Potential Genetic Factors of DID

DID is a type of mental disorder characterized by enduring at least two different identities and suffering from memory lost due to switching between identities [1]. No gene has been suggested to own a direct link with DID throughout the literature. The genetic factor is not the only thing that remains unclear about this disorder, so does its diagnosis. In most cases, patients with borderline personality disorder are also diagnosed with DID. Although no evidence shows that genes causing BPD will cause DID as well, these genes may become candidate genes for DID in the future. This part of the Neurowiki will introduce three genes - SLC6A4, monoamine oxidase A (MAO) and tryptophan hydroxylase 1 (TPH1), and their connections with mental disorders based on literature [2]. Instead of relating single genes to disease condition recent studies started to attribute disease condition to complex forms of mechanism which include gene-gene interaction and gene-environment interaction. Two examples from serotonin system will be given to help our understanding of these mechanisms.

1.1 Co-ocurrence of Dissociative Identity Disorder and Borderline Personality Disorder

Epidemiology and Comorbidity of DID

1.2 Genes Related to Mental Disorder

1.2a SLC6A4

SLC6A4
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Serotonin transporter showing the 5HTTLPR region and the positions of several SNPs
Source: Heils and Lesch et al, 1996.

Serotonin transporter gene (SLC6A4) has two polymorphisms. The variant site that locates in the promoter region of SLC6A4 is known as 5-HTTLPR. The length of the smallest repeat unit is 22 base pair for both long allele and short allele. However, long allele contains 16 repeat copies, which is 4 copies more than the short allele. Previous studies have shown that the short allele of SLC6A4 can cause inadequate gene transcription, which in turn decreases the reuptake rate of serotonin by pre-synaptic neuron [3]. Such deficit of serotonin system has been suggested to own a relationship with affective disorders and emotional dysfunction [4]. Before 2011, most studies of BPD were done on adults and none has done on children and adolescents, so Hankin and his colleagues started their research on youth and published an article in 2011. This study team used multiple informants approach, in which both children and their parents were asked to report BPD traits related to the children. Using multiple informants approach decreased the bias generated from self-esteem and increased the reliability of the study. Results confirmed the hypothesis that short allele is associated with many BPD symptoms in youth. Higher levels of BPD traits were observed at youth carrying one or two copies of short allele. Their study suggested relationships between 5-HTTLPR and some BPD traits including stress reactivity and emotional dysfunction, but they failed to find relations with depressive symptoms that usually co-occur with BPD [3].

Another study found that women carrying two short alleles had more obsessive-compulsive behaviors and higher levels of anxiety, so the conclusion is that ss homogeneous women are more susceptible to BPD compared to those carrying one or none short allele of SLC6A4 gene [4]. However, other co-occurring symptoms such as self-injury actions or suicidal attempts do not show significant differences between women carrying two long alleles and ss homogenous women [4]. Moreover, studies showed that 5-HTTLPR is associated with dysfunction of amygdala and increased cortisol production under stress observed at adult BPD patients [3].

Recently, a polymorphism of long allele of SLC6A4 gene has been described in the literature. There are two forms of long allele- lA and lG. lG functions at a similar way as the short allele in serotonin expression; while actually lA is the long allele that has been described in most studies.

One possible explanation of inconsistent findings reported by previous studies is that researchers do not distinguish lG from lA due to the lack of knowledge. They may include lG individuals into the long allele category, while in fact lG is more resemble to the short allele [5][6]. In conclusion, most studies about BPD agree that 5-HTTLPR is associated with some specific BPD traits, but whether 5-HTTLPR is linked to increased OCD behaviors and suicidal attempts remain controversial.

1.2b MAOA

MAOA
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The degradation of serotonin by MAOA
Source: Rang HP, Dale MM and Ritter JM. Pharmacology, 4th edition.

Monoamine oxidase (MAO) is a mitochondrial enzyme that functions to degrade neurotransmitter amines. There are two types of MAO – MAOA and MAOB. We will focus on MAOA in this wiki, since it involves in the degradation of serotonin. Human MAO gene has 15 exons. In exon 8, there is a single nucleotide polymorphism (SNP) called rs6323, which is used as a polymorphic marker in many studies about MAO. The level of gene expression is determined by a variable number of tandem repeat (VNTR) in the promoter region of MAO gene. Studies showed that alleles with 3.5 or 4 copies of VNTR have the highest transcriptional rate. These alleles are referred as high activity VNTR alleles in many studies. In 2007, Ni and his colleagues published the first paper that studied the association between MAOA and BPD and reported that BPD patients had more high activity VNTR alleles than controls. In conclusion, they suggested that MAOA is a candidate etiological factor of BPD and it plays an important role in the development of BPD [7].

1.2c TPH1 and TPH2

TPH1 and TPH2 encode two isoforms of tryptophan hydroxylase. TPH2 is a rate-limiting enzyme in central nerve system affecting serotonin biosynthesis. TPH1 is expressed mainly in tissues except for the brain. The process of converting tryptophan to 5-HT by TPH1 is the rate-limiting step in serotonin metabolic pathway. There are two single nucleotide polymorphisms of TPH1; they are TPH1 A218C and A779C.Whether TPH1 SNP is associated with BDP or not has been studied by many researchers over years. A recent study concluded that TPH1 A218C is associated with BPD. However, such SNP is not a reliable predictor of impulsiveness behaviors. This study included both suicide attempters and non-attempters and compared the gene sequence of TPH1 of BPD patients and normal controls. They found that the majority of TPH1 A218C carriers are in the BPD group, which indicates that there might be an association between polymorphisms of TPH1 and BPD [8].

1.3 Inconsistent Findings

Recent studies focus on suggesting potential genetic factors associated with BPD. Although many well-designed studies have been carried out, conflict findings can be found throughout the literature. Some reported that BPD is associated with polymorphisms of SLC6A4, MAOA or TPH1 gene, while others failed to draw the conclusion. In order to deal with inconsistent findings, a study group carried out a systematic meta-analysis and published their research paper in 2013. Researchers combine data reported by some recent studies and conduct a meta-analysis to analysis the data. No direct association has been found between SNP and BPD [9]. Inconsistent findings and lack of replication are two major problems in the study of complex human diseases. Mental disorders are complex disease, which means that obtains a large sample for study is very difficult. Small sample size determines that only candidate gene approach can be used in studies. This approach is way less informative and reