Genome-Wide DNA Methylation Scan in Major Depressive Disorder

While genome-wide association studies are ongoing to identify sequence variation influencing susceptibility to major depressive disorder (MDD), epigenetic marks, such as DNA methylation, which can be influenced by environment, might also play a role. Here we present the first genome-wide DNA methylation (DNAm) scan in MDD. We compared 39 postmortem frontal cortex MDD samples to 26 controls. DNA was hybridized to our Comprehensive High-throughput Arrays for Relative Methylation (CHARM) platform, covering 3.5 million CpGs. CHARM identified 224 candidate regions with DNAm differences >10%. These regions are highly enriched for neuronal growth and development genes. Ten of 17 regions for which validation was attempted showed true DNAm differences; the greatest were in PRIMA1, with 12–15% increased DNAm in MDD (p = 0.0002–0.0003), and a concomitant decrease in gene expression. These results must be considered pilot data, however, as we could only test replication in a small number of additional brain samples (n = 16), which showed no significant difference in PRIMA1. Because PRIMA1 anchors acetylcholinesterase in neuronal membranes, decreased expression could result in decreased enzyme function and increased cholinergic transmission, consistent with a role in MDD. We observed decreased immunoreactivity for acetylcholinesterase in MDD brain with increased PRIMA1 DNAm, non-significant at p = 0.08

Taking child abuse and mothering into account - Intersectional feminism as an alternative for the study of domestic violence

Feminist scholars have been engaged in an ongoing debate to determine which theoretical perspective offers the best framework for understanding domestic violence, and this debate has been crystallized around two pole positions: radical and postmodern feminism. This article presents a journey throughout the development of a theoretical perspective for the study of domestic violence, child abuse, and mothering. It argues that the intersectional feminist perspective has much to offer these debates and that it constitutes a promising theoretical framework for understanding domestic violence that takes into account issues of child abuse and mothering

Epigenetic signatures of autism: trimethylated H3K4 landscapes in prefrontal neurons

CONTEXT: Neuronal dysfunction in cerebral cortex and other brain regions could contribute to the cognitive and behavioral defects in autism. OBJECTIVE: To characterize epigenetic signatures of autism in prefrontal cortex neurons. DESIGN: We performed fluorescence-activated sorting and separation of neuronal and nonneuronal nuclei from postmortem prefrontal cortex, digested the chromatin with micrococcal nuclease, and deeply sequenced the DNA from the mononucleosomes with trimethylated H3K4 (H3K4me3), a histone mark associated with transcriptional regulation. Approximately 15 billion base pairs of H3K4me3-enriched sequences were collected from 32 brains. SETTING: Academic medical center. PARTICIPANTS: A total of 16 subjects diagnosed as having autism and 16 control subjects ranging in age from 0.5 to 70 years. MAIN OUTCOME MEASURES: Identification of genomic loci showing autism-associated H3K4me3 changes in prefrontal cortex neurons. RESULTS: Subjects with autism showed no evidence for generalized disruption of the developmentally regulated remodeling of the H3K4me3 landscape that defines normal prefrontal cortex neurons in early infancy. However, excess spreading of H3K4me3 from the transcription start sites into downstream gene bodies and upstream promoters was observed specifically in neuronal chromatin from 4 of 16 autism cases but not in controls. Variable subsets of autism cases exhibit altered H3K4me3 peaks at numerous genes regulating neuronal connectivity, social behaviors, and cognition, often in conjunction with altered expression of the corresponding transcripts. Autism-associated H3K4me3 peaks were significantly enriched in genes and loci implicated in neurodevelopmental diseases. CONCLUSIONS: Prefrontal cortex neurons from subjects with autism show changes in chromatin structures at hundreds of loci genome-wide, revealing considerable overlap between genetic and epigenetic risk maps of developmental brain disorders

Immunohistochemical pattern of AChE in frontal cortex.

<p>(A) In controls there is diffuse and intense pattern of immunoreactivity involving mainly the neuropil. (B) In MDD subjects, though variable, immunostaining was reduced. Both 200×. (C) In controls, there is virtually no perikaryal staining. (D) The latter contrasts with the pattern observed in some areas in MDD subjects, in which groups of pyramidal neurons display intense perikaryal staining, suggesting redistribution of the enzyme to the cell body. The red circles highlight examples. Both 640×.</p

Examples of CHARM results for two of the regions showing greatest DNAm differences between MDD cases and controls.

<p>The plots show percent methylation versus genomic location with each point representing the methylation level of an individual sample for a given probe. The curve represents averaged smoothed percent methylation values. The locations of CpG dinucleotides are indicated with black tickmarks on the X-axis. CpG density was calculated across the region using a standard density estimator and is represented by the smoothed black line. The location of the CpG island is denoted on the X-axis as an orange line. Gene annotation is indicated, showing <i>LASS2</i> in (a) and <i>PRIMA1</i> in (b). The thin outer grey line represents the transcript, while the thin inner lines represent a coding region. Filled in grey boxes represent exons.</p

Results of bisulfite pyrosequencing for validation of CHARM in brain samples.

<p>Regions in or near four genes showed differences that remained statistically significant after correction for having tested 17 genes: (a) <i>LASS2</i>, (b) <i>CPSF3</i>, (c) <i>ZNF263</i>, (d) <i>PRIMA1</i>. The grey bars represent values from control brain sample DNA, while the black bars represent those from MDD brain samples. The Y-axis is percent DNA methylation, while the X-axis shows distance along the chromosome for each CpG dinucleotide assayed. One asterisk indicates a difference between MDD and control of p<0.05. Two asterisks indicates p<0.0029 (a correction for 17 regions tested). Three asterisks indicates p<0.00054 (a correction for 92 CpGs tested).</p

Stanley Medical Research Institute MDD and control brain samples.

<p>Stanley Medical Research Institute MDD and control brain samples.</p

<i>PRIMA1</i> DNAm by diagnosis, and by covariate status^a.

a<p>Dx = diagnosis; PMI = postmortem interval; DNAm = DNA methylation; p-values<0.05 are italicized for clarity.</p