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Childhood Trauma May Silence Stress Gene in Humans

26 February 2009. Childhood trauma, a risk factor for psychosis, blocks the functioning of a gene that keeps the human response to stress under check, according to research released online by Nature Neuroscience on February 22. The study, from a team that includes Michael Meaney of McGill University in Montreal, Quebec, extends prior observations that rat pups’ early life experiences may cause epigenetic changes. The new study suggests that being severely abused or neglected in childhood reduces expression of the glucocorticoid receptor gene in the hippocampus. It hints that adversity early in life induces lifelong changes in gene function that could increase the toll taken by stress and increase the likelihood of developing psychiatric disorders.

Normally, the hypothalamic-pituitary axis (HPA) helps organisms adapt to stress, which unleashes a cascade of events that tells the adrenal glands to release glucocorticoids. In humans, the glucocorticoid cortisol coordinates the stress response by binding to glucocorticoid and mineralocorticoid receptors on neurons and other cells. Through a negative feedback loop, the expression of glucocorticoid receptors in the hypothalamus dampens HPA reactivity to stress.

Individuals’ childhood experiences may shape their stress responses throughout life. For instance, rat pups with nurturing mothers that lick and groom them a lot show sustained decreases in HPA stress responses, an effect that Meaney’s group has linked to epigenetic factors that affect the expression of glucocorticoid receptors in the hippocampus (see Weaver et al., 2004; Weaver, 2009). In schizophrenia, adverse childhood experiences may intensify reactions to later hardships in life, thereby contributing to abnormalities in the hippocampus and other brain areas (see Walker et al., 2008; Lawrie et al., 2008; and see SRF related news story).

Meaney and colleagues, including first author Patrick McGowan, of the Douglas Mental Health University Institute in Montreal, note that severe childhood stress and psychiatric conditions associated with reduced expression of hippocampal glucocorticoid receptors seem to foster suicide. This, coupled with the prior findings from Meaney’s lab, led them to ask whether epigenetic processes might account for the effects of severe childhood stress on the brains of adult humans who commit suicide.

To address this issue, the researchers obtained samples of hippocampal tissue from the Quebec Suicide Brain Bank. All of the tissue came from male subjects: 12 suicide victims with a history of childhood abuse, 12 suicide victims with no such history, and 12 non-abused controls who died of other causes without receiving medical treatment. The abuse victims had suffered sexual abuse, severe physical abuse, or severe neglect.

McGowan and colleagues found less glucocorticoid receptor expression in the tissue from the abused suicide victims than in that from the other suicide victims or the control subjects. The same pattern emerged when they studied the expression of transcripts containing the exon 1F NR3C1 promoter, which regulates the expression of glucocorticoid receptors in human neurons. This promoter resembles the one in rats that showed epigenetic changes in response to the mother’s touch. Since the two groups of non-abused subjects showed similar expression levels, McGowan and colleagues attribute the expression differences to the abuse rather than other factors related to suicide.

Importantly, nucleotide sequences in the region of the NR3C1 promoter did not vary among groups. This suggests that the expression differences might stem from epigenetic factors rather than the genetic code itself.

Methylation revelations
One way that epigenetic changes occur is through the addition of a methyl group, or tag, to cytosine. This turns off the expression of the tagged gene (see SRF related news story; SRF news story). McGowan and colleagues found more of these tags in the abused suicide victims than in the other subjects, but only at specific sites in the NR3C1 promoter.

Previously, Meaney, Moshe Szyf at McGill University in Montreal, and their associates found that a transcription factor called nerve growth factor-inducible protein A (NGFI-A) controls expression of the Nr3c1 promoter in rats and that DNA methylation hinders this process (Weaver et al., 2007). In the new study, McGowan and colleagues report that a parallel process occurs in the human hippocampus, where NGFI-A normally starts transcription by binding with the exon 1F NR3C1 promoter. The methyl tags hamper its ability to do so.

Implications for schizophrenia
McGowan and colleagues conclude that childhood trauma correlates with altered glucocorticoid receptor expression in the hippocampus. They write, “It is tempting to speculate that epigenetic processes might mediate the effects of the social environment during childhood on hippocampal gene expression and that stable epigenetic marks such as DNA methylation might then persist into adulthood and influence the vulnerability for psychopathology through effects on intermediate levels of function, such as HPA activity.”

