Pathway analyses of genomic data make intuitive sense to me for conditions like Parkinson’s disease. Only a handful of single genes have been consistently associated with Parkinson’s, but the genomic picture is certainly larger, and we are faced with the complex possibility that numerous rarer variations play a role. The underlying assumption of pathway analyses is that diverse genomic variations may be part of common pathways that, when dysfunctional, may lead to disease.

That’s why one of my favorite articles of the past few years is a pathway analysis.¹ Edwards and colleagues integrated the results of gene expression and genome wide association studies (GWAS) to identify biological pathways in which the top candidate genes participate. Results were interesting: the pathways identified are not exactly household names in Parkinson’s disease research. Additionally, 4 of the top 7 pathways were the same between the GWAS and the gene expression studies.  Such agreement across studies and methods seems rare, save for the few genes closely associated with Parkinson’s disease (eg, SNCA and LRRK2).

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Top 10 Over-Represented Pathways in Edwards et al, 2011

• Axon guidance
• Focal adhesion
• Calcium signaling pathway
• Cell adhesion molecules (CAMs)
• Adherens junctions
• Renal cell carcinoma
• Regulation of actin cytoskeleton
• Non-small cell lung cancer
• Melanogenesis
• ErbB signaling pathway

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Recently, Hu and colleagues published a pathway analysis based on pooled results of GWAS in the Chinese Han population.² Guess what they found in a population geographically and culturally distinct from that of Edwards and colleagues? Yep, they identified many similar pathways, including axon guidance, extracellular matrix-receptor interaction, focal adhesion, and adherens junctions.

What do these results mean? It’s hard to know exactly, but the pathways identified connect cells to one another and to the extracellular matrix, which is necessary for cell survival. They also maintain cells’ distinctive shapes, which are necessary for function. Axon guidance pathways help neurons connect with their targets during development, and actin is further involved in the synaptic vesicle cycle. These pathways clearly can’t be too adversely affected or development would simply not occur.

More likely is the possibility that genomic variations in these pathways interact with environmental or other endogenous factors to cause disease. Of course we don’t know what these factors are yet, but few researchers have followed up on the pathway findings. If these pathways are involved, it seems likely that they meet up with alpha synuclein at some point. In fact, alpha synuclein binds actin and affects cytoskeletal structure and dynamics.³ Alpha synuclein, actin, and myosin are also involved in the synaptic vesicle cycle, providing additional points for interaction.^{4, 5}

So, where do these pathway results lead us? Should research be examining the role of adherens junctions, axon guidance, focal adhesions, and the other identified pathways in Parkinson’s disease? How can we best study the role of a pathway in disease? Or are there alternate interpretations of this research that should be considered? Please leave a comment if you have any thoughts on these questions. Thanks!

References

1. Edwards YJ, Beecham GW, Scott WK, et al. Identifying consensus disease pathways in Parkinson’s disease using an integrative systems biology approach. PLoS One. 2011;6(2):e16917.
2. Hu Y, Deng L, Zhang J, et al. A Pooling Genome-Wide Association Study Combining a Pathway Analysis for Typical Sporadic Parkinson’s Disease in the Han Population of Chinese Mainland. Mol Neurobiol. Sep 2016;53(7):4302-4318.
3. Sousa VL, Bellani S, Giannandrea M, et al. {alpha}-synuclein and its A30P mutant affect actin cytoskeletal structure and dynamics. Mol Biol Cell. Aug 2009;20(16):3725-3739.
4. Cingolani LA, Goda Y. Actin in action: the interplay between the actin cytoskeleton and synaptic efficacy. Nat Rev Neurosci. May 2008;9(5):344-356.
5. Fusco G, Pape T, Stephens AD, et al. Structural basis of synaptic vesicle assembly promoted by alpha-synuclein. Nat Commun. 2016;7:12563.