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Overlaps between autism and language impairment: phenomimicry or shared etiology?

Bishop DV - Behav. Genet. (2010)

Bottom Line: Traditionally, autistic spectrum disorder (ASD) and specific language impairment (SLI) are regarded as distinct conditions with separate etiologies.Yet these disorders co-occur at above chance levels, suggesting shared etiology.A modified simulation involving G x G interactions obtained levels of comorbidity and rates of impairment in relatives more consistent with observed values.

View Article: PubMed Central - PubMed

Affiliation: Department of Experimental Psychology, University of Oxford, Oxford OX1 3UD, UK. dorothy.bishop@psy.ox.ac.uk

ABSTRACT
Traditionally, autistic spectrum disorder (ASD) and specific language impairment (SLI) are regarded as distinct conditions with separate etiologies. Yet these disorders co-occur at above chance levels, suggesting shared etiology. Simulations, however, show that additive pleiotropic genes cannot account for observed rates of language impairment in relatives, which are higher for probands with SLI than for those with ASD + language impairment. An alternative account is in terms of 'phenomimicry', i.e., language impairment in comorbid cases may be a consequence of ASD risk factors, and different from that seen in SLI. However, this cannot explain why molecular genetic studies have found a common risk genotype for ASD and SLI. This paper explores whether nonadditive genetic influences could account for both family and molecular findings. A modified simulation involving G x G interactions obtained levels of comorbidity and rates of impairment in relatives more consistent with observed values. The simulations further suggest that the shape of distributions of phenotypic trait scores for different genotypes may provide evidence of whether a gene is involved in epistasis.

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Related in: MedlinePlus

Simulated data from correlated risks with epistasis model showing distributions of scores for 5000 probands on language trait (three leftmost plots) and ASD trait (three rightmost plots) for aa, aA and AA genotypes of 10 genes. For genes 1–5, the a allele confers risk for language impairment, and for genes 1 and 6–10 the a allele confers risk for ASD. G × G interaction is specified so that when the aa genotype is present for gene 1 in the context of either aa genotypes for genes 7 and 8, or for genes 9 and 10, its effect is doubled. Red denotes that the mean on a trait for aa genotype is significantly lower than for other genotypes on t-test, and magenta that the mean for the aA genotype is lower than for AA. Bold lines denote cases where the variance on a trait for the aa genotype is significantly greater than for other genotypes on F-test
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Fig7: Simulated data from correlated risks with epistasis model showing distributions of scores for 5000 probands on language trait (three leftmost plots) and ASD trait (three rightmost plots) for aa, aA and AA genotypes of 10 genes. For genes 1–5, the a allele confers risk for language impairment, and for genes 1 and 6–10 the a allele confers risk for ASD. G × G interaction is specified so that when the aa genotype is present for gene 1 in the context of either aa genotypes for genes 7 and 8, or for genes 9 and 10, its effect is doubled. Red denotes that the mean on a trait for aa genotype is significantly lower than for other genotypes on t-test, and magenta that the mean for the aA genotype is lower than for AA. Bold lines denote cases where the variance on a trait for the aa genotype is significantly greater than for other genotypes on F-test

Mentions: The skew in liability trait markers induced by epistasis is of potential interest for those who aim to detect epistasis using association analysis. Figure 7 shows boxplots of phenotypic scores on SLI and ASD liability markers for aa, aA and AA genotypes for each gene in the simulation described above, based on 5000 probands (to give a sample size that is in the range of realism). A plot shown in red denotes that the mean on the trait for aa genotype is significantly lower than for other genotypes on t-test, and magenta indicates that the mean for the aA genotype is lower than for AA. This kind of comparison relates to the statistical testing for association for a quantitative trait that is performed in conventional molecular genetic analyses. As expected, the left-hand set of genes (1–5) show differences between genotypes for the language trait, and the right-hand set (6–10) as well as the pleiotropic gene (1) show differences between genotypes for the ASD trait. Gene 4 gives a false positive result on the ASD trait, which disappears if a larger sample is taken. Overall, the t-test comparisons show that if we simply compare mean values of language trait scores for different genotypes for genes 6–10, which interact with gene 1, we are unlikely to detect an effect of an ASD gene on a language phenotype, with gene 8 being the only one to show a significant (though very small) effect. This confirms the low power of means comparisons for detecting epistasis.Fig. 7


Overlaps between autism and language impairment: phenomimicry or shared etiology?