Speaking of psychopathology, the study could not tie mood disorders or substance abuse disorders to overall glucocorticoid receptor expression or to glucocorticoid receptor 1F expression. It did not specifically examine schizophrenia or psychosis. Whether childhood trauma actually causes psychosis remains controversial (see Read et al., 2005; Morgan and Fisher, 2007; Bendall et al., 2008). Even so, the possibility that such trauma leaves epigenetic scars on the brain offers plenty of fodder for future explorations of gene-environment interactions in schizophrenia.—Victoria L. Wilcox.

Reference:
McGowan PO, Sasaki A, D’Alessio AC, Dymov S, Labonté B, Szyf M, Turecki G, Meaney MJ. Epigenetic regulation of the glucocorticoid receptor in human brain associates with childhood abuse. Nat Neurosci. 2009 February 22. Abstract

Comments on Related News


Related News: Trauma Link to Psychosis Is Strengthened

Comment by:  Margaret Almeida
Submitted 28 June 2006
Posted 30 June 2006
  I recommend the Primary Papers

This article supported absolutely what our research clinic is anecdotally experiencing. On more than several occasions we have conducted a Structured Clinical Interview for DSM-IV Axis I disorders (SCID) to find a diagnosis of schizophrenia or schizoaffective disorder. However, in contrast, the clinical chart is describing psychotic symptoms, but the clinical diagnosis is post-traumatic stress disorder alone or perhaps along with borderline personality disorder with depression. All of these cases involved younger clients (18-25 years old), either just beginning mental health services or certainly without a long history of mental health care to reflect on. They also had histories (according to primary care providers) of severe childhood abuse and trauma.

View all comments by Margaret Almeida

Related News: Trauma Link to Psychosis Is Strengthened

Comment by:  Craig Morgan
Submitted 30 July 2006
Posted 31 July 2006
  I recommend the Primary Papers

This is a fascinating study investigating the relationship between psychological trauma and the development of psychotic symptoms using data from the Early Developmental Stages of Psychopathology (EDSP) study conducted in Munich, Germany.

There are a number of interesting findings: 1) Self-reported trauma (any) was associated with experiencing one (OR 1.40; 95 percent CI 1.09, 1.78), two (OR 1.88; 95 percent CI 1.35-2.62) and three or more (OR 2.60; 95 percent CI 1.66-4.09) psychotic symptoms during the follow-up period. While these odds ratios increase linearly with number of psychotic symptoms, when potential confounders, such as urbanicity and psychosis proneness, were controlled for, only the association with three or more psychotic symptoms remained significant (Adj. OR 1.89, 95 percent CI 1.16-3.08); 2) Most specific categories of trauma showed positive associations with psychotic symptoms, particularly at the level of three or more, though only physical threat, natural catastrophe and terrible event to other reached statistical significance (though this may be largely an issue of statistical power); and 3) There was evidence that the association between trauma and psychotic symptoms varied by psychosis proneness. That is, the association between trauma and psychosis was strongest in those with pre-existing vulnerability to psychosis.

There has been recent controversy, at least in the U.K., about the role of trauma in the etiology of psychosis, largely as a consequence of a review paper published by John Read and colleagues which concluded that child abuse is a cause of schizophrenia (Read et al., 2005). Does the study by Spauwen et al. provide support for this conclusion? The findings allow interpretation both ways.

On the one hand, there is a robust association between any traumatic event and subsequent development of three or more psychotic symptoms. There are also indications that this may be a dose-response relationship. Further, this study has a number of methodological advantages over much of what has gone before. The prospective design overcomes many of the concerns regarding potential recall bias and direction of causation, as does the inclusion of a measure of psychosis proneness. The sample was large, and the analyses sophisticated.

