A genomic pathway approach to a complex disease: Axon guidance and parkinson disease

被引:306
作者
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.
机构
[1] Mayo Clin & Mayo Fdn, Rochester, MN 55905 USA
[2] Univ Miami, Miller Sch Med, Dept Neurol, Miami, FL 33152 USA
[3] Gene Log, Giathersburg, MD USA
[4] Univ Miami, Miller Sch Med, Miami, FL 33152 USA
[5] Mayo Clin, Coll Med, Dept Physiol & Biomed Engn, Rochester, MN USA
[6] Mayo Clin, Coll Med, Dept Hlth Sci Res, Div Epidemiol, Rochester, MN USA
[7] Mayo Clin, Coll Med, Dept Neurol, Rochester, MN USA
来源
PLOS GENETICS | 2007年 / 3卷 / 06期
关键词
D O I
10.1371/journal.pgen.0030098
中图分类号
Q3 [遗传学];
学科分类号
071007 ; 090102 ;
摘要
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.
引用
收藏
页码:984 / 995
页数:12
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