list/total number of genes in pathway list. "Genes" lists the DEGs present in each pathway.
TermOverlapP-valueAdjusted P-valueGenes
TNF signalling pathway10/1100.0000190.004103MAP2K3, NFKBIA, IKBKB, TAB2, CXCL1, CXCL3, PTGS2, IL15R1, CXCL5, MAPK3
Lysosome10/1230.0000510.005396PLA2G15, CD63, ATP6V0B, NPC1, SORT1, FUCA1, SMPD1, LITAF, CTSD, ATP6V0A1
Small cell lung cancer8/860.0001120.007545NFKBIA, ITGB1, IKBKB, CDKN1B, ITGA3, FN1, ITGA6, PTGS2
Circadian rhythm5/300.0001420.007545PER1, CSNK1D, NR1D1, CSNK1E, ARNTL
Rap1 signalling pathway12/2110.0002920.010408MAP2K3, ITGB1, KITLG, PLCB4, PRKD3, PDGFD, ITGB2, GNAS, RAPGEF5, RAPGEF6
  • lvii) "TNF signalling" and "Lysosome" were most markedly increased
  • lviii) Of the 10 genes overlapping with this lysosome upregulated in patients (Table 3) including CTSD (그런데 PIGD 보면 Cathepsin D activity는 많이 줄어 있네!).
  • lix)
Tx response In sPD fibroblasts with mild mitochondrial impairment (ATP or MMP levels >2 SD but <3 SD below the mean of controls, in order to assess the potential of UDCA treatment to be beneficial in a larger patient population.)
UDCA→ normalized ATP, MMP, MC1 activity (but not MC4 activity)

Uncertain Spans

  • “(QIAGEN) Ingenuity Pathway Analysis” — column header in source straddles two columns “(QIAGEN)” + “Ingenuity Pathway Analysis (IPA)”; merged into one header.
  • “Whitel bar” — appears literally as Whitel (likely a typo for White); transcribed as printed.
  • “Annafreud521” — in IPA login note appears as Annafreud521; transcribed as printed (could be a password placeholder).
  • “Kegg pathway results — 1659 gene” — uses Korean particle 으로 after “1659 gene”; transcribed verbatim.
  • “RNA levlel” — original prints levlel (likely typo for level); transcribed as printed.
  • “lix)” trailing list item — appears as a numbered marker lix) with empty content in the source.

그래프 뷰

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