Borderline Personality Disorder (BPD) is thought to arise from both environmental and genetic factors. From twin studies, the concordance rate for having BPD for monozygotic twins has been found to be 35-69%[1] while the concordance rate for dizygotic twins is only 7%[2]. This indicates that there is a genetic contribution to the development of BPD. Although a causative gene has not yet been found, certain polymorphisms in several genes in the serotonergic and dopaminergic pathways have been found to be associated with having BPD. Genes that have been found in the serotonergic pathway include the serotonin transporter 5HTT[3], the Monamine Oxidase A gene MAOA[4], and the Serotonin 1A receptor HTR1A[1]. Genes that have been found in the dopaminergic pathway include the dopamine transporter DAT1[1],[5], and the dopamine receptors DRD2 and DRD4[6]. Epigenetic differences, such as the aberrant methylation of genes, have been examined as well[7]. There has additionally been some research beginning to look at genes that regulate the circadian rhythm as being implicated in patients with BPD[8]. Further research must certainly be undertaken to fully understand the genetics of BPD.
1.1 The Dopaminergic Pathway
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| The pathway of dopamine's action on brain structures in BPD, and the affected behaviours. Adapted from Friedel (2004)[9]. |
Several aspects of the dopaminergic pathway have been implicated as potentially contributing to the etiology of BPD. Since BPD patients often exhibit signs of addiction and substance abuse, the reward aspect of the dopaminergic system is thought to be involved[5]. The impulsivity and the abnormal cognitive and emotional processing exhibited by many BPD patients are also thought to arise from abnormal dopaminergic activity, since dopamine affects one’s emotional responses to positive and negative occurrences[1], [9]. Some genes in the dopaminergic pathway that have been studied for their potential association with BPD include DAT1, DRD2, and DRD4. Having the CC variant of the single nucleotide polymorphism (SNP) -616G/C in the promoter of the D4 dopamine receptor gene DRD4 was found to be a risk factor for BPD[6]. Variations in the dopamine 2 receptor gene DRD2 were found to be associated with the impulsive self-harming behaviours exhibited by BPD patients[6]. The TaqIA and TaqIB SNPs of DRD2 were found to be associated with having BPD[6].
1.1a Dopamine Transporter (DAT1)
| Figure 2 |
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| Here shown is the relationship between the probability of having BPD when considering the factors of having a history of childhood abuse, presenting with a borderline temperament, and having the 9-repeat VNTR polymorphism in the DAT1 gene. Black bars represent patients that have the 9-repeat of the VNTR. White bars represent patients that do not have the 9-repeat VNTR. Adapted from Joyce et al. (2006)[5]. |
The DAT1 gene encodes a Na+/Cl- -dependant dopamine transporter, which is used to re-uptake dopamine from the synapse[5]. Mice that are knockouts for the DAT1 gene have been shown to exhibit abnormal social interactions. Additionally, DAT1 dopamine transporter density has been found to be diminished in animal models that have been exposed to prolonged stress[5]. Both stress and abnormal social interactions are associated with human BPD.
Within the DAT1 gene, there is a variable number of tandem repeats (VNTR) in the untranslated region that varies from 3-12 repeats. By comparing BPD patients to depressed controls, it was found that having the 9-repeat allele of DAT1 was associated with having BPD[5]. The association was still significant after taking into account other contributing factors (e.g., having a history of childhood abuse) when statistical analyses were performed (Figure 2)[5]. Interestingly, it was also found that the 9-repeat allele was more highly associated with having BPD in older patients. This suggests that 9-repeat VNTR may contribute to the form of BPD that lasts into adulthood, but not to the more common youth form of the disorder[5].
1.2 The Serotonergic Pathway
Several aspects of the serotonergic pathway have also been implicated as potentially contributing to the etiology of BPD. In particular, the serotonergic pathway is likely involved in the suicide-ideation, aggression, impulsivity, and emotional lability exhibited by BPD patients[1]. In addition, the depressive symptoms of BPD are frequently treated with selective serotonin re-uptake inhibitors[1]. Most genes that have been studied for association with BPD are genes that are part of the serotonergic pathway[6], including 5-HTT, MAOA, and HTR1A.