On the other hand, it could be countered, the observed association between any trauma and psychotic symptoms was modest (Adj. OR 1.89) and much smaller than that found in other studies (e.g., Janssen et al. (2004) reported an adjusted odds ratio of 7.3 over a 2-year period). The evidence for a dose-response relationship was weak, and when confounders were adjusted for, only the association with the most severe level of psychotic symptoms remained significant. Furthermore, and issues of statistical power notwithstanding, it is important to note that only a small number of specific types of trauma were significantly associated with risk of developing psychotic symptoms, and these did not include sexual abuse. And there remains the ongoing issue of the relationship, if any, between psychotic-like symptoms reported in general population samples and the clinical syndromes of psychosis, particularly schizophrenia.

So, there are reasons to retain a healthy skepticism, particularly in relation to claims that child abuse causes schizophrenia. But equally, the emerging evidence suggests it would be wrong to reject a possible role for psychological trauma out of hand. Studies are becoming more methodologically robust, and that by Spauwen et al. is an example of this. There is, however, clearly a need for much more research. Until this is available, we should remain open-minded.

References:

Janssen I, Krabbendam L, Bak M, Hanssen M, Vollebergh W, de Graaf R, van Os J. Childhood abuse as a risk factor for psychotic experiences. Acta Psychiatr Scand. 2004 Jan;109(1):38-45. Abstract

Read J, van Os J, Morrison AP, Ross CA. Childhood trauma, psychosis and schizophrenia: a literature review with theoretical and clinical implications. Acta Psychiatr Scand. 2005 Nov;112(5):330-50. Review. Abstract

View all comments by Craig Morgan

Related News: Trauma Link to Psychosis Is Strengthened

Comment by:  Ezra Susser, SRF Advisor
Submitted 9 August 2006
Posted 9 August 2006

I agree with most of the comments already posted by others on the very interesting paper by Spauwen et al on psychological trauma and psychotic symptoms. I'd like to raise just one additional point. This pertains to the specificity for psychotic symptoms. It appears that the study found no relation of these psychological traumas to depression or bipolar disorder, but it isn't clear whether there was any relation to depressive symptoms. It's worth considering this point in the interpretation of the results, because psychological traumas have been related to a number of other conditions in previous studies.

View all comments by Ezra Susser

Related News: Trauma Link to Psychosis Is Strengthened

Comment by:  Maurits Van den NoortPeggy Bosch
Submitted 10 August 2006
Posted 10 August 2006
  I recommend the Primary Papers

We read the paper by Spauwen et al. (2006) with great interest. Their findings suggest a specific relationship between psychological trauma and psychosis. Previous studies already showed that psychological trauma is clearly associated with depression and other symptoms of post-traumatic stress disorder, but the link between childhood trauma and psychosis was controversial. The current finding is very interesting and based on a study with a large data set and a good methodology. However, more research on this topic needs to be done. This research should measure the type of trauma in greater detail since this could give a better understanding of the exact link between trauma and psychosis. Moreover, the focus of future research should be more on the underlying neurological mechanisms by which childhood trauma increases the risk of psychosis. For instance, it would be interesting to conduct neuroimaging studies (Ni Bhriain et al., 2005), that focus on dopamine abnormalities (McGowan et al., 2004) in patients with traumatic experiences early in life.

References:

McGowan S, Lawrence AD, Sales T, Quested D, Grasby P. Presynaptic dopaminergic dysfunction in schizophrenia: a positron emission tomographic [18F]fluorodopa study. Arch Gen Psychiatry. 2004 Feb;61:134-142. Abstract

Ni Bhriain S, Clare AW, Lawlor BA. Neuroimaging: a new training issue in psychiatry? Psychiat Bull. 2005 May;29:189-192.

Spauwen J, Krabbendam L, Lieb R, Wittchen HU, van Os J. Impact of psychological trauma on the development of psychotic symptoms: relationship with psychosis proneness. Br J Psychiatry. 2006 Jun;188:527-33. Abstract

View all comments by Maurits Van den Noort
View all comments by Peggy Bosch

Related News: Trauma Link to Psychosis Is Strengthened

Comment by:  James ScottJohn McGrath (SRF Advisor)
Submitted 10 August 2006
Posted 10 August 2006
  I recommend the Primary Papers

Spauwen and colleagues add further weight to research linking traumatic experiences and psychotic symptoms (Spauwen et al., 2006). There are now a number of studies showing an association between trauma and psychotic symptoms (Bebbington et al., 2004; Janssen et al., 2004; Sareen et al., 2005; Shevlin et al., 2006; Whitfield et al., 2005). There are also a number of large community-representative studies showing that psychotic symptoms are highly prevalent in community populations (Eaton et al., 1991; Scott et al., 2006; van Os et al., 2000).

