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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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Final Models Predicting ALS Outcomes.Figure 1A (left). Goodness-of-Fit of Final Model Using Axon Guidance Genes to Predict Susceptibility to ALS. Histogram of predicted probabilities of ALS in cases (a). Histogram of predicted probabilities of ALS in controls (b). A perfect fit would have all predicted probabilities for cases equal to one, and all predicted probabilities for controls equal to zero. A model with no explanatory value would have histograms that were indistinguishable from each other. Figure 1B (center). Kaplan-Meier Survival Plot for Age at Onset in ALS Patients, Grouped by Categorized Risk Score from Proportional Hazards Model. The model clearly differentiates between early age at onset cases and late age at onset cases. Cases generating the long-dashed line were predicted to be at highest risk for early onset of ALS, followed by the medium-dashed, short-dashed, and continuous lines respectively. Since only cases were included, all of the lines end at zero percent free of ALS. Figure 1C (right). Predicted vs. Reported Age at Onset in ALS Patients. Points indicate reported individual values, and the line represents perfect agreement. In this case, the pattern shows a fairly tight elliptical pattern, reflecting a good fit and high R2 of 0.86. The fit appears equally good from the minimum to maximum reported age at onset.
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pone-0001449-g001: Final Models Predicting ALS Outcomes.Figure 1A (left). Goodness-of-Fit of Final Model Using Axon Guidance Genes to Predict Susceptibility to ALS. Histogram of predicted probabilities of ALS in cases (a). Histogram of predicted probabilities of ALS in controls (b). A perfect fit would have all predicted probabilities for cases equal to one, and all predicted probabilities for controls equal to zero. A model with no explanatory value would have histograms that were indistinguishable from each other. Figure 1B (center). Kaplan-Meier Survival Plot for Age at Onset in ALS Patients, Grouped by Categorized Risk Score from Proportional Hazards Model. The model clearly differentiates between early age at onset cases and late age at onset cases. Cases generating the long-dashed line were predicted to be at highest risk for early onset of ALS, followed by the medium-dashed, short-dashed, and continuous lines respectively. Since only cases were included, all of the lines end at zero percent free of ALS. Figure 1C (right). Predicted vs. Reported Age at Onset in ALS Patients. Points indicate reported individual values, and the line represents perfect agreement. In this case, the pattern shows a fairly tight elliptical pattern, reflecting a good fit and high R2 of 0.86. The fit appears equally good from the minimum to maximum reported age at onset.

Mentions: Of the 4,133 SNPs within brain-expressed genes of the axon-guidance pathway, 442 SNPs (10.7%) were individually associated with susceptibility to ALS, as detailed in Text S1. Table S1A contains results for the final model produced by running SNPs through the multi-stage process to predict ALS susceptibility. This model used data from 542 unmatched ALS patients and unrelated controls (2 subjects were missing data on one or more SNPs). The ORs (95% CIs) for the groups defined by predicted ALS probability of <0.25, 0.25–0.50, 0.50–0.75, and >0.75 were as follows: 1 (reference), 17.60 (5.70–54.36), 112.00 (35.45–353.83), and 1739.73 (523.53–5781.32) respectively. Since we were interested in the significance of the pathway, rather than individual SNPs, the p value for the overall model was of primary importance. In this case, the model had an overall p value of 2.92×10−60 (95% CI 8.34×10−52-1.16×10−68). This model significantly predicted whether an individual was a case or an unrelated control. The predicted probabilities of ALS were very high (towards 1) for most of the cases, and very low (towards 0) for most of the unrelated controls (Figure 1A). Indeed 78% of the cases had predicted probabilities above 0.9, and 77% of unrelated controls had predicted probabilities below 0.1. As shown by Figure 1A, the model did not completely distinguish the two groups; some ALS cases had low predicted probabilities, and some controls had high predicted probabilities. However, the concordance for the model was about 0.99, indicating excellent agreement between predicted and observed case/control status.


