Neither replication nor simulation supports a role for the axon guidance pathway in the genetics of Parkinson's disease
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). Simulated multi-marker models built using a procedure similar to that used to build the reported model but containing SNPs from randomly chosen genes as well as similar models where disease status was permuted produced P-values ranging from 3.13x10-23 to 4.90x10-64, demonstrating the potential for overfitting in the model building process. The odds ratios observed in the independent sample sets we tested are in stark contrast to the reported strong association with PD risk (odds ratio as high as 90.8, P=4.64x10-38). 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.
Yonghong Li, Charles Rowland, Georgia Xiromerisiou, Robert J. Lagier, Steven J. Schrodi, Efthimios Dradiotis, David Ross, Nam Bui, Joseph Catanese, Konstantinos Aggelakis, Andrew Grupe, and Georgios Hadjigeorgiou. "Neither replication nor simulation supports a role for the axon guidance pathway in the genetics of Parkinson's disease" PLoS ONE (2008).
Available at: http://works.bepress.com/steve_schrodi/36