TY - JOUR
T1 - A genomic pathway approach to a complex disease
T2 - Axon guidance and Parkinson disease
AU - Lesnick, Timothy G.
AU - Papapetropoulos, Spiridon
AU - Mash, Deborah C.
AU - Ffrench-Mullen, Jarlath
AU - Shehadeh, Lina
AU - De Andrade, Mariza
AU - Henley, John R.
AU - Rocca, Walter A.
AU - Ahlskog, J. Eric
AU - Maraganore, Demetrius M.
PY - 2007/6
Y1 - 2007/6
N2 - 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 wholegenome 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.
AB - 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 wholegenome 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.
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U2 - 10.1371/journal.pgen.0030098
DO - 10.1371/journal.pgen.0030098
M3 - Article
C2 - 17571925
AN - SCOPUS:34347338776
VL - 3
SP - 984
EP - 995
JO - PLoS Genetics
JF - PLoS Genetics
SN - 1553-7390
IS - 6
ER -