A genomic pathway approach to a complex disease: axon guidance and Parkinson disease.

Timothy G. Lesnick, Spiridon Papapetropoulos, Deborah C. Mash, Jarlath Ffrench-Mullen, Lina Shehadeh, Mariza De Andrade, John R Henley, Walter A Rocca, J. Eric Ahlskog, Demetrius M. Maraganore

Research output: Contribution to journalArticle

224 Citations (Scopus)

Abstract

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 x 10(-38)), survival free of PD (hazards ratio = 19.0, p = 5.43 x 10(-48)), and PD age at onset (R(2) = 0.68, p = 1.68 x 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.

Original languageEnglish (US)
JournalPLoS Genetics
Volume3
Issue number6
DOIs
StatePublished - Jun 2007

Fingerprint

Parkinson disease
axons
Parkinson Disease
genomics
Single Nucleotide Polymorphism
single nucleotide polymorphism
Genes
genes
polymorphism
Genome
gene
Tobacco Use Disorder
Disease Susceptibility
Genetic Association Studies
genome
nicotine
Alcoholism
Alzheimer disease
alcohol abuse
diabetes mellitus

ASJC Scopus subject areas

  • Genetics
  • Molecular Biology
  • Ecology, Evolution, Behavior and Systematics
  • Cancer Research
  • Genetics(clinical)

Cite this

Lesnick, T. G., Papapetropoulos, S., Mash, D. C., Ffrench-Mullen, J., Shehadeh, L., De Andrade, M., ... Maraganore, D. M. (2007). A genomic pathway approach to a complex disease: axon guidance and Parkinson disease. PLoS Genetics, 3(6). https://doi.org/10.1371/journal.pgen.0030098

A genomic pathway approach to a complex disease : axon guidance and Parkinson disease. / Lesnick, Timothy G.; Papapetropoulos, Spiridon; Mash, Deborah C.; Ffrench-Mullen, Jarlath; Shehadeh, Lina; De Andrade, Mariza; Henley, John R; Rocca, Walter A; Ahlskog, J. Eric; Maraganore, Demetrius M.

In: PLoS Genetics, Vol. 3, No. 6, 06.2007.

Research output: Contribution to journalArticle

Lesnick, TG, Papapetropoulos, S, Mash, DC, Ffrench-Mullen, J, Shehadeh, L, De Andrade, M, Henley, JR, Rocca, WA, Ahlskog, JE & Maraganore, DM 2007, 'A genomic pathway approach to a complex disease: axon guidance and Parkinson disease.', PLoS Genetics, vol. 3, no. 6. https://doi.org/10.1371/journal.pgen.0030098
Lesnick, Timothy G. ; Papapetropoulos, Spiridon ; Mash, Deborah C. ; Ffrench-Mullen, Jarlath ; Shehadeh, Lina ; De Andrade, Mariza ; Henley, John R ; Rocca, Walter A ; Ahlskog, J. Eric ; Maraganore, Demetrius M. / A genomic pathway approach to a complex disease : axon guidance and Parkinson disease. In: PLoS Genetics. 2007 ; Vol. 3, No. 6.
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