Effects of Child Abuse on Child Development - Free Essay Example

While it has been known for a while that there is obviously an extremely high importance of maternal care in child development. Some research now suggests that the importance of this may lie partially on its effects on anxiety-like behaviors and the regulation of the stress reaction in the hypothalamic pituitary adrenal (HPA) axis, also known as the stress response control center, which are both significantly lowered (Ramo-Fernndez et al., 2015). However, an effective opposite, child abuse, also shows may also yield negative consequences. Based on data that was collected in 2016 of children raised in the U.S. 9% experience physical abuse and another 4% experience sexual abuse, making for the understanding of its effects of high importance (US Bureau of Children data shit). Where maternal care showed gains in the individuals ability to interact with stress related mechanisms, many of the issues (behavioral, health, psychological) stem from some form of detriment in the individuals ability to cope with these mechanisms. In children experiencing child abuse we see significant increase in the likelihood that theyll experience abuse in other relationships in adulthood, whether they be platonic or intimate relationships. Psychological disorders such as depression, post traumatic stress disorder, suicidality, anxiety not only are experienced at increased rates, but also severity within the population of children experiencing child abuse (Ehlert U. 2013). Additionally, physical health is something that comes into play with th ings such as cardiovascular disease or infections (Norman, et al., 2012). As result of having this many conditions that are interacting with stress mechanisms funding for research focuses on the how these stress reactions are influenced by varying polymorphisms in the genome. While there are many genes that seem to interact in epistatic and pleiotropic ways with stress regulation systems, I will be doing a parallel comparison of two genes: FKBP5 and NR3K1. The FKBP5 gene goes through transcription and translation to form the FK506 binding protein 51. Although the protein gene relationship was only discovered in 1990, many developments in the understanding of the function of this gene have occured (Sanchez, 1990). In the FKBP5 proteins normal function, it intimately interacts with multiple receptors, but the glucocorticoid receptor is of most relevance to us because it is responsible for upregulation of anti-inflammatory proteins and downregulation of proinflammatory proteins (Menke, et al., 2013). The interaction with proteins is important because many forms of issues that correlate with child abuse seem overlap when there is displacement from these proteins normal expression. The FKBP5 gene is activated to down regulate the expression the glucocorticoid receptor in what is known as a negative feedback loop, which when bound to the glucocorticoid receptor prevents its interaction with glucocorticoids like cortisol (Binder, 2009). Altho ugh the FKBP5 protein has several single nucleotide polymorphisms (SNPs) that could interact with the expression of the glucocorticoid receptor because of potential changes proteins ability to appropriately function; some SNPs that are tested in many forms rs4713902, rs3800373, rs1360780, rs9470080, rs9296158 and rs3777747 (Collip, et al., 2013; Green, et al., 2015). Polymorphisms and Genotypes of FKBP5 Related to Depression Treatment Before the effects of child abuse on this gene and its effects on behavior can be appropriately determined, it is first important to determine what polymorphisms, if any are attributed to varying regulation of the glucocorticoid receptor. Binder et al. (2004) began the sifting of SNPs by looking for sufficient responsiveness of SNPs of depressed individuals to antidepressant treatment, a selective serotonin reuptake inhibitor, and rates of remission beyond points of experimental influence. After an additional initial screening of the FKBP5 gene, consisting of the promoter region and exons, 57 SNPs were used to for analysis, including nine newly discovered genes. Using the Hamilton Depression Rating Scale to evaluate the 233 participants, a noteworthy response to the antidepressants and remission was observed in SNPs rs1360780, rs1334894 and rs755658. However, a replication of the analysis of SNPs was conducted to control for a large portion of the gene that was encompassed by a gene linkage band that was found to go 288 kb from the 5 exterior of the gene. The replication resulted in the three polymorphisms, rs4713916, rs1360780 and rs3800373, ultimately were found to have the strongest, sufficient correlation, which are located putative promoter region, intron 2 and 3 untranslated region respectively of the FKBP5 gene. Based on the three SNPs falling into FKBP5 range the study was able to conclude that the substantial association of the responses to treatment was, in fact a result of the FKBP5 gene and not adjacent linked genes. Following the confirmation of these SNPs as notable contributors to treatment reactivity, Binder et al. (2004) then looked to discern whether there was variance in the genotypic expression within any of these polymorphisms. Given the sample of the participants from Bavarian psychiatric hospitals, the only polymorphisms that showed notable expression in the population was the rs1360780. A correlative analysis was then conducted on each of the genotypic expressions of the rs1360780, TT, TC and CC (assuming standard nucleotide pairing). The analysis showed an indicative proportion of the individuals within the rs1360780 polymorphism that experience effects from the antidepressant treatment and remission were those of the homozygous TT genotype. Additionally over the course of their lifetime each individual had more than double the likelihood of experiencing depressive episodes. As a result of the positive results for the varying experiences of those of different genotypes of the rs1360780 SNP, the researchers hypothesized an altered phenotypic expression would be measurable in lymphocytes and plasma