While major inroads have been made in identifying the genetic causes of rare Mendelian disorders, little progress has been made in the discovery of common gene variations that predispose to complex diseases. The single gene variants that have been shown to associate reproducibly with complex diseases typically have small effect sizes or attributable risks. However, the joint actions of common gene variants within pathways may play a major role in predisposing to complex diseases (the paradigm of complex genetics). The goal of this study was to determine whether polymorphism in a candidate pathway (axon guidance) predisposed to a complex disease (Parkinson disease [PD]). We mined a whole-genome association dataset and identified single nucleotide polymorphisms (SNPs) that were within axon-guidance pathway genes. We then constructed models of axon-guidance pathway SNPs that predicted three outcomes: PD susceptibility (odds ratio = 90.8, p = 4.64 × 10−38), survival free of PD (hazards ratio = 19.0, p = 5.43 × 10−48), and PD age at onset (R2 = 0.68, p = 1.68 × 10−51). By contrast, models constructed from thousands of random selections of genomic SNPs predicted the three PD outcomes poorly. Mining of a second whole-genome association dataset and mining of an expression profiling dataset also supported a role for many axon-guidance pathway genes in PD. These findings could have important implications regarding the pathogenesis of PD. This genomic pathway approach may also offer insights into other complex diseases such as Alzheimer disease, diabetes mellitus, nicotine and alcohol dependence, and several cancers.
Funding. This work was supported in part by grants from the National Institutes of Health (R01 ES10751 [to DMM] and R01 NS33978 [to WAR]), the Michael J. Fox Foundation (Linked Efforts to Accelerate Parkinson Solutions award to DMM), the National Parkinson Foundation (to DCM), and from Gene Logic, (to DCM).
Competing interests. TGL and DMM report a provisional application for patent under 37 CFR § 1.53 (c) entitled “Predicting Parkinson's Disease.” No monies have been awarded to date. JFM is employed by Gene Logic.
Editor: Suzanne M. Leal, Baylor College of Medicine, United States of America
Citation: Lesnick TG, Papapetropoulos S, Mash DC, Ffrench-Mullen J, Shehadeh L, et al. (2007) A Genomic Pathway Approach to a Complex Disease: Axon Guidance and Parkinson Disease. PLoS Genet 3(6): e98 doi:10.1371/journal.pgen.0030098
Received: December 29, 2006; Accepted: May 2, 2007; Published: June 15, 2007
Copyright: © 2007 Lesnick et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Abbreviations: CI, confidence interval; HR, hazards ratio; KEGG, Kyoto Encyclopedia of Genes and Genomes; OR, odds ratio; PD, Parkinson disease; SNP, single nucleotide polymorphism
* To whom correspondence should be addressed. E-mail: dmaraganore@mayo.edu