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)

Final Models Predicting ALS Outcomes.Figure 1A (left). Goodness-of-Fit of Final Model Using Axon Guidance Genes to Predict Susceptibility to ALS. Histogram of predicted probabilities of ALS in cases (a). Histogram of predicted probabilities of ALS in controls (b). A perfect fit would have all predicted probabilities for cases equal to one, and all predicted probabilities for controls equal to zero. A model with no explanatory value would have histograms that were indistinguishable from each other. Figure 1B (center). Kaplan-Meier Survival Plot for Age at Onset in ALS Patients, Grouped by Categorized Risk Score from Proportional Hazards Model. The model clearly differentiates between early age at onset cases and late age at onset cases. Cases generating the long-dashed line were predicted to be at highest risk for early onset of ALS, followed by the medium-dashed, short-dashed, and continuous lines respectively. Since only cases were included, all of the lines end at zero percent free of ALS. Figure 1C (right). Predicted vs. Reported Age at Onset in ALS Patients. Points indicate reported individual values, and the line represents perfect agreement. In this case, the pattern shows a fairly tight elliptical pattern, reflecting a good fit and high R2 of 0.86. The fit appears equally good from the minimum to maximum reported age at onset.
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pone-0001449-g001: Final Models Predicting ALS Outcomes.Figure 1A (left). Goodness-of-Fit of Final Model Using Axon Guidance Genes to Predict Susceptibility to ALS. Histogram of predicted probabilities of ALS in cases (a). Histogram of predicted probabilities of ALS in controls (b). A perfect fit would have all predicted probabilities for cases equal to one, and all predicted probabilities for controls equal to zero. A model with no explanatory value would have histograms that were indistinguishable from each other. Figure 1B (center). Kaplan-Meier Survival Plot for Age at Onset in ALS Patients, Grouped by Categorized Risk Score from Proportional Hazards Model. The model clearly differentiates between early age at onset cases and late age at onset cases. Cases generating the long-dashed line were predicted to be at highest risk for early onset of ALS, followed by the medium-dashed, short-dashed, and continuous lines respectively. Since only cases were included, all of the lines end at zero percent free of ALS. Figure 1C (right). Predicted vs. Reported Age at Onset in ALS Patients. Points indicate reported individual values, and the line represents perfect agreement. In this case, the pattern shows a fairly tight elliptical pattern, reflecting a good fit and high R2 of 0.86. The fit appears equally good from the minimum to maximum reported age at onset.
Mentions: Of the 4,133 SNPs within brain-expressed genes of the axon-guidance pathway, 442 SNPs (10.7%) were individually associated with susceptibility to ALS, as detailed in Text S1. Table S1A contains results for the final model produced by running SNPs through the multi-stage process to predict ALS susceptibility. This model used data from 542 unmatched ALS patients and unrelated controls (2 subjects were missing data on one or more SNPs). The ORs (95% CIs) for the groups defined by predicted ALS probability of <0.25, 0.25–0.50, 0.50–0.75, and >0.75 were as follows: 1 (reference), 17.60 (5.70–54.36), 112.00 (35.45–353.83), and 1739.73 (523.53–5781.32) respectively. Since we were interested in the significance of the pathway, rather than individual SNPs, the p value for the overall model was of primary importance. In this case, the model had an overall p value of 2.92×10−60 (95% CI 8.34×10−52-1.16×10−68). This model significantly predicted whether an individual was a case or an unrelated control. The predicted probabilities of ALS were very high (towards 1) for most of the cases, and very low (towards 0) for most of the unrelated controls (Figure 1A). Indeed 78% of the cases had predicted probabilities above 0.9, and 77% of unrelated controls had predicted probabilities below 0.1. As shown by Figure 1A, the model did not completely distinguish the two groups; some ALS cases had low predicted probabilities, and some controls had high predicted probabilities. However, the concordance for the model was about 0.99, indicating excellent agreement between predicted and observed case/control status.

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