1.2a Serotonin Transporter 5-HTT
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| Here shown is a comparison of the S and L polymorphisms of the 5-HTT gene promoter region. The S allele is shown to make less mRNA, leading to fewer serotonin receptors to re-uptake serotonin from the synapse. Adapted from Shiroma, Geda & Mrazek (2010)[10]. |
The 5-HTT gene encodes a serotonin transporter. The association between BPD and the 5-HTT gene was tested in Toronto using patients with BPD and controls[3]. From participants’ DNA samples, researchers examined the 3 alleles of the 5HTTLPR polymorphic region of the gene: long A (LA), short (S), and long G (LG). People who have the LA allele have been found to also have more 5-HTT mRNA, and therefore more serotonin transporters being made in their brains (Figure 3)[3]. Additionally, 3 alleles of the VNTR in intron 2 of the gene (9, 10 or 12 repeats) were examined. A significant association between BPD and 5-HTT was found: when studying this VNTR region alone, BPD patients were found to have a higher frequency of the 10 repeat VNTR and a lower frequency of the 12 repeat VNTR in intron 2 of the 5-HTT gene relative to controls[3]. However, there were not found to be significant differences between the BPD and controls with regards to the 5HTTLPR gene variants alone[3]. Considering these 2 polymorphisms as haplotypes, the researchers were able to conclude that BPD patients were more likely to have the S-10 haplotype than the LA-12 haplotype. This suggests a possible combined effect of the two polymorphisms together on the functioning of the 5-HTT serotonin transporter and BPD symptoms[3].
Animal models have shown that there are likely gene-environment interactions involving the 5-HTT gene. It was found that monkeys with the S allele of 5-HTT that were separated from their mothers were found to be at an increased risk for developing BPD-like symptoms[2].
1.2b Monoamine Oxidase A (MAOA)
The function of the enzyme monoamine oxidase A (MAOA) is to degrade serotonin and other monoamines, and has also been associated with Major Depressive Disorder. Additionally, variation in the MAOA gene has been linked to impulsive behaviour[4]. MAOA is known to have several alleles: 2, 3, 3.5, 4, or 5 VNTRs in the promoter region of exon 8 of the gene[4]. The 3.5 and 4 VNTRs have been found to allow high transcriptional activity for the gene while the 2, 3, and 5 VNTRs have been found to provide lower transcriptional activity. The high activity allele contributes to a higher activity level of the MAOA enzyme, which then results in more serotonin being broken down and an overall decreased level of serotonin in the brain[4]. The MAOA gene has been examined in patients with BPD compared to controls. A statistically significant difference was found between MAOA VNTR allele frequencies in BPD patients and controls. It was found that, compared to controls, BPD patients were significantly more likely to have one of the high activity VNTR alleles, and were significantly less likely to have one of the low activity VNTR alleles[4]. Therefore, having the high activity MAOA allele might be a genetic risk factor for developing BPD.
1.3 An Interaction Between DAT1 and HTR1A Genes
Many studies have previously looked at the implications of different genes in either the dopaminergic or serotonergic pathways in the etiology of BPD. In addition, researchers have begun to study the potential interaction of genes from both neurotransmitter pathways. One study has focused on the dopamine transporter (DAT1) and the serotonin 1 A receptor (HTR1A)[1]. The serotonin 1A receptors are auto-receptors that work by decreasing the firing rate of serotonergic neurons from the raphe nucleus and altering neuronal firing patterns in the amygdala and other brain structures[11]. There have been several previous studies focussing on the HTR1A gene alone, and the results are inconclusive about its significance in the etiology of BPD[1]. It was found in one study that the single nucleotide polymorphism (SNP) of C1019G of the promoter region of HTR1A was correlated with a significantly smaller amygdala size in BPD patients. Having a G allele rather than the C,C genotype may alter the HTR1A gene’s functioning, decreasing the amount of serotonin that reaches the amygdala and contributing to its smaller size [11].
