parkinson’s disease gwas and enrichment with metacore™
DESCRIPTION
Parkinson’s Disease GWAS and enrichment with MetaCore™. Ewan Hunter, PhD. January 18, 2010. GeneGo Services. Customization/ Integration. Knowledge base Management. Annotation and Curation. Wet Lab Services. Data Repository. Data parsers Maps, interactions, interface skins. - PowerPoint PPT PresentationTRANSCRIPT
GeneGo. Your GPS in pathway analysis.
Confidential © GeneGo Inc.
Parkinson’s Disease GWAS and enrichment with MetaCore™
Ewan Hunter, PhDJanuary 18, 2010
Confidential © GeneGo Inc. 2
GeneGo Services
Knowledge base
Management
Pathway Analysis Platforms
Develop Ontologies
Develop Disease
platforms
Annotation and Curation
Data Repository
Project analysis (on/off site)
Wet Lab Services
Data parsers Maps,
interactions, interface skins
Customization/ Integration
Compound Assessment
analysis
Confidential © GeneGo Inc. 3
MetaMiner Initiatives
Eli LillyAstra Zeneca
Chicago Children’s Hospital
University of GlasgowSheffield
QueenslandUSC
Research and Discovery Clinical
CNSOncology
Skin
Stem Cells
TSRI
Cardiac
Jackie
Immunology
Metabolic
Knowledge Management
Information Technology
VertexIOP
Pharma TBA
Eli LillyTgen
Van AndelHarvard
Johns HopkinsExclusive PC contract with
top Pharma
GSKTop Pharma
Nutrition
TBA
Toxicology Drug Metabolism/ Positioning
Dry Eye
Exclusive Project
3 cosmetic co’s
FDAISB
University of Amsterdam
Respiratory
TSRI
Infectious Disease
TBA
Cystic Fibrosis
Complete
Confidential © GeneGo Inc. 4
MetaBase Content OverviewDatabase
Human genes 45.471 Human SwissProt proteins 20.328 Mouse genes 61.311 Mouse SwissProt proteins 16.209 Rat genes 36.870 Rat SwissProt proteins 7.459 Chemical compounds 691.896 Compounds with structures 673.207 Drugs 5.594
- FDA approved drugs 1.085- EU approved drugs 169- Drugs approved by other committees
692- US withdrawn drugs 140- EU withdrawn drugs 54- Clinical trial drugs
2.258- Discontinued drugs 1.205- Preclinical drugs
134- Biologics 618
Endogenous compounds 4.776 Nutritional compounds 93 Metabolite of xenobiotic 8.199
Networkable Objects
Human genes in network19.910
Mouse genes in network18.381
Rat genes in network 16.228 Chemical compounds
221.076 Drugs 2.737 Endogenous compounds 2.449 Metabolic Reactions 8.899 Pubmed journals 2.664 Pubmed articles (total)
758.139 Pubmed articles (single citation)
130.058
Total amount of interactions941.946
Protein-Protein365.129
Compound – Protein 502.572 Compound – Compound 9.618 Protein -Reaction 19.449 Substrate, Product-Reaction 29.366 RNA – Protein 15.812
Confidential © GeneGo Inc. 5
GeneGo Ontologies
Ontologies with graphic content
GeneGo maps: 808(regulatory processes maps
Disease maps Metabolic maps)
GeneGo networks 942UNIQUE for GeneGo
(regulatory networksdrug target networks
toxicity networks metabolic networks
disease biomarker networks)
Groups and Complexes: 2247UNIQUE for GeneGo
Schemas for human, mouse or rat
ACM2 and ACM4 activation of ERK
Inflammation_IL-6 signaling
NF-kB_HUMAN
Confidential © GeneGo Inc. 6
GeneGo Pathway Formats
GeneGo Canonical Maps GeneGo Networks
Insulin Receptor Signaling PathwaySignal transduction_Insulin signaling
• Total number to date: 808• Subset of a bigger-global network
• Static, pre-built• Interactive• Multistep
• Well accepted in the field • “Review-article” style- mainstream
signaling
• Total number to date: 942• Dynamic
• Interactive• Pre-built and build your own
• Bigger-global network• Include single or multistep
• Include newer findings, more than mainstream signaling
Confidential © GeneGo Inc. 7
How to Approach MetaCore
Input list Data Mining
Functional RepresentationWhat do the items on the
list collectively represent?
ConnectivityHow do the items on
the list connect?
Confidential © GeneGo Inc. 8
GWAS- Pakinson’s Disease
Data: SNP identifiers, allelic frequency and odds ratio The odds ratio = as the ratio of the odds of an event occurring in one group (PD siblings) to the odds of it
occurring in another group (non-PD siblings). odds ratio =1 condition or event under study is equally likely in both groups.
odds ratio > 1 condition or event is more likely in the first groupodds ratio <1 condition or event is less likely in the second group.
