A genomic pathway approach to a complex disease: axon guidance and Parkinson disease.
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 disease...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2007-06-01
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| Series: | PLoS Genetics |
| Online Access: | http://europepmc.org/articles/PMC1904362?pdf=render |
| _version_ | 1819060256037142528 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Timothy G Lesnick |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-21T14:24:06Z |
| format | Article |
| id | doaj.art-69ad72c5c8eb41c0bc042f38bd2f619e |
| institution | Directory Open Access Journal |
| issn | 1553-7390 1553-7404 |
| language | English |
| last_indexed | 2024-12-21T14:24:06Z |
| publishDate | 2007-06-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Genetics |
| spelling | doaj.art-69ad72c5c8eb41c0bc042f38bd2f619e2022-12-21T19:00:42ZengPublic Library of Science (PLoS)PLoS Genetics1553-73901553-74042007-06-0136e9810.1371/journal.pgen.0030098A genomic pathway approach to a complex disease: axon guidance and Parkinson disease.Timothy G LesnickSpiridon PapapetropoulosDeborah C MashJarlath Ffrench-MullenLina ShehadehMariza de AndradeJohn R HenleyWalter A RoccaJ Eric AhlskogDemetrius M MaraganoreWhile 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.http://europepmc.org/articles/PMC1904362?pdf=render |
| spellingShingle | 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 A genomic pathway approach to a complex disease: axon guidance and Parkinson disease. PLoS Genetics |
| title | A genomic pathway approach to a complex disease: axon guidance and Parkinson disease. |
| title_full | A genomic pathway approach to a complex disease: axon guidance and Parkinson disease. |
| title_fullStr | A genomic pathway approach to a complex disease: axon guidance and Parkinson disease. |
| title_full_unstemmed | A genomic pathway approach to a complex disease: axon guidance and Parkinson disease. |
| title_short | A genomic pathway approach to a complex disease: axon guidance and Parkinson disease. |
| title_sort | genomic pathway approach to a complex disease axon guidance and parkinson disease |
| url | http://europepmc.org/articles/PMC1904362?pdf=render |
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