Associations between DNA methylation and schizophrenia-related intermediate phenotypes — A gene set enrichment analysis

Hass, Johanna; Walton, Esther; Wright, Carrie; Beyer, Andreas; Scholz, Markus; Turner, Jessica A.; Liu, Jingyu; Smolka, Michael N.; Roessner, Veit; Sponheim, Scott R.; Gollub, Randy L.; Ehrlich, Stefan

doi:10.1016/j.pnpbp.2015.01.006

Cited by 31 publications

(16 citation statements)

References 122 publications

(113 reference statements)

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“…For example, PBX/Knotted 1 Homeobox 1 ( Pknox1 ) has been associated with schizophrenia-related intermediate phenotypes and hippocampal volume (Hass et al, 2015). In addition, genetic mutations in the early growth response 2 ( EGR2 ) transcription factor are linked to schizophrenia and bipolar disorder (Hu et al, 2015; Kim et al, 2012).…”

Section: Discussionmentioning

confidence: 99%

Sex-specific hippocampal 5-hydroxymethylcytosine is disrupted in response to acute stress

Papale

Madrid

et al. 2016

Neurobiology of Disease

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Environmental stress is among the most important contributors to increased susceptibility to develop psychiatric disorders. While it is well known that acute environmental stress alters gene expression, the molecular mechanisms underlying these changes remain largely unknown. 5-hydroxymethylcytosine (5hmC) is a novel environmentally sensitive epigenetic modification that is highly enriched in neurons and is associated with active neuronal transcription. Recently, we reported a genome-wide disruption of hippocampal 5hmC in male mice following acute stress that was correlated to altered transcript levels of genes in known stress related pathways. Since sex-specific endocrine mechanisms respond to environmental stimulus by altering the neuronal epigenome, we examined the genome-wide profile of hippocampal 5hmC in female mice following exposure to acute stress and identified 363 differentially hydroxymethylated regions (DhMRs) linked to known (e.g., Nr3c1 and Ntrk2) and potentially novel genes associated with stress response and psychiatric disorders. Integration of hippocampal expression data from the same female mice found stress-related hydroxymethylation correlated to altered transcript levels. Finally, characterization of stress-induced sex-specific 5hmC profiles in the hippocampus revealed 778 sex-specific acute stress-induced DhMRs some of which were correlated to altered transcript levels that produce sex-specific isoforms in response to stress. Together, the alterations in 5hmC presented here provide a possible molecular mechanism for the adaptive sex-specific response to stress that may augment the design of novel therapeutic agents that will have optimal effectiveness in each sex.

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Section: Discussionmentioning

confidence: 99%

Sex-specific hippocampal 5-hydroxymethylcytosine is disrupted in response to acute stress

Papale

Madrid

et al. 2016

Neurobiology of Disease

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“…An increasing number of studies suggest a role for epigenetic mechanisms in the development of psychiatric disorders as well as multiple sclerosis (140,141). Altered methylation pattern of potential risk genes have been associated with both MS (142) and schizophrenia (117,143). As noted above, hypomethylation correlates to reactivation of a range of HERV members in a range of cancers.…”

