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Beyond Parkinson disease: amyotrophic lateral sclerosis and the axon guidance pathway.

Lesnick TG, Sorenson EJ, Ahlskog JE, Henley JR, Shehadeh L, Papapetropoulos S, Maraganore DM - PLoS ONE (2008)

Bottom Line: We also extended our analyses of a whole-genome association dataset of PD, which shared 320,202 genomic SNPs in common with the whole-genome association dataset of ALS.We compared for ALS and PD the genes represented by SNPs in the final models for susceptibility, survival free of disease, and age at onset of disease and noted that 52.2%, 37.8%, and 34.9% of the genes were shared respectively.Our findings for the axon guidance pathway and ALS have prior biological plausibility, overlap partially with PD, and may provide important insight into the causes of these and related neurodegenerative disorders.

View Article: PubMed Central - PubMed

Affiliation: Division of Biostatistics, Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota, United States of America.

ABSTRACT

Background: We recently described a genomic pathway approach to study complex diseases. We demonstrated that models constructed using single nucleotide polymorphisms (SNPs) within axon guidance pathway genes were highly predictive of Parkinson disease (PD) susceptibility, survival free of PD, and age at onset of PD within two independent whole-genome association datasets. We also demonstrated that several axon guidance pathway genes represented by SNPs within our final models were differentially expressed in PD.

Methodology/principal findings: Here we employed our genomic pathway approach to analyze data from a whole-genome association dataset of amyotrophic lateral sclerosis (ALS); and demonstrated that models constructed using SNPs within axon guidance pathway genes were highly predictive of ALS susceptibility (odds ratio = 1739.73, p = 2.92x10(-60)), survival free of ALS (hazards ratio = 149.80, p = 1.25x10(-74)), and age at onset of ALS (R(2) = 0.86, p = 5.96x10(-66)). We also extended our analyses of a whole-genome association dataset of PD, which shared 320,202 genomic SNPs in common with the whole-genome association dataset of ALS. We compared for ALS and PD the genes represented by SNPs in the final models for susceptibility, survival free of disease, and age at onset of disease and noted that 52.2%, 37.8%, and 34.9% of the genes were shared respectively.

Conclusions/significance: Our findings for the axon guidance pathway and ALS have prior biological plausibility, overlap partially with PD, and may provide important insight into the causes of these and related neurodegenerative disorders.

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Related in: MedlinePlus

Distributions of the Significant SNPs in the Genes from the ALS and PD Final Models.This figure shows results from our final models for susceptibility (a), survival free of disease (b), and age at onset of disease (c). Blue bars represent ALS, and red bars, PD.
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pone-0001449-g003: Distributions of the Significant SNPs in the Genes from the ALS and PD Final Models.This figure shows results from our final models for susceptibility (a), survival free of disease (b), and age at onset of disease (c). Blue bars represent ALS, and red bars, PD.

Mentions: Figure 3 displays the distributions of the significant SNPs in the genes from the ALS and PD final models (as listed in Tables S1A-S2C). While the samples for the ALS and PD whole-genome association studies were genotyped in the same laboratory using an Illumina platform, the SNPs assayed overlapped only partially. Specifically, 320,202 SNPs were common to both the ALS and PD datasets, but 234,957 SNPs were unique to the ALS dataset and 88,599 SNPs were unique to the PD dataset. In other words, of the SNPs present in the ALS dataset, only 57.6% were also present in the PD dataset; and of the SNPs present in the PD dataset, only 78.3% were also present in the ALS dataset. We again note that the final models were not exclusive; other combinations of SNPs (and genes) also had predictive value for the three outcomes for either ALS or PD (data not shown).


Beyond Parkinson disease: amyotrophic lateral sclerosis and the axon guidance pathway.

Lesnick TG, Sorenson EJ, Ahlskog JE, Henley JR, Shehadeh L, Papapetropoulos S, Maraganore DM - PLoS ONE (2008)

Distributions of the Significant SNPs in the Genes from the ALS and PD Final Models.This figure shows results from our final models for susceptibility (a), survival free of disease (b), and age at onset of disease (c). Blue bars represent ALS, and red bars, PD.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2175528&req=5

pone-0001449-g003: Distributions of the Significant SNPs in the Genes from the ALS and PD Final Models.This figure shows results from our final models for susceptibility (a), survival free of disease (b), and age at onset of disease (c). Blue bars represent ALS, and red bars, PD.
Mentions: Figure 3 displays the distributions of the significant SNPs in the genes from the ALS and PD final models (as listed in Tables S1A-S2C). While the samples for the ALS and PD whole-genome association studies were genotyped in the same laboratory using an Illumina platform, the SNPs assayed overlapped only partially. Specifically, 320,202 SNPs were common to both the ALS and PD datasets, but 234,957 SNPs were unique to the ALS dataset and 88,599 SNPs were unique to the PD dataset. In other words, of the SNPs present in the ALS dataset, only 57.6% were also present in the PD dataset; and of the SNPs present in the PD dataset, only 78.3% were also present in the ALS dataset. We again note that the final models were not exclusive; other combinations of SNPs (and genes) also had predictive value for the three outcomes for either ALS or PD (data not shown).

Bottom Line: We also extended our analyses of a whole-genome association dataset of PD, which shared 320,202 genomic SNPs in common with the whole-genome association dataset of ALS.We compared for ALS and PD the genes represented by SNPs in the final models for susceptibility, survival free of disease, and age at onset of disease and noted that 52.2%, 37.8%, and 34.9% of the genes were shared respectively.Our findings for the axon guidance pathway and ALS have prior biological plausibility, overlap partially with PD, and may provide important insight into the causes of these and related neurodegenerative disorders.

View Article: PubMed Central - PubMed

Affiliation: Division of Biostatistics, Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota, United States of America.

ABSTRACT

Background: We recently described a genomic pathway approach to study complex diseases. We demonstrated that models constructed using single nucleotide polymorphisms (SNPs) within axon guidance pathway genes were highly predictive of Parkinson disease (PD) susceptibility, survival free of PD, and age at onset of PD within two independent whole-genome association datasets. We also demonstrated that several axon guidance pathway genes represented by SNPs within our final models were differentially expressed in PD.

Methodology/principal findings: Here we employed our genomic pathway approach to analyze data from a whole-genome association dataset of amyotrophic lateral sclerosis (ALS); and demonstrated that models constructed using SNPs within axon guidance pathway genes were highly predictive of ALS susceptibility (odds ratio = 1739.73, p = 2.92x10(-60)), survival free of ALS (hazards ratio = 149.80, p = 1.25x10(-74)), and age at onset of ALS (R(2) = 0.86, p = 5.96x10(-66)). We also extended our analyses of a whole-genome association dataset of PD, which shared 320,202 genomic SNPs in common with the whole-genome association dataset of ALS. We compared for ALS and PD the genes represented by SNPs in the final models for susceptibility, survival free of disease, and age at onset of disease and noted that 52.2%, 37.8%, and 34.9% of the genes were shared respectively.

Conclusions/significance: Our findings for the axon guidance pathway and ALS have prior biological plausibility, overlap partially with PD, and may provide important insight into the causes of these and related neurodegenerative disorders.

Show MeSH
Related in: MedlinePlus