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Title: From early life stress to adult psychopathology: An epigenetic view from monozygotic twin based approaches
Author: Palma Gudiel, Helena
Director/Tutor: Fañanás Saura, Lourdes
Keywords: Psicopatologia
Pathological psychology
Issue Date: 15-Feb-2019
Publisher: Universitat de Barcelona
Abstract: [eng] Psychiatric disorders are highly prevalent and one of the leading causes of disease burden worldwide. Nevertheless, there are no validated biomarkers to be used for either diagnostic or prognostic purposes and their etiology remains largely unknown. Thanks to heritability studies, it has been recognized that both nature (genetics) and nurture (environment) contribute to the onset of mental disorders. Accordingly, exposure to both prenatal stress and childhood maltreatment has been reliably identified as a risk factor for a wide range of psychiatric disorders. However, not all individuals facing this kind of early environmental insults ends up developing psychopathological conditions. Thus, gene—environment (GxE) interactions have been proposed to be involved in the physiopathology of mental disorders; epigenetic mechanisms such as DNA methylation have been hypothesized to mediate these interactions. In this framework, the present dissertation aimed to disentangle the role of DNA methylation both in increasing anxious-depressive liability, and embedding the experience of severe prenatal stress, thanks to two independent samples of monozygotic twins. NR3C1 gene, encoding the glucocorticoid receptor, was selected as a candidate gene of interest due to its crucial role in the regulation of the stress response. A systematic review of the available scientific literature revealed a great interest in NR3C1 methylation, and specifically in its exon 1F, in the context of both exposure to stress and stress-related disorders, highlighting the association between exposure to early life stress and NR3C1 hypermethylation. Additionally, this revision also pointed out the lack of studies regarding other promoter regions of this gene. Thus, we explored NR3C1 exon 1D methylation near a glucocorticoid responsive element (GRE) describing its association with both (i) the familial component of anxious-depressive liability, and (ii) hippocampal connectivity within the brain emotional network. Our second candidate gene of interest was SLC6A4, encoding the serotonin transporter, which is the primary pharmacological target of the most widely prescribed antidepressants to date (SSRIs). Again, a systematic review of the literature revealed the association between SLC6A4 methylation and exposure to early life stress, further suggesting its mediator role in previously discussed GxE interactions involving a long polymorphic region of this gene (5-HTTLPR). Complementarily, we assessed SLC6A4 methylation in a CpG island shore region characterized by a sex-differential methylation pattern; specifically, women exhibit higher methylation at this region when compared to men. Remarkably, we found an association between methylation at this region and the presence of somatization symptoms, suggesting the involvement of SLC6A4 methylation in known sexual differences regarding internalizing psychopathology globally. Since epigenetic signatures can arise in a stochastic fashion, monozygotic twins were also analyzed to identify methylation outliers which could potentially contribute to anxious-depressive psychopathology. In this regard, we reported the presence of methylation outliers in genes previously involved in neuropsychiatric disorders. Finally, the role of prenatal stress in fetal DNA methylation signatures was also explored. First, a meta-analysis on maternal psychosocial stress experienced during pregnancy and newborn NR3C1 methylation exhibited the association between both variables in line with non-genetic intergenerational transmission of stress hypotheses. On the other hand, a sample of monochorionic monozygotic newborn twins exposed to several prenatal complications was epigenomically assessed with regard to an obstetric routine measure predictive of perinatal morbid risk. The latter study revealed newborns exposed to prenatal stress during the third trimester of pregnancy exhibit developmental immaturity in terms of epigenetic (DNA methylation based) age; furthermore, differential CpG-specific methylation was found in EP300 gene, a previously identified candidate gene conferring risk for schizophrenia and involved in hypoxia response. Together, these findings support the notion that DNA methylation is involved both in the embedding of early life stress exposure and the pathophysiology of several psychiatric disorders.
[spa] El objetivo de la presente tesis doctoral fue explorar la metilación del ADN tanto en genes candidatos de relevancia para la regulación del estrés y el riesgo para desarrollar depresión (NR3C1, SLC6A4) como realizar aproximaciones masivas centradas en la identificación de valores de metilación atípicos (outliers) y patrones que muestren plasticidad ante la exposición a estrés temprano. Estas aproximaciones se desarrollaron gracias al estudio de dos muestras independientes de gemelos monocigóticos; la primera, tomada de población general adulta mientras que la segunda se constituye por recién nacidos expuestos a distintos tipos de complicaciones obstétricas. Así, describimos la asociación entre la metilación en una nueva región del gen NR3C1, el exón 1D, tanto con el riesgo de padecer psicopatología ansioso-depresiva como de mostrar una menor conectividad hipocampal. De la misma forma, la metilación sexo-específica del gen SLC6A4 se asoció con una mayor presencia de sintomatología psicosomática. También se identificaron outliers de metilación en genes previamente implicados en trastornos neuropsiquiátricos. Finalmente, la exposición a estrés prenatal severo se asoció con una mayor inmadurez en términos epigenéticos y con una menor metilación en el gen EP300, previamente identificado en estudios de asociación para esquizofrenia, funcionalmente implicado en la respuesta a hipoxia. Todos estos hallazgos sugieren el rol de mecanismos epigenéticos y, más específicamente, de la metilación del ADN, en la etiopatogenia de los trastornos psiquiátricos. Además, la metilación del ADN puede ser utilizada como biomarcador de la exposición a estrés. Sin embargo, se necesitan estudios longitudinales para poder determinar tanto la causalidad como la estabilidad temporal de dichas marcas.
Appears in Collections:Tesis Doctorals - Departament - Biologia Evolutiva, Ecologia i Ciències Ambientals

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