Childhood maltreatment and mental illness
Early life experiences exert a profound and lasting influence on mental health throughout life. Experience of maltreatment in the first decade of life increases the risk for most types of mental illness in adulthood.Reference Scott, McLaughlin, Smith and Ellis1 The effects of childhood maltreatment persist into old age, contribute to chronicity and treatment resistance.Reference Nanni, Uher and Danese2 For example, a history of childhood maltreatment not only doubles the risk of depression in adulthood, but also increases the likelihood that the disease will be chronic and reduces the likelihood that it will remit with treatment.Reference Nanni, Uher and Danese2,Reference Uher3 These powerful effects lasting many decades raise puzzling questions: how does early experience get engraved in the circuitry of the developing brain and influence long-term physical and mental health? How are these effects maintained into adulthood? Are the effects of early childhood experience reversible later in life?
Epigenetics, DNA methylation
Epigenetics has the potential to provide answers to these important questions.Reference Uher3 The term epigenetics describes modifications to the genetic material that influence the way genes function without changing the DNA sequence. The best understood epigenetic modifications include DNA methylation. This involves addition of a methyl group (a single carbon residue) to a cytosine nucleotide to form 5-methylcytosine. The effect of DNA methylation on gene function varies depending on the period of development during which the methylation occurs and location of the methylated cytosine. Methylation of DNA in gene regulatory sequences (promoter and enhancer regions) usually results in gene silencing and reduced gene expression. This is a powerful regulatory mechanism that ensures that genes are only expressed when needed.
Rodent studies give clues about how childhood maltreatment affects humans
Research in animal models has demonstrated that methylation of certain genes mediates the long-term effects of adverse early experiences on behaviour. It shows that the level of care experienced in infancy permanently shapes the stress responses in the brain, which then affect memory, attention and emotion. In rat pups, low maternal nurturing (licking and grooming) during the first week of life is associated with increased methylation of a neuron-specific promoter of the glucocorticoid receptor gene.Reference Weaver, Cervoni, Champagne, D'Alessio, Sharma and Seckl4 The expression of this gene is then reduced, the number of glucocorticoid receptors in the brain is decreased and the animals show a higher hormonal response to stress throughout their life.Reference Zhang, Labonte, Wen, Turecki and Meaney5 The effects of maternal care on cortisol response and behaviour can be eliminated by pharmacological treatment that erases epigenetic marks.Reference Weaver, Cervoni, Champagne, D'Alessio, Sharma and Seckl4,Reference Zhang, Labonte, Wen, Turecki and Meaney5 This impressive series of experiments shows that methylation of the glucocorticoid receptor gene promoter is a necessary link in the process leading to the long-term physiological and behavioural sequelae of poor maternal care. The translational potential of these findings depends on whether they generalise to humans. Examination of brain tissue from individuals who died by suicide found that the human equivalent of the glucocorticoid receptor gene promoter is also more methylated in the brains of individuals who had experienced maltreatment during childhood.Reference McGowan, Sasaki, D'Alessio, Dymov, Labonte and Szyf6 This finding suggests that DNA methylation mediates the effects of early environment in both rodents and humans and points to the possibility of new therapeutic approaches with epigenetic mechanisms of action. This type of research is, however, limited by the inaccessibility of human brain samples. The practical implications of this finding would be enhanced if the relevant epigenetic modification could be measured in an accessible tissue, such as blood or saliva.
A blood test for childhood abuse?
