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Autism and increased paternal age related changes in global levels of gene expression regulation.

Alter MD, Kharkar R, Ramsey KE, Craig DW, Melmed RD, Grebe TA, Bay RC, Ober-Reynolds S, Kirwan J, Jones JJ, Turner JB, Hen R, Stephan DA - PLoS ONE (2011)

Bottom Line: This premise can be tested by evaluating for changes in the overall distribution of gene expression levels.Variance in the distribution of gene expression levels from each microarray was compared between groups of children.Traditional approaches to microarray analysis of gene expression suggested a possible mechanism for decreased variance in gene expression.

View Article: PubMed Central - PubMed

Affiliation: Center for Neurobiology and Behavior, Department of Psychiatry, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America. markalter1968@gmail.com

ABSTRACT
A causal role of mutations in multiple general transcription factors in neurodevelopmental disorders including autism suggested that alterations in global levels of gene expression regulation might also relate to disease risk in sporadic cases of autism. This premise can be tested by evaluating for changes in the overall distribution of gene expression levels. For instance, in mice, variability in hippocampal-dependent behaviors was associated with variability in the pattern of the overall distribution of gene expression levels, as assessed by variance in the distribution of gene expression levels in the hippocampus. We hypothesized that a similar change in variance might be found in children with autism. Gene expression microarrays covering greater than 47,000 unique RNA transcripts were done on RNA from peripheral blood lymphocytes (PBL) of children with autism (n = 82) and controls (n = 64). Variance in the distribution of gene expression levels from each microarray was compared between groups of children. Also tested was whether a risk factor for autism, increased paternal age, was associated with variance. A decrease in the variance in the distribution of gene expression levels in PBL was associated with the diagnosis of autism and a risk factor for autism, increased paternal age. Traditional approaches to microarray analysis of gene expression suggested a possible mechanism for decreased variance in gene expression. Gene expression pathways involved in transcriptional regulation were down-regulated in the blood of children with autism and children of older fathers. Thus, results from global and gene specific approaches to studying microarray data were complimentary and supported the hypothesis that alterations at the global level of gene expression regulation are related to autism and increased paternal age. Global regulation of transcription, thus, represents a possible point of convergence for multiple etiologies of autism and other neurodevelopmental disorders.

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Increased paternal age at birth is negatively associated with overall variance in gene expression in peripheral blood lymphocytes (PBL) of normal children.Paternal age at birth was found in multiple studies to be a risk factor for autism [26], [28], [34], [35]. Previous work indicated that factors or interventions that modified mouse hippocampal-dependent behavior also modified the overall variance in gene expression in the predicted direction. In controls (figure 3a) but not in children with autism (not shown), overall variance in log-transformed measures of gene expression was significantly and negatively associated with paternal age at birth (r = -.283, R2 = .08, p = .03, number of subjects  = 57). For the evaluation of paternal age effects, paternal ages were available for 78 children with autism and 57 control children. To directly compare overall microarray variance in children with autism to children of older fathers, we divided subjects by the median paternal age at birth in our study (31 years) and created 2 groups: 1) children from younger fathers (less than 31 years) (65 subjects: 30 controls and 35 children with autism); and 2) children from older fathers (31 years or older) (70 subjects: 27 controls and 43 children with autism). We compared mean levels of overall variance between children with autism and controls of older and younger fathers. As predicted, we found that overall variance was the same in children of older fathers and children with autism with fathers of any age (figure 3b). We found that the association of autism with decreased overall variance was only found in children of younger fathers and represented a difference of .78 standard deviations within our sample (p = .0007) (figure 3b). Error bars represent standard error.
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pone-0016715-g003: Increased paternal age at birth is negatively associated with overall variance in gene expression in peripheral blood lymphocytes (PBL) of normal children.Paternal age at birth was found in multiple studies to be a risk factor for autism [26], [28], [34], [35]. Previous work indicated that factors or interventions that modified mouse hippocampal-dependent behavior also modified the overall variance in gene expression in the predicted direction. In controls (figure 3a) but not in children with autism (not shown), overall variance in log-transformed measures of gene expression was significantly and negatively associated with paternal age at birth (r = -.283, R2 = .08, p = .03, number of subjects  = 57). For the evaluation of paternal age effects, paternal ages were available for 78 children with autism and 57 control children. To directly compare overall microarray variance in children with autism to children of older fathers, we divided subjects by the median paternal age at birth in our study (31 years) and created 2 groups: 1) children from younger fathers (less than 31 years) (65 subjects: 30 controls and 35 children with autism); and 2) children from older fathers (31 years or older) (70 subjects: 27 controls and 43 children with autism). We compared mean levels of overall variance between children with autism and controls of older and younger fathers. As predicted, we found that overall variance was the same in children of older fathers and children with autism with fathers of any age (figure 3b). We found that the association of autism with decreased overall variance was only found in children of younger fathers and represented a difference of .78 standard deviations within our sample (p = .0007) (figure 3b). Error bars represent standard error.