Section: Dna Methylation and Chromatin Modificationmentioning

confidence: 99%

Expression and regulation of human endogenous retrovirus W elements

Karlsson

2016

APMIS

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Human endogenous retroviruses (HERV) comprise 8% of the human genome and can be classified into at least 31 families. A typical HERV provirus consists of internal gag, pol and env genes, flanked by two long terminal repeats (LTRs). No single provirus is capable of engendering infectious particles. HERV are by nature repetitive and have with few notable exceptions lost their protein-coding capacity. Therefore, HERV have consistently been excluded from array-based expression studies and hence little is known of their expression, regulation, and potential functional significance. An increasing number of studies have, however, observed expression of the W family of HERV in various human tissues and cells, predominantly in placenta. HERV-W LTRs act as promoters in directing transcription of HERV-W members, contribute to their tissue-specific and highly diversified expression pattern. Furthermore, leaky transcription originating from adjacent genes plays a role in the transcription initiation of HERV-W psudoelements. It has been reported that HERV-W elements, including ERVWE1 (the so far only known HERV-W locus harboring a gene (env) functionally adopted by the human host to critically participate in placenta biogenesis), can become transactivated in a range of human non-placental cell-lines during exogenous virus infections. Aberrant expression of HERV-W has been associated with human diseases, such as cancer, multiple sclerosis, and schizophrenia. Based on published reports, transcriptional activities of HERV-W appear to be influenced by several mechanisms; binding of transcription factors to LTR promoters and enhancers outside of LTRs, genetic variation and alteration in DNA methylation and histone modification. Emerging mechanistic studies support the notion that HERV-W represents a potential marker or mediator of environmental exposures (e.g., virus infection) in the development of chronic complex diseases.Key words: HERV-W; LTR-directed; virus infection; aberrant expression; DNA methylation; histone modification.Fang Li, Department of Basic Medical Science, Changsha Medical University, 410219, Changsha, China. e-mail: li-evans@hotmail.com Sequencing of the human genome has revealed that approximately 2% of the genome is composed of protein-coding regions, whereas approximately 8% of our DNA is recognized as containing human endogenous retrovirus (HERV) elements (1, 2). A high prevalence of ERVs in 65 investigated vertebrate genomes, and the detection of highly related sequences in the genomes of distantly related vertebrates was recently reported (3). Thus, infection, endogenization, and intragenomic expansion of a wide range of retroviruses appear to have been common during evolution. Although some individual integration events have clearly been beneficial to the host during evolution, the roles of other integrations and their massive expansions in the host genome remain unclear. Interestingly, differential expression of HERV have been associated with a range of human diseases, such as cancer and multiples ...

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“…Epigenetic profiles of the hippocampus and the amygdala have been examined in healthy controls and in relation to a range of psychiatric disorders such as schizophrenia and depression. Taking a gene set enrichment approach using methylome-wide data, Hass et al (2015) found altered epigenetic patterns in the hsa-miR-219a-5p microRNA target gene set to correlate with hippocampal volume in a schizophrenia sample. Methylation in the serotonin transporter gene SLC6A4, a risk locus for depression, has been found to associate with hippocampal grey matter volume and parts of the amygdala in healthy controls (Dannlowski et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

Longitudinal epigenetic predictors of amygdala:hippocampus volume ratio

Walton

Cecil

Suderman

et al. 2017

Child Psychology Psychiatry

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Background The ratio between amygdala:hippocampal (AH) volume has been associated with multiple psychiatric problems, including anxiety and aggression. Yet, little is known about its biological underpinnings. Here, we used a methylome-wide approach to test (1) whether DNA methylation in early life (birth, age 7) prospectively associates with total AH volume ratio in early adulthood, and (2) whether significant DNA methylation markers are influenced by prenatal risk factors. Methods Analyses were based on a subsample (n = 109 males) from the Avon Longitudinal Study of Parents and Children (ALSPAC), which included measures of prenatal risk, DNA methylation (Infinium Illumina 450k), T1-weighted brain scans and psychopathology in early adulthood (age 18-21). Amygdala and hippocampus measures were derived using Freesurfer 5.3.0. Methylation markers related to AH volume ratio across time were identified using longitudinal multi-level modeling. Results AH volume ratio correlated positively with age 18 psychosis-like symptoms (p = 0.007). Methylation of a probe in the gene SP6 associated longitudinally with (1) higher AH volume ratio (FDR q-value = 0.01) and (2) higher stressful life events during pregnancy (p = 0.046). SP6 is expressed in the hippocampus and amygdala and has been implicated in cognitive decline in Alzheimer's disease. The association between SP6 DNA methylation, AH volume ratio and psychopathology was replicated in an independent dataset of 101 patients with schizophrenia and 111 healthy controls. Conclusions Our findings suggest that epigenetic alterations in genes implicated in neurodevelopment may contribute to a brain-based biomarker of psychopathology.

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Associations between DNA methylation and schizophrenia-related intermediate phenotypes — A gene set enrichment analysis

Cited by 31 publications

References 122 publications

Sex-specific hippocampal 5-hydroxymethylcytosine is disrupted in response to acute stress

Sex-specific hippocampal 5-hydroxymethylcytosine is disrupted in response to acute stress

Expression and regulation of human endogenous retrovirus W elements

Longitudinal epigenetic predictors of amygdala:hippocampus volume ratio

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