Common DNA methylation alterations in multiple brain regions in autism

Abstract

Autism spectrum disorders (ASD) are increasingly common neurodevelopmental disorders defined clinically by a triad of features including impairment in social interaction, impairment in communication in social situations, and restricted and repetitive patterns of behavior and interests, with considerable phenotypic heterogeneity among individuals. Although heritability estimates for ASD are high, conventional genetic-based efforts to identify genes involved in ASD have yielded only few reproducible candidate genes that account for only a small proportion of ASDs. There is mounting evidence to suggest environmental and epigenetic factors play a stronger role in the etiology of ASD than previously thought. To begin to understand the contribution of epigenetics to ASD, we have examined DNA methylation (DNAm) in a pilot study of post-mortem brain tissue from 19 autism cases and 21 unrelated controls, among three brain regions including dorsolateral prefrontal cortex, temporal cortex, and cerebellum. We measured over 485,000 CpG loci across a diverse set of functionally relevant genomic regions using the Infinium HumanMethylation450 BeadChip and identified 4 genome-wide significant differentially methylated regions (DMRs) using a novel bumphunting approach and a permutation-based multiple testing correction method. We replicated 3/4 DMRs identified in our genome-wide screen in a different set of samples and across different brain regions. The DMRs identified in this study represent suggestive evidence for commonly altered methylation sites in ASD and provide several promising new candidate genes.

Dissociable Deficits of Executive Function Caused by Gestational Adversity are Linked to Specific Transcriptional Changes in the Prefrontal Cortex

“…Both SGA and LGA mice demonstrate decreased genome-wide DNA methylation in PFC (Grissom and Reyes, 2012;Vucetic et al, 2010a). PFC from patients with schizophrenia and autism have substantial alterations in DNA methylation and overexpress the DNA methyltransferase DNMT1 (Grayson and Guidotti, 2013;Ladd-Acosta et al, 2013). Collectively, these findings suggest that epigenetic dysregulation and aberrant transcription in the PFC may be a crucial mechanism linking gestational adversity to neurodevelopmental disorders.…”

Microbiome Disturbances and Autism Spectrum Disorders

“…The term epigenetics has become vastly overused to define broadly any transcriptomic change occurring independent of DNA mutation. The field of neuroepigenetics was born under these auspices and is currently invoked as the genesis of many neurologic disorders not explained by genetics alone, including ASD (Wilkinson and Campbell, 2013;Berko et al, 2014;Ladd-Acosta et al, 2014;Lesseur et al, 2014;Tordjman et al, 2014;Wong et al, 2014). Alterations in the gut microbiome might trigger epigenetic changes leading to downstream behavioral manifestations (Mischke and Plösch, 2013;Kumar et al, 2014;Stilling et al, 2014).…”

Genetics in child and adolescent psychiatry: methodological advances and conceptual issues

“…If blood cells prove to be a suitable surrogate tissue for studying epigenetic regulation in psychiatric disorders, this would enable researchers to examine the impact of environmental changes on methylation patterns directly in the affected individual. A recent genome-wide examination conducted post-mortem in brains of individuals with autism spectrum disorders has shown differentially methylated DNA regions, supporting the need to search for biomarkers of environmental factors [65]. Longitudinal-prospective studies are likely to provide most informative findings in the search for epigenetic associations with psychiatric diseases [49,91] and environmental factors acting during early life [75].…”