Bishop DV - Behav. Genet. (2010)

Simulated data from correlated risks with epistasis model showing distributions of scores for 5000 probands on language trait (three leftmost plots) and ASD trait (three rightmost plots) for aa, aA and AA genotypes of 10 genes. For genes 1–5, the a allele confers risk for language impairment, and for genes 1 and 6–10 the a allele confers risk for ASD. G × G interaction is specified so that when the aa genotype is present for gene 1 in the context of either aa genotypes for genes 7 and 8, or for genes 9 and 10, its effect is doubled. Red denotes that the mean on a trait for aa genotype is significantly lower than for other genotypes on t-test, and magenta that the mean for the aA genotype is lower than for AA. Bold lines denote cases where the variance on a trait for the aa genotype is significantly greater than for other genotypes on F-test
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2921070&req=5

Fig7: Simulated data from correlated risks with epistasis model showing distributions of scores for 5000 probands on language trait (three leftmost plots) and ASD trait (three rightmost plots) for aa, aA and AA genotypes of 10 genes. For genes 1–5, the a allele confers risk for language impairment, and for genes 1 and 6–10 the a allele confers risk for ASD. G × G interaction is specified so that when the aa genotype is present for gene 1 in the context of either aa genotypes for genes 7 and 8, or for genes 9 and 10, its effect is doubled. Red denotes that the mean on a trait for aa genotype is significantly lower than for other genotypes on t-test, and magenta that the mean for the aA genotype is lower than for AA. Bold lines denote cases where the variance on a trait for the aa genotype is significantly greater than for other genotypes on F-test
Mentions: The skew in liability trait markers induced by epistasis is of potential interest for those who aim to detect epistasis using association analysis. Figure 7 shows boxplots of phenotypic scores on SLI and ASD liability markers for aa, aA and AA genotypes for each gene in the simulation described above, based on 5000 probands (to give a sample size that is in the range of realism). A plot shown in red denotes that the mean on the trait for aa genotype is significantly lower than for other genotypes on t-test, and magenta indicates that the mean for the aA genotype is lower than for AA. This kind of comparison relates to the statistical testing for association for a quantitative trait that is performed in conventional molecular genetic analyses. As expected, the left-hand set of genes (1–5) show differences between genotypes for the language trait, and the right-hand set (6–10) as well as the pleiotropic gene (1) show differences between genotypes for the ASD trait. Gene 4 gives a false positive result on the ASD trait, which disappears if a larger sample is taken. Overall, the t-test comparisons show that if we simply compare mean values of language trait scores for different genotypes for genes 6–10, which interact with gene 1, we are unlikely to detect an effect of an ASD gene on a language phenotype, with gene 8 being the only one to show a significant (though very small) effect. This confirms the low power of means comparisons for detecting epistasis.Fig. 7

Bottom Line: Traditionally, autistic spectrum disorder (ASD) and specific language impairment (SLI) are regarded as distinct conditions with separate etiologies.Yet these disorders co-occur at above chance levels, suggesting shared etiology.A modified simulation involving G x G interactions obtained levels of comorbidity and rates of impairment in relatives more consistent with observed values.

View Article: PubMed Central - PubMed

Affiliation: Department of Experimental Psychology, University of Oxford, Oxford OX1 3UD, UK. dorothy.bishop@psy.ox.ac.uk

ABSTRACT
Traditionally, autistic spectrum disorder (ASD) and specific language impairment (SLI) are regarded as distinct conditions with separate etiologies. Yet these disorders co-occur at above chance levels, suggesting shared etiology. Simulations, however, show that additive pleiotropic genes cannot account for observed rates of language impairment in relatives, which are higher for probands with SLI than for those with ASD + language impairment. An alternative account is in terms of 'phenomimicry', i.e., language impairment in comorbid cases may be a consequence of ASD risk factors, and different from that seen in SLI. However, this cannot explain why molecular genetic studies have found a common risk genotype for ASD and SLI. This paper explores whether nonadditive genetic influences could account for both family and molecular findings. A modified simulation involving G x G interactions obtained levels of comorbidity and rates of impairment in relatives more consistent with observed values. The simulations further suggest that the shape of distributions of phenotypic trait scores for different genotypes may provide evidence of whether a gene is involved in epistasis.

Show MeSH
Related in: MedlinePlus