In a recent study, no significant differences were found between BPD patients and depressed controls when analyzing the alleles of HTR1A alone. However, the HTR1A allele contributed significant differences when studied for interaction with DAT1 gene alleles[1]. By comparing all the allelic combinations of the genotypes for the HRT1A gene (G,G, G,C or C,C) and the 9 or 10 VNTR polymorphism of DAT1 (9,9, 9,10 or 10,10), it was found that that the highest risk for having BPD was being homozygous G,G for the HTR1A gene, and having either the 9,9 or 9,10 DAT1 alleles[1]. It was also found that the highest risk for having BPD was being heterozygous C,G for the HTR1A gene, and being homozygous 10,10 for the DAT1 gene VNTR. In this study, for those that had the 9,9 DAT1, having a G allele of HTR1A was found to significantly increase the likelihood of having BPD[1]. Overall, it was highlighted that genes in the dopaminergic and serotonergic systems of the brain do not function independently in the etiology of BPD. Therefore, there is great importance in studying genes in the dopaminergic and serotonergic systems toegether[1].
2.1 Epigenetic Factors
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| The difference in methylation at CpG sites in certain neuropsychiatric genes for BPD patients compared to controls is shown here. The significance of the increase in methylation for the mean CpG sites for each gene is indicated as a p-value. Adapted from Dammann et al. (2011)[12]. |
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| The difference in methylation at CpG sites in genes for BPD patients compared to controls is shown here. The significance of the increase in methylation for the mean CpG sites for genes with multiple CpG sites is indicated as a p-value. Adapted from Teschler et al. (2013)[7]. |
Of course, epigenetic factors likely also contribute to the etiology of BPD. Researchers have examined the methylation of CpG sites in patients with BPD compared to controls. Using blood samples from BPD patients and controls and the Infinium HumanMethylation27 bead chip panel, researchers were able to target thousands of CpG sites in gene promoter regions[7]. There was found to be differential methylation of CpG sites for many genes, which were also confirmed with bisulfite pyrosequencing[7]. In one study, neuropsychiatric genes S-COMT, HTR2A, MAOA, MAOB, and NR3C1 were found to be more highly methylated in BPD patients compared to controls (Figure 4)[12]. In a further study, several other genes of interest, APBA2, APBA3, GATA4, KCNQ1, MCF2, NINJ2, and TAAR5, were also found to be more highly methylated in BPD patients (Figure 5)[7]. The increased methylation of these genes was found to lead to decreased gene expression, working by preventing the binding of transcription factors to the CpG sites in the promoter region of the genes’ mRNA. Although the current results are interesting, these findings should be replicated with a larger sample to form more conclusive results[7]. The epigenetic changes found in BPD patients may have arisen during childhood, as a result of neglect or trauma. This has been shown in animal models; maternal care of offspring has been found to be related to the aberrant methylation of genes in the offspring[7],[12]. Future research may focus on the relationship between childhood trauma and epigenetic changes in humans[7].
3.1 Clock Genes
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| Activity of Mammalian Circadian Rhythm Genes. Adapted from Fu & Lee (2003)[14]. |
Researchers are just beginning to study the role of endogenous clock genes (such as CLOCK, PER1, PER2) in the etiology of BPD and other disorders. It has been found that BPD patients often report having sleep problems (e.g., insomnia, nightmares, dream anxiety)[8]. It was found, using a Pittsburgh Sleep Quality Index (PSQI) survey, that BPD patients rate themselves as having poor sleep quality and duration, as well as having poor daytime functioning[13]. It was also found that patients with increasingly severe BPD symptoms had increasingly worse sleep problems[13]. These sleep problems may contribute to the problems with emotional regulation that BPD patients frequently experience.
Additionally, BPD patients often report staying up late and sleeping a lot during the day, suggesting that they may be experiencing abnormal circadian rhythms. Irregular circadian rhythms may be the result of irregularities in clock genes[8]. BPD patients have also been found to have higher cortisol levels than controls. The circadian clock is also important for determining cortisol release rhythms, so irregularities in clock genes may lead to the abnormal cortisol release levels[8].
Researchers have started studying these clock genes by running molecular and endocrine assays for circadian markers such as cortisol, and performing EEG studies on patients to measure their sleep patterns. Further research will likely examine associations between gene polymorphisms in clock genes and BPD[8].
I like the inclusion of material covered in class, such as the 5-HTT gene and MAOs, which made the technical bits easier to read through. Good job!
I think that you should incorporate links into your page as I feel that the links help in understanding the sections or words that are unfamiliar to unsuspecting individuals. Other than that, the material is thorough and the visuals are tied in very well.