Whole Genome Survey of Coding SNPs Reveals a Reproducible Pathway Determinant of Parkinson Disease

Department of Statistics, Stanford University, Stanford, California, USA.
Human Mutation (Impact Factor: 5.14). 02/2009; 30(2):228-38. DOI: 10.1002/humu.20840
Source: PubMed


It is quickly becoming apparent that situating human variation in a pathway context is crucial to understanding its phenotypic significance. Toward this end, we have developed a general method for finding pathways associated with traits that control for pathway size. We have applied this method to a new whole genome survey of coding SNP variation in 187 patients afflicted with Parkinson disease (PD) and 187 controls. We show that our dataset provides an independent replication of the axon guidance association recently reported by Lesnick et al. [PLoS Genet 2007;3:e98], and also indicates that variation in the ubiquitin-mediated proteolysis and T-cell receptor signaling pathways may predict PD susceptibility. Given this result, it is reasonable to hypothesize that pathway associations are more replicable than individual SNP associations in whole genome association studies. However, this hypothesis is complicated by a detailed comparison of our dataset to the second recent PD association study by Fung et al. [Lancet Neurol 2006;5:911-916]. Surprisingly, we find that the axon guidance pathway does not rank at the very top of the Fung dataset after controlling for pathway size. More generally, in comparing the studies, we find that SNP frequencies replicate well despite technologically different assays, but that both SNP and pathway associations are globally uncorrelated across studies. We thus have a situation in which an association between axon guidance pathway variation and PD has been found in 2 out of 3 studies. We conclude by relating this seeming inconsistency to the molecular heterogeneity of PD, and suggest future analyses that may resolve such discrepancies.

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Available from: Caroline G L Lee
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    • "In the rat SN, using a complementary approach, we found that expression of wild-type but not inactive Nedd4 decreased degeneration of dopaminergic neurons that is induced by chronic overexpression of A53T mutant human α-synuclein. A role for Nedd4 in the human condition is supported by the identification of a coding SNP as a risk factor for idiopathic PD (Srinivasan et al., 2009), the finding that Nedd4 mRNA expression is increased in brain regions with Lewy body pathology (Dumitriu et al., 2012) and our neuropathological observations that Nedd4 is up-regulated in a subpopulation of pigmented neurons containing Lewy bodies (Tofaris et al., 2011). Since Nedd4 is a ubiquitin ligase that functions in the endosomal–lysosomal pathway, our data are also consistent with other studies which have implicated this pathway in PD pathogenesis (Dodson et al., 2012) and genetic screens showing that genetic Fig. 2. Increased neuronal Nedd4 reduces α-synuclein levels in the Drosophila brain. "
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    • "Building on approaches originally developed in the context of microarray gene expression experiments, the common theme in the pathway analysis approaches is that they examine whether a group of related loci in the same biological pathway are jointly associated with a trait of interest. In line with the observations in microarray gene expression studies, it has been shown that in those cases where there is only a modest overlap in the variant or gene-level findings between different studies, due to factors such as differences in the genetic structure, the pathway-level associations may be much more reproducible even between different study populations [57-60]. These findings support the concept that individuals with the same disease phenotype may have marked inter-individual genetic heterogeneity in the sense that their disease predisposing variants may lie in distinct loci within the same or related pathways [14]. "
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