Parkinson’s Disease GWAS and enrichment with MetaCore™

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Parkinson’s Disease GWAS and enrichment with MetaCore™

Ewan Hunter, PhDJanuary 18, 2010

Confidential © GeneGo Inc. 2

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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.


Data Format and Data Loading


Define Thresholds


Single Experiment Workflow: Enrichment Histograms forCanonical Pathway Maps


Alzheimer's disease: extracellular Amyloid beta toxicity.


Disease Biomarker Map Overlay


Alzheimer's disease: extracellular Amyloid beta toxicity Ca++ Channels


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


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


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


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™


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


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

Documents

Parkinson’s Disease GWAS and enrichment with MetaCore™