Abstract
Susceptibility to sporadic Parkinson's disease (PD) is thought to be influenced by both genetic and environmental factors and their interaction with each other. Statistical models including multiple variants in axon guidance pathway genes have recently been purported to be capable of predicting PD risk, survival free of the disease and age at disease onset; however the specific models have not undergone independent validation. Here we tested the best proposed risk panel of 23 single nucleotide polymorphisms (SNPs) in two PD sample sets, with a total of 525 cases and 518 controls. By single marker analysis, only one marker was significantly associated with PD risk in one of our sample sets (rs6692804: P = 0.03). Multi-marker analysis using the reported model found a mild association in one sample set (two sided P = 0.049, odds ratio for each score change = 1.07) but no significance in the other (two sided P = 0.98, odds ratio = 1), a stark contrast to the reported strong association with PD risk (P = 4.64×10−38, odds ratio as high as 90.8). Following a procedure similar to that used to build the reported model, simulated multi-marker models containing SNPs from randomly chosen genes in a genome wide PD dataset produced P-values that were highly significant and indistinguishable from similar models where disease status was permuted (3.13×10−23 to 4.90×10−64), demonstrating the potential for overfitting in the model building process. Together, these results challenge the robustness of the reported panel of genetic markers to predict PD risk in particular and a role of the axon guidance pathway in PD genetics in general.
Highlights
Parkinson’s disease (PD) is the second most prevalent neurodegenerative disease only after Alzheimer’s disease
The findings and its implication on the method of pathway association studies are presented. In their hypothesis generation sample set, Lesnick and colleagues reported the identification of a PD risk signature composed of 23 single nucleotide polymorphisms (SNPs) in the axon guidance pathway [16]
Findings from genome-wide association (GWA) studies suggest that individual genetic variants make very modest contributions to the risk of common complex diseases, such as type II diabetes and autoimmune diseases
Summary
Parkinson’s disease (PD) is the second most prevalent neurodegenerative disease only after Alzheimer’s disease. The majority of cases are sporadic and usually manifest symptoms at 50 years or older while a small proportion of cases are inherited in Mendelian fashion. While several known mutations lead to the Mendelian forms of PD (for a recent review, see [1]), much remains to be uncovered to understand genetic causes of sporadic PD. A single variant in the leucine-rich repeat kinase 2 (LRRK2), Gly2019Ser, may explain ,2% of the sporadic cases [2] and almost as many as 30% of cases in Ashkenazi Jews and North African Arab populations [3,4]. A dinucleotide repeat sequence polymorphism in the promoter region of the a-synuclein gene (SCNA) and a haplotype in the microtubuleassociated protein tau gene (MAPT) are associated with increased PD risk (for recent meta-analyses of large sample sets, see [5,6]). Association of various other polymorphisms with PD risk has been reported (www.pdgene.org), but requires further validation before more definitive conclusion can be made as to whether any are genuine PD risk factors
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