cortisol levels. Their hypothesis was accurate on lymphocyte expression with FKBP5 levels being nearly two times the expression in TT versus TC or CC genotypes. However, cortisol levels in the rs1360780 polymorphism found no significant distinguishable representation of plasma cortisol levels. The researchers explain these results by suggesting that these changes in expression may have lead to increased sensitivity of the glucocorticoid receptor due to structure variation in the heterocomplex that interacts with the FKBP5 protein. In later literature it is described that the genotype homologous TT, actually forms a TATA Box complex which is known for its enhancement of the transcription on the rs1360780 polymorphism. It is described that this upregulation could also result in the increased sensitivity that was described here (Klengel et al., 2012). FKBP5 Polymorphisms and Genotypes Related to Child Abuse Following an in depth analysis of the different polymorphisms of the FKBP5 gene that are relatively involved in the regulation of some depressive effects without considering experience; now it is important to consider how these different may polymorphisms may act in conjunction with childhood abuse. Binder et al. (2008) using 900 non-psychiatric clinic patients with significant levels of child abuse and non-child abuse trauma. The level of trauma was determined in individuals by cross-section analysis of the individuals scores using the traumatic events inventory assessment, which importantly describes the majority of non-child abuse trauma occurring in adulthood, and Childhood Trauma Questionnaire. This study functionally placed participants into 3 levels for both groups described: none (verbal abusive), 1 type (physical or sexual abuse) and 2 type (physical and sexual abuse). This data was regressionally analyzed to rates of PTSD found in participants that was determined using the PTSD symptom scale (PSS). Lastly and most importantly these individuals were placed categorically based on SNPs expression. These polymorphisms including the three functionally correlated with responsiveness and remission in the previous study (rs4713916, rs1360780, and rs3800373) and five others that spanned a 120 kb range within the FKBP5 gene. The Binder et al (2008) study then does a series of cross-sectional analyses to enlighten the relationships between many of these interplaying factors. Firstly, the comparisons of the non-child abuse and child abuse traumas with the PTSD itself. Non-child abuse and PTSD showed a 5 fold increase when comparing the PSS scores from the individuals that experience the low to high levels of trauma. While the child abuse didnt experience as dramatic an increase in PSS, the scores were significantly higher for each one of the levels. Additionally, the researchers found that when the type 1 and type 2 levels of child abuse and non-child abuse were paired together PSS substantially increased in terms of non-child abuse. This suggests that PTSD symptoms may effectively increase after experience of non-child abuse as a result of having experienced child abuse prior. Immediately this raises the question of whether the functional ability of how that form is changed as result of having childhood abuse. Now the case study looked to investigate the relationship between FKBP5 SNPs and PTSD, including whether child abuse or non-child abuse traumas were mediating factors that could be used as potential predictors of that relationship. Using -log10 to determine main genetic effect, there appeared to be no simple correlation between the FKBP5 polymorphism and PTSD experience within the non-child abuse group. However, in the child abuse trauma group there were three different polymorphisms that showed noteworthy PTSD outcome interaction. Two polymorphisms that were demonstrated in the previous study to show an interaction with depression, rs3800373 and rs1360780, and the third and most crucial rs9296158 found in intron 5, all showed an interrelation with PTSD. These polymorphisms specifically resulted in an additive effect suggesting theyre expression or interaction with the glucocorticoid receptor is directly influenced by trauma experienced in early child development. Additionally, when each of these three polymorphisms were tested for variances in expression based on genotype. Binder et al. (2008) conducted an analysis across the separate genotypes in relation to levels of child trauma for PSS. Each mean PSS increased by a factor of approximately four for the most significant genotypes, although these genotypes were only different from others within the SNP when they were at the highest level of child abuse. This suggests that these genotypically distinguishable polymorphisms may experience a form of stress threshold for early developing children that can lead to proportionally higher PTSD outcomes in adult life. Child Abuse Level Relationship with FKBP5 Methylation To this point there is significant evidence that is connecting the levels of child abuse with multiple polymorphisms that vary in their effects genotypically with stress related disorders; however, as was implied in the last case there seems to be mechanism by which the FKBP5 gene or expression of it that is altered seemingly indefinitely after child abuse trauma experiences. Klengel et al. (2012) is a continuation of the last study through the same lab and looks to determine, whether epigenetic methylation effects on the polymorphisms that have been relevant towards present research could be due to childhood trauma. Since this is a continuation of the previous article, the same forms of collecting participant samples, genotyping and data analysis were conducted. Although, to appropriately to determine methylation of the genome the DNA was bisulfite treated and had pyrosequencing performed. The researchers predicted that child abuse events would lead to demethylation occurring at glucocorticoid response elements (GREs), sequences that directly mediate interaction with the glucocorticoid receptors, in the FKBP5 gene with a high risk genotype. First, the researchers determined by using the Illumina