Read and colleagues have argued that child abuse may be an etiological factor for schizophrenia in some individuals (Read et al., 2001; Read et al., 2005). In a clinical study of adolescent inpatients who hallucinated, we found using a structured questionnaire and structured clinical interview (K-SADS) that the hallucinations of schizophrenia and those of post-traumatic stress disorder (PTSD) were very similar in form and content (Scott et al., 2006, in press). Thus, clinicians and researchers need to remain mindful of the overlap of psychotic symptoms in these disorders.

A possible explanation for the above is that psychotic symptoms are non-specific experiences. Perhaps they represent a final common pathway to a range of stressors including unemployment, social isolation, migration, substance use and trauma. From a different perspective in relation to trauma, psychotic symptoms may be part of a dissociative process (van der Kolk et al., 1996), and the positive psychotic symptoms in PTSD are phenomenologically difficult to distinguish from those of schizophrenia.

The association between trauma and psychotic symptoms is a fascinating one requiring further objective, open-minded research.

References:

Bebbington PE, Bhugra D, Brugha T, Singleton N, Farrell M, Jenkins R, Lewis G, Meltzer H. Psychosis, victimisation and childhood disadvantage: evidence from the second British National Survey of Psychiatric Morbidity. Br J Psychiatry. 2004 Sep;185:220-6. Abstract

Eaton WW, Romanoski A, Anthony JC, Nestadt G. Screening for psychosis in the general population with a self-report interview. J Nerv Ment Dis. 1991 Nov;179(11):689-93. Abstract

Janssen I, Krabbendam L, Bak M, Hanssen M, Vollebergh W, de Graaf R, van Os J. Childhood abuse as a risk factor for psychotic experiences. Acta Psychiatr Scand. 2004 Jan;109(1):38-45. Abstract

Read J, Perry BD, Moskowitz A, Connolly J. The contribution of early traumatic events to schizophrenia in some patients: a traumagenic neurodevelopmental model. Psychiatry. 2001 Winter;64(4):319-45. Review. Abstract

Read J, van Os J, Morrison AP, Ross CA. Childhood trauma, psychosis and schizophrenia: a literature review with theoretical and clinical implications. Acta Psychiatr Scand. 2005 Nov;112(5):330-50. Review. Abstract

Sareen J, Cox BJ, Goodwin RD, J G Asmundson G. Co-occurrence of posttraumatic stress disorder with positive psychotic symptoms in a nationally representative sample. J Trauma Stress. 2005 Aug;18(4):313-22. Abstract

Scott J, Chant D, Andrews G, McGrath J. Psychotic-like experiences in the general community: the correlates of CIDI psychosis screen items in an Australian sample. Psychol Med. 2006 Feb;36(2):231-8. Epub 2005 Nov 23. Abstract

Scott J, Nurcombe B, Sheridan J, et al. (2006) Hallucinations in Adolescents with Post-traumatic Stress Disorder and Psychotic Disorder. Australasian Psychiatry, In press.

Shevlin M, Dorahy M, Adamson G. Childhood traumas and hallucinations: An analysis of the National Comorbidity Survey. J Psychiatr Res. 2006 Apr 24; [Epub ahead of print] Abstract

Spauwen J, Krabbendam L, Lieb R, Wittchen HU, van Os J. Impact of psychological trauma on the development of psychotic symptoms: relationship with psychosis proneness. Br J Psychiatry. 2006 Jun;188:527-33. Abstract

van der Kolk BA, Pelcovitz D, Roth S, Mandel FS, McFarlane A, Herman JL. Dissociation, somatization, and affect dysregulation: the complexity of adaptation of trauma. Am J Psychiatry. 1996 Jul;153(7 Suppl):83-93. Review. Abstract

van Os J, Hanssen M, Bijl RV, Ravelli A. Strauss (1969) revisited: a psychosis continuum in the general population? Schizophr Res. 2000 Sep 29;45(1-2):11-20. Abstract