Mentions: Because the group of children with autism was significantly younger than the control group (autism: mean - 5.5 years SD - 2.1; control: mean - 7.9 SD - 2.2, p<.0001), we tested whether subject age had an effect on the relationship between diagnosis and overall variance. An analysis of covariance (ANCOVA) demonstrated that even when controlling for subject age, variance in gene expression continued to be significantly decreased by the same amount in the blood of children with autism compared to controls (p = .018, parameter estimate  = −.45 Std Dev lower in autism). When scan batch was included with subject age in the ANCOVA the results also remained significant (p = .03, parameter estimate  = −.42 Std Dev lower in autism). Importantly, parameter estimates for the relationship of diagnosis to variance were virtually unchanged in the ANCOVAs indicating that increasing p-values were related to increases in the degrees of freedom in the analysis, and not to a decreased association.


Autism and increased paternal age related changes in global levels of gene expression regulation.

Alter MD, Kharkar R, Ramsey KE, Craig DW, Melmed RD, Grebe TA, Bay RC, Ober-Reynolds S, Kirwan J, Jones JJ, Turner JB, Hen R, Stephan DA - PLoS ONE (2011)

Increased paternal age at birth is negatively associated with overall variance in gene expression in peripheral blood lymphocytes (PBL) of normal children.Paternal age at birth was found in multiple studies to be a risk factor for autism [26], [28], [34], [35]. Previous work indicated that factors or interventions that modified mouse hippocampal-dependent behavior also modified the overall variance in gene expression in the predicted direction. In controls (figure 3a) but not in children with autism (not shown), overall variance in log-transformed measures of gene expression was significantly and negatively associated with paternal age at birth (r = -.283, R2 = .08, p = .03, number of subjects  = 57). For the evaluation of paternal age effects, paternal ages were available for 78 children with autism and 57 control children. To directly compare overall microarray variance in children with autism to children of older fathers, we divided subjects by the median paternal age at birth in our study (31 years) and created 2 groups: 1) children from younger fathers (less than 31 years) (65 subjects: 30 controls and 35 children with autism); and 2) children from older fathers (31 years or older) (70 subjects: 27 controls and 43 children with autism). We compared mean levels of overall variance between children with autism and controls of older and younger fathers. As predicted, we found that overall variance was the same in children of older fathers and children with autism with fathers of any age (figure 3b). We found that the association of autism with decreased overall variance was only found in children of younger fathers and represented a difference of .78 standard deviations within our sample (p = .0007) (figure 3b). Error bars represent standard error.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3040743&req=5