OmniExpress database determined that of the polymorphisms that had already been previously associated that with child abuse effects in PTSD that the rs1360780 was most closely integrated with GREs and was contained in a methylation tagging bin of 192 kb long. Following the determination of the highest risk polymorphism rs1360780, a direct comparison between amount of methylation on the FKBP5 gene GREs of the rs1360780 with both physical and sexual abuse were compared to the individuals that had experienced no form of child abuse. The pyrosequencing showed that of the participants that experienced the high degree of child abuse that the FKBP5 gene GRE demethylation occurred in notably high amounts (5%) on the GREs found in the promoter regions as well as introns 2 and 7. Although when genotypic interaction was assessed with each of the demethylated regions, the researchers found that only the demethylation found in intron 7 was also correlated with the highest risk homozygous alleles and heterozygous risk allele carrier. Determining this correlation, emphasizes the effects of early trauma severity on FKBP5 demethylation in risk allele carriers, but not in protective genotype carriers (Klengel et al. 2012). Klengel et al. (2012) then went on to determine whether the demethylation effects were correlated with the childhood trauma questionnaire scores. They found that not only was there correlation with the individuals that had experienced the highest forms of trauma, but also that there was individual correlations with each categorized form of trauma (physical, emotional, and sexual). Although, the effect size, or the mean total demethylation that occured, of the demethylation events were significant smaller than the individuals that had experience multiple forms of trauma. The researchers concluded as result that demethylation of these portions of the genome was proportional to the amount of childhood trauma experienced. Up to this point in the case study, these researchers have been using DNA samples from peripheral blood cells and wanted to determine whether the methylation effects were transferable to neuronal cells. Dexamethasone, demethylation inducing chemical, was used to treat hippocampal progenitor cells found a considerable overlap in portions of the FKBP5 gene demethylation. The demethylation occurred in all introns as a well as the promoter region. It then suggests that there may strong overlap in how these FKBP5 proteins are expressed as a result of child abuse in cells in the brain and not only the those residing in the blood. Methylation of FKBP5 Relationship with Mental Health Disorders It was determined that the FKBP5 gene is a target of demethylation as a result of a child abuse leading to an overall change in its expression based having polymorphisms of particular high risk. The last thing to discern is whether there are statistical merits for whether the demethylation process contributes to some form of mental health disorder. Bustamante et al. (2018) focus on the methylation correlation with major depressive disorder and hypothesized that many of the methylation events that were present in promoter, intron 7 and 2 would be important in determining the depression. 184 participants recruited for this study were selected based on availability of blood sampling for performing the same pyrosequencing that was conducted for the previous study. As it seems to be most consistently representative of the polymorphisms for interacting with child abuse, the rs1360780 was selected to be the mediating methylated gene. The first problem that occurs in this instance is that when the study went to confirm some of the previous percent methylation correlations with level of child abuse from previous studies, Bustamante et al. (2018) found that while the methylation was still different, the methylation was much higher in the high child abuse participants than was expected. In the promoter region, intron 2 and intron 7 the methylation percentages compared to the levels of child abuse in the participants were all much higher than would have been anticipated based on the results of the previous study. Although, there still was present the general association between child abuse level and depression symptom severity (DSS), as well as the genotypic expression of the rs1360780 varying the DSS. While technically the percentages of methylation did see a notable shift between levels of abuse, it potentially brings to question the overall understanding of what controls the base levels of methylation observable w ithin the genome. When the case study followed up these initial analyses with determining if there the methylation percentages acted as significant mediator towards the childhood trauma and the DSS they conducted a regression analysis for each of the GRE linked regions, promoter, intron 2 and intron 7. While of these GRE linked regions were predetermined to have significant correlation with child abuse level, none of these regions were predictors of DSS. The researchers suggest that because of a less significant difference between the mean total methylation percentages that there was far more overlap in data points. Ultimately, the researchers concluded that based on data represented in their research that there was no significant correlation, between methylation and gene expression. Conclusion Based on the evidence provided from a number of resources there is a significant overlap between the FKBP5 gene and a number of health disorders. While PTSD and and major depressive disorder were of the most relevance in this paper, things like suicidality also have a notable increase based on the polymorphic expression of this glucocorticoid receptor mediating gene (Roy et al. 2010). Not only are these genes correlated polymorphically to whether these disorders may be developed in an individual, but based on what was discussed it is also noteworthy, that this gene can actually vary a persons ability to appropriate react to treatment. And even further can FKBP5 polymorphism rs1360780 actually regulates this on the genotypic level of its expression (Binder et al, 2004).