Whitfield CL, Dube SR, Felitti VJ, Anda RF. Adverse childhood experiences and hallucinations. Child Abuse Negl. 2005 Jul;29(7):797-810. Abstract

View all comments by James Scott
View all comments by John McGrath

Related News: Trauma Link to Psychosis Is Strengthened

Comment by:  Ella Matthews
Submitted 24 August 2006
Posted 27 August 2006

Spauwen and colleagues find that exposure to psychological trauma may increase the risk of psychotic symptoms in people vulnerable to psychoses. The experiences of war, natural disasters and child abuse cannot be good for anyone. Am I wrong to think that these add up to much more than psychological trauma or that such events would also tend to bring on and exacerbate the symptoms of myriad other conditions such as those relating to the heart, lungs and other bodily organs?

View all comments by Ella Matthews

Related News: Epigenetic Analysis Finds Widespread DNA Methylation Changes in Psychosis

Comment by:  Dennis Grayson
Submitted 26 March 2008
Posted 27 March 2008
  I recommend the Primary Papers

The paper by Mill et al. is one of the first comprehensive attempts to examine changes in methylation across the entire genome in patients with various diagnoses of mental illness. The study is well designed, extensive, and uses fairly new technology to examine changes in methylation profiles across the genome. In the frontal cortex, the authors provide evidence for psychosis-associated differences in DNA methylation in numerous loci, including those involved in glutamatergic and GABAergic transmission, brain development, and other processes linked with disease etiology. Methylation in the frontal cortex of the BDNF gene is correlated with a non-synonymous SNP previously associated with major psychosis. These data provide further support for an epigenetic origin of major psychosis, as evidenced by DNA methylation-induced changes likely important to gene expression.

In many ways, this seems reminiscent of the trend in genetics several years ago when the inclination was to move from single gene loci association and linkage studies to genomewide scans. The only downside of the approach is that what one gains in information, one (at least initially) loses in biology. That is given the wealth of new findings uncovered; we now need to go back and examine these results in light of what we know regarding gene function in neurobiology and cognition. Of course, this is the trend, now that microarrays have increased our capacity to look at all things at the same time. The flipside is that it will take several large-scale studies of this sort to better understand which findings are replicable and which are not. That is, do the results of the Mill paper agree with data obtained and carried out by laboratories using the methyl DIP or MeCP2 ChIP assays coupled with microarrays. While these experiments ask different questions, the implication is that there may be some degree of overlap in comparing these different methodologies. While this may be premature, there is a sense that this information will be available shortly.

Finally, I would like to focus on recent findings regarding the methylation of the reelin promoter. These authors (Mill et al.) and Tochigi and colleagues (Tochigi et al., 2008) have found that the reelin promoter is not hypermethylated in patients with schizophrenia. In fact, Tochigi et al., 2008, found that the reelin promoter is not methylated at all using pyrosequencing. However, several groups (Grayson et al., 2005; Abdolmaleky et al., 2005; Tamura et al., 2007; Sato et al., 2006) have shown that the human reelin promoter is methylated in different circumstances. Interestingly, there is little consensus in the precise bases that are methylated in these latter studies. Our group (Grayson et al., 2005) performed bisulfite treatment of genomic DNA and sequencing of individual clones. Moreover, we analyzed two distinct patient populations. The clones were sequenced at a separate facility. What was intriguing was that the baseline methylation patterns in the two populations was different, and yet several sites stood out as being relevant in both. We mapped methylation to the somewhat rare CpNpG sites proximal to the promoter. Interestingly, these bases were located in a transcription factor-rich portion (Chen et al., 2007) of the promoter and in a region that shows 100 percent identity with the mouse promoter over a 45 bp stretch. We have also been able to show that changing one of these two bases to something other than cytosine reduces activity 50 percent in a transient transfection assay. So the question becomes, How do we reconcile these disparate findings regarding methylation? As suggested by Dr. McCaffrey, the answer may lie in regional differences that arise due to the nature of the material available for each study. We have found a degree of reproducibility by using human neuronal precursor (NT2) cells for many of our studies. At the same time, this cell line is somewhat artificial and cannot be used to reconcile differences found in human tissue. Perhaps it might be prudent to examine material taken by using laser capture microdissection to enrich in more homogenous populations of neurons/glia. In moving ahead, it might be best to now focus on the mechanism for these differences in methylation patterns and try to understand the biology associated with the new findings (Mill et al., 2008) as a starting point.