pone-0016715-g003: Increased paternal age at birth is negatively associated with overall variance in gene expression in peripheral blood lymphocytes (PBL) of normal children.Paternal age at birth was found in multiple studies to be a risk factor for autism [26], [28], [34], [35]. Previous work indicated that factors or interventions that modified mouse hippocampal-dependent behavior also modified the overall variance in gene expression in the predicted direction. In controls (figure 3a) but not in children with autism (not shown), overall variance in log-transformed measures of gene expression was significantly and negatively associated with paternal age at birth (r = -.283, R2 = .08, p = .03, number of subjects  = 57). For the evaluation of paternal age effects, paternal ages were available for 78 children with autism and 57 control children. To directly compare overall microarray variance in children with autism to children of older fathers, we divided subjects by the median paternal age at birth in our study (31 years) and created 2 groups: 1) children from younger fathers (less than 31 years) (65 subjects: 30 controls and 35 children with autism); and 2) children from older fathers (31 years or older) (70 subjects: 27 controls and 43 children with autism). We compared mean levels of overall variance between children with autism and controls of older and younger fathers. As predicted, we found that overall variance was the same in children of older fathers and children with autism with fathers of any age (figure 3b). We found that the association of autism with decreased overall variance was only found in children of younger fathers and represented a difference of .78 standard deviations within our sample (p = .0007) (figure 3b). Error bars represent standard error.
Mentions: Because the group of children with autism was significantly younger than the control group (autism: mean - 5.5 years SD - 2.1; control: mean - 7.9 SD - 2.2, p<.0001), we tested whether subject age had an effect on the relationship between diagnosis and overall variance. An analysis of covariance (ANCOVA) demonstrated that even when controlling for subject age, variance in gene expression continued to be significantly decreased by the same amount in the blood of children with autism compared to controls (p = .018, parameter estimate  = −.45 Std Dev lower in autism). When scan batch was included with subject age in the ANCOVA the results also remained significant (p = .03, parameter estimate  = −.42 Std Dev lower in autism). Importantly, parameter estimates for the relationship of diagnosis to variance were virtually unchanged in the ANCOVAs indicating that increasing p-values were related to increases in the degrees of freedom in the analysis, and not to a decreased association.

Bottom Line: This premise can be tested by evaluating for changes in the overall distribution of gene expression levels.Variance in the distribution of gene expression levels from each microarray was compared between groups of children.Traditional approaches to microarray analysis of gene expression suggested a possible mechanism for decreased variance in gene expression.

View Article: PubMed Central - PubMed

Affiliation: Center for Neurobiology and Behavior, Department of Psychiatry, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America. markalter1968@gmail.com

ABSTRACT
A causal role of mutations in multiple general transcription factors in neurodevelopmental disorders including autism suggested that alterations in global levels of gene expression regulation might also relate to disease risk in sporadic cases of autism. This premise can be tested by evaluating for changes in the overall distribution of gene expression levels. For instance, in mice, variability in hippocampal-dependent behaviors was associated with variability in the pattern of the overall distribution of gene expression levels, as assessed by variance in the distribution of gene expression levels in the hippocampus. We hypothesized that a similar change in variance might be found in children with autism. Gene expression microarrays covering greater than 47,000 unique RNA transcripts were done on RNA from peripheral blood lymphocytes (PBL) of children with autism (n = 82) and controls (n = 64). Variance in the distribution of gene expression levels from each microarray was compared between groups of children. Also tested was whether a risk factor for autism, increased paternal age, was associated with variance. A decrease in the variance in the distribution of gene expression levels in PBL was associated with the diagnosis of autism and a risk factor for autism, increased paternal age. Traditional approaches to microarray analysis of gene expression suggested a possible mechanism for decreased variance in gene expression. Gene expression pathways involved in transcriptional regulation were down-regulated in the blood of children with autism and children of older fathers. Thus, results from global and gene specific approaches to studying microarray data were complimentary and supported the hypothesis that alterations at the global level of gene expression regulation are related to autism and increased paternal age. Global regulation of transcription, thus, represents a possible point of convergence for multiple etiologies of autism and other neurodevelopmental disorders.

Show MeSH
Related in: MedlinePlus