Open AccessA Genomic Pathway Approach to a Complex Disease: Axon Guidance and Parkinson Disease
Author(s) -
Timothy G. Lesnick,
Spiridon Papapetropoulos,
Deborah C. Mash,
J. M. H. FfrenchMullen,
Lina A. Shehadeh,
Mariza de Andrade,
John R. Henley,
Walter A. Rocca,
J. Eric Ahlskog,
Demetrius M. Maraganore
Publication year - 2007
Publication title -
plos genetics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.587
H-Index - 233
eISSN - 1553-7404
pISSN - 1553-7390
DOI - 10.1371/journal.pgen.0030098
Subject(s) - single nucleotide polymorphism , biology , genome wide association study , genetics , parkinson's disease , disease , genetic association , locus (genetics) , mendelian inheritance , omim : online mendelian inheritance in man , bioinformatics , computational biology , gene , genotype , medicine , phenotype
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 ( R 2 = 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.