Whole genome survey of coding SNPs reveals a reproducible pathway determinant of Parkinson disease

Abstract

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.

Single‐cell expression profiling of dopaminergic neurons combined with association analysis identifies pyridoxal kinase as Parkinson's disease gene

“…15 Together with subsequent studies, two out of four GWA PD studies show this significant association. 18,19 With the identification of differential regulation of SRGAP3 in dopaminergic neurons of the SNc, we provide functional data supporting the importance of the axon guidance pathway in the development of PD.…”

“…15 Together with subsequent studies, two out of four GWA PD studies show this significant association. 18,19 With the identification of differential regulation of SRGAP3 in dopaminergic neurons of the SNc, we provide functional data supporting the importance of the axon guidance pathway in the development of PD.TRAPPC4 appears to be a good candidate as it is localized in neuronal synapses and is part of the human transport protein particle complex I that is required for tethering endoplasmic reticulum (ER)-derived vesicles to Golgi membranes. 20,21 Evidence for impaired synaptic …”

Genome-wide pathway analysis implicates intracellular transmembrane protein transport in Alzheimer disease

“…2 This is a relatively new approach, stemming from the application of GO-based analyses to gene expression data, 3 but despite promise only a handful of replicated cases of pathway enrichment have emerged. 4,5 One of the critical issues in enabling this strategy is to convert with high fidelity the single-nucleotide polymorphism (SNP) lists from genome-wide platforms to the list of the genes they represent. Toward this end, we developed a software program implemented in Perl, using as input genome-wide SNP results (primarily from PLINK 6 ), that considers linkage disequilibrium (LD) across regions of significance that corrects for the inflation of significance due to gene length.…”

SNPs in axon guidance pathway genes and susceptibility for Parkinson’s disease in the Korean population

“…Srinivasan et al 14 developed a statistical method for finding pathways associated with PD that controls for pathway size. They confirmed the axon guidance association reported by Lesnick et al, 13 and also indicated that variation in the ubiquitin-mediated proteolysis and T-cell receptor signaling pathways may have been predictive of PD susceptibility in their patients.…”