Confidential © GeneGo Inc. 9
Data Format and Data Loading
Confidential © GeneGo Inc. 10
Define Thresholds
Confidential © GeneGo Inc. 11
Single Experiment Workflow: Enrichment Histograms forCanonical Pathway Maps
Confidential © GeneGo Inc. 12
Alzheimer's disease: extracellular Amyloid beta toxicity.
Confidential © GeneGo Inc. 13
Disease Biomarker Map Overlay
Confidential © GeneGo Inc. 14
Alzheimer's disease: extracellular Amyloid beta toxicity Ca++ Channels
Confidential © GeneGo Inc. 15
From this table we can also appreciate that another gene of interest from this canonical pathway map is not only the Amyloid beta A4 precursor protein but that 3 subunits of the Ca2 channel have a significant association to Parkinson’s. This is of interest as there are studies that suggest the disruption in Ca2+ homeostasis within the dopamine neurons of the substantia nigra lead to loss of these SN neurons
Sulzer and Schmitz (2007) Parkinson’s Disease: Return of an Old Prime Suspect. Neuron, 55, 8-10
Interesting SNPs and Associated Genes for Parkinson’s
Confidential © GeneGo Inc. 16
A recent review in Trends in Neurosciences, “Calcium homeostasis, selective vulnerability and Parkinson's disease” (TINS, 23 March 2009 doi:10.1016/)
Has pointed that a very good theory of neuronal degeration/death of the dopamine neurons in the substantia nigra pas compacta (SNc)Is to do with the homeostatic control of Ca2+ within these neurons. The neurons of the SNc are selectively vulnerable to homeostaticCa2+ stress as particularly Ca2+ ion channels are responsible for maintaining an autonomous pacemaking within these neurons. This Function is unlike other adult neurons in the brain, the pacemaking activity is believed to be important in maintaining dopamine levels in regions that are innervated by these neurons, particularly the striatum.
The L-type Ca2+ channels are responsible for this pacemaker activity within the SNc neurons and the combined GWAS and Enrichment analysis within MetaCore, we have indentified 3 subunits of the Ca2+ channel
Recent Review in the Parkinson’s Disease Field
Confidential © GeneGo Inc. 17
A recent review in Trends in Neurosciences, “Calcium homeostasis, selective vulnerability and Parkinson's disease” (TINS, 23 March 2009 doi:10.1016/)
Has pointed that a very good theory of neuronal degeration/death of the dopamine neurons in the substantia nigra pas compacta (SNc)Is to do with the homeostatic control of Ca2+ within these neurons. The neurons of the SNc are selectively vulnerable to homeostaticCa2+ stress as particularly Ca2+ ion channels are responsible for maintaining an autonomous pacemaking within these neurons. This Function is unlike other adult neurons in the brain, the pacemaking activity is believed to be important in maintaining dopamine levels in regions that are innervated by these neurons, particularly the striatum.
The L-type Ca2+ channels are responsible for this pacemaker activity within the SNc neurons and the combined GWAS and Enrichment analysis within MetaCore, we have indentified 3 subunits of the Ca2+ channel
Recent Review in the Parkinson’s Disease Field
Confidential © GeneGo Inc. 18
The L-type Ca2+ channels are responsible for this pacemaker activity within the SNc neurons and the combined GWAS and Enrichment analysis within MetaCore, we indentified 3 subunits of the Ca2+ channel
The beta-subunit of the L-type Ca2+ has a large Odds Ratio (1.781)And relatively significant association p-value 0.0094 for association
To Parkinson’s Disease
Recent findings in relation to results found with MetaCore™
Confidential © GeneGo Inc. 19
Therefore Is PD simply a reflection of accelerated aging in neurons that rely too heavily upon Ca2+ channels to do theirbusiness? Age is undoubtedly the single strongest risk factor for PD.
The ‘wear and tear’ theory of PD does not require a pathogenic agent. Moreover, it argues that there is nodisease ‘onset’ other than the one created by the emergence of symptoms when the surviving SNc DA neuronsAre incapable of fully compensating for the loss of neighboring neurons (1). It also predicts that we will all developsymptoms if we live long enough.
Why then do some people become symptomatic in their 50 s, others in their 60 s or 70 s or not at all? Genetic and environmental factors certainly could account for this variation
One of these genetic factors could be mutations within the Ca2+ L-type channel, which through malfunction, the Homeostasis of Ca2+ is not regulated and accelerate the ageing process within these neurons.
(1) Zigmond, M.J. et al. (1990) Compensations after lesions of central dopaminergic neurons: some clinical and basic implications. Trends Neurosci. 13, 290–296
Conclusion of GWAS and MetaCore
Confidential © GeneGo Inc. 20
Can PD be prevented?If PD is a consequence of Ca2+-accelerated aging in SNc DA neurons (and in those neurons with a similar phenotype) then reducing Ca2+ flux should delay the onset of PDsymptoms and slow its progression.
A recent case-control study of hypertensive patients found a significant reduction inthe observed risk of PD with Calcium channel Antagonists( CCA) use, but not withmedications that reduce blood pressure in other ways