A new study from the University of Geneva, led by Perroud and Dayer and published in this issue of the British Journal of Psychiatry, suggests that epigenetic traces of childhood maltreatment are indeed readily detectable in peripheral blood samples.Reference Perroud, Dayer, Piguet, Nallet, Favre and Malafosse7 Perroud et al have examined methylation patterns in the promoter of the human glucocorticoid receptor gene (NR3C1) in blood samples from adult patients with bipolar disorder, who also retrospectively reported on their experiences of childhood maltreatment, including physical, emotional and sexual abuse and emotional and physical neglect. They found that the degree of DNA methylation in the NR3C1 promoter was strongly positively related to the reported experience of childhood maltreatment decades earlier. This finding was not only highly statistically significant, but also large in magnitude, indicating a robust relationship between a reported experience remote in time and a molecular laboratory measure. For a relationship between a molecular measure and reported historical exposure, the effect size is extraordinarily large. This opens a range of new possibilities: given the large effect size of this association, measurement of the NR3C1 promoter methylation may effectively become a blood test measuring the physiological traces left on the genome by early experiences. Although it is unlikely that a blood test could replace the need to ask upsetting questions about personal history, the possibility that it may add unique additional information is more realistic and even more exciting. Near future research will examine whether this measure adds value over and above simple report of early adversity when it comes to predicting important outcomes, such as response to treatment or suicide.
Opening the human epigenome
The finding by Perroud et al also provides the proof of principle that molecular measures in the peripheral blood can be used to index epigenetic modifications relevant to mental illness and other brain disorders. This was not necessarily expected, since many epigenetic modifications are tissue-specific. Indeed, the promoter examined in the rat model and the human studies specifically regulates the expression of glucocorticoid receptor in neurons. It is likely that this modification has no functional role in blood cells, even if it is detectable there. Alongside research suggesting that specific types of epigenetic modifications correspond across the brain, blood and saliva,Reference Davies, Volta, Pidsley, Lunnon, Dixit and Lovestone8 these findings open the field for exploring the whole epi-genome in large human samples. Although the findings regarding the NR3C1 gene are exciting, it is likely that other useful information is hidden in the epigenetic modifications of genes that have yet to be explored. The concordant signal from epigenetic modification of the glucocorticoid receptor gene promoter in blood and brain in rodents and humans is proof of a principle that opens the door to large-scale epigenetic research. Future studies will show whether the glucocorticoid receptor research provided the first example of a successful strategy leading to further replicable findings.
Epigenetic strategy to understanding gene-environment interactions
The links between early environment and epigenetic modifications may also suggest a mechanism underlying gene-environment interactions.Reference Uher3 Early environmental adversity is not a sufficient cause of mental illness, since many individuals with a history of severe childhood maltreatment or trauma remain healthy.Reference Collishaw, Pickles, Messer, Rutter, Shearer and Maughan9 It is increasingly becoming evident that inherited differences in specific genes may moderate the effects of adversity and determine who is sensitive and who is resilient through a gene-environment interplay.Reference Rutter, Moffitt and Caspi10 The glucocorticoid receptor coding the NR3C1 gene may be among the genes that moderate the effects of childhood adversity on mental health and illness.Reference Bet, Penninx, Bochdanovits, Uitterlinden and Beekman11 Other genes where variations may influence the long-term impact of early adverse experiences include the brain-derived neurotrophic factor gene (BDNF), the serotonin transporter gene (SLC6A4) and a gene coding a glucocorticoid receptor co-chaperone (FKBP5).Reference Aguilera, Arias, Wichers, Barrantes-Vidal, Moya and Villa12-Reference Uher, Caspi, Houts, Sugden, Williams and Poulton15 Remarkably, in all of these genes, epigenetic DNA modifications have been identified that may underlie the long-lasting effects of environment on biological functions.Reference Klengel, Mehta, Anacker, Rex-Haffner, Pruessner and Pariante14,Reference Koenen, Uddin, Chang, Aiello, Wildman and Goldmann16,Reference Roth, Lubin, Funk and Sweatt17 This epigenetic research is pointing to a new research strategy where epigenetic marks detectable in peripheral blood can help identify the genes that influence sensitivity to environment and uncover the mechanisms underlying gene-environment interactions. The value of such a research strategy will depend on the replicability of its findings. The next decade of research will show whether this potential can be exploited in the development of new therapeutic options that may alter the traces that early environment leaves on the genome.
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