References:

Abdolmaleky HM, Cheng KH, Russo A, Smith CL, Faraone SV, Wilcox M, Shafa R, Glatt SJ, Nguyen G, Ponte JF, Thiagalingam S, Tsuang MT. Hypermethylation of the reelin (RELN) promoter in the brain of schizophrenic patients: a preliminary report. Am J Med Genet B Neuropsychiatr Genet. 2005 Apr 5;134(1):60-6. Abstract

Chen Y, Kundakovic M, Agis-Balboa RC, Pinna G, Grayson DR. Induction of the reelin promoter by retinoic acid is mediated by Sp1. J Neurochem. 2007 Oct 1;103(2):650-65. Abstract

Grayson DR, Jia X, Chen Y, Sharma RP, Mitchell CP, Guidotti A, Costa E. Reelin promoter hypermethylation in schizophrenia. Proc Natl Acad Sci U S A. 2005 Jun 28;102(26):9341-6. Abstract

Mill J, Tang T, Kaminsky Z, Khare T, Yazdanpanah S, Bouchard L, Jia P, Assadzadeh A, Flanagan J, Schumacher A, Wang SC, Petronis A. Epigenomic profiling reveals DNA-methylation changes associated with major psychosis. Am J Hum Genet. 2008 Mar 1;82(3):696-711. Abstract

Sato N, Fukushima N, Chang R, Matsubayashi H, Goggins M. Differential and epigenetic gene expression profiling identifies frequent disruption of the RELN pathway in pancreatic cancers. Gastroenterology. 2006 Feb 1;130(2):548-65. Abstract

Tamura Y, Kunugi H, Ohashi J, Hohjoh H. Epigenetic aberration of the human REELIN gene in psychiatric disorders. Mol Psychiatry. 2007 Jun 1;12(6):519, 593-600. Abstract

Tochigi M, Iwamoto K, Bundo M, Komori A, Sasaki T, Kato N, Kato T. Methylation status of the reelin promoter region in the brain of schizophrenic patients. Biol Psychiatry. 2008 Mar 1;63(5):530-3. Abstract

View all comments by Dennis Grayson

Related News: Epigenetic Forces May Blaze Divergent Heritable Paths From Same DNA

Comment by:  Shiva SinghRichard O'Reilly
Submitted 2 February 2009
Posted 3 February 2009

The methylation difference between twins is clearly demonstrated using newer methods in this publication. However, conceptually it’s an old story now. A quick PubMed search for "monozygotic twins and non-identical" yielded a total of 7,653 publications. There is no doubt that the more we look, the more difference we will find between monozygotic twins. Also, monozygotic twin differences in methylation and gene expression are expected to increase with age. It is also affected by a variety of genetic and environmental factors. We have come a long way in genetic research on twins and the time has come to modify our thinking about monozygotic twins as "non-identical but closest possible" rather than as "identical." They started from a single zygote, but have diverged during development and differentiation including upbringing.

The implication of the published results is that the methylation (epigenetic) differences (in monozygotic twins) will be powerful in any genetic analysis of disease(s). Once again, it is probably more problematic than usually assumed. Also, it is particularly problematic for behavioral/psychiatric disorders including schizophrenia. The reason is multi-fold and includes the effect of (known and unknown) environment including pregnancy, upbringing, drugs, life style, food, etc. All these are known to affect DNA methylation and gene expression. As a result, they add unavoidable confounding factors to the experimental design. It does not mean that epigenetics is not involved in these diseases. Rather, directly establishing a role for methylation in schizophrenia will be challenging. A special limitation is the fact that methylation is known to be cell-type specific, and perfectly matched affected and normal (twin) human brain (region) samples for necessary experiments are problematic and methylation studies on other cell types may or may not be informative.

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