19436
Epigenetic Alterations Tied to Brain Enlargement in Autism Spectrum Disorder
Until recently, little was known about the relationship between brain epigenetic alterations and the genetic risk architecture for autism. Now, strong evidence has emerged to indicate changes in histone methylation that affect hundreds of loci in prefrontal cortical neurons from subjects with autism. Remarkably, these alterations exhibit significant overlap with current estimates of the genetic risk architecture of autism, identifying histone methylation as a promising epigenetic biomarker for genomic loci.
Objectives:
In the present study, we related epigenetic signatures to a key biological phenotype for Autism Spectrum Disorder (ASD), that of brain size. A relationship between these two measures is plausible, since there is ample evidence in the literature relating epigenetic factors to overgrowth, including brain enlargement. Though increased brain size and its proxy, head circumference, have often been reported for autism – particularly among younger cases – relatively little is known of causal factors for these phenotypes.
Methods:
We addressed this question here, focusing on epigenetic hypotheses. The study employed post-mortem brain epigenetic signature data and brain anatomic dependent measures from the Autism Speaks Autism Tissue Program (N=16). These samples were made available by the Harvard/McLean and the University of Maryland Brain Banks. ChIP-seq libraries from H3K4me3 immunoprecipitates are sequenced with the Illumina Genome Analyzer GAII. We performed single-end sequencing of 36bp reads. To detect regions that were enriched in H3K4me3 in a subset of disease samples against all controls, we ran MACS on each autism sample against the input dataset, retaining a peak if its MACS p-value were < 1E-10 and tag density in the ASD sample were > 0.015.
Results:
Our prediction was that post-mortem brain epigenetic H3K4me3 alterations would be positively correlated with brain weight across subjects. There were wide individual differences in the frequencies of altered epigenetic peaks, and in brain size, with the latter skewed toward increased weight. The predicted relationship was borne out: the nonparametric Spearman correlation coefficient for these cases was r = + 0.58 (p < .05). Moreover, we found that cases with increased brain weight relative to normative data shared peak alterations tied to specific genes linked to brain growth, as referenced in the NCBI Gene Database.
Conclusions:
This study extended our findings of widespread brain epigenetic alterations in chromatin structures at hundreds of loci genome-wide in ASD, with overlap between epigenetic and genetic risk maps for autism/IDD. Here we found a significant association between these epigenetic alterations and brain weight, which may be of explanatory value in understanding the underlying biology of brain/cranial enlargement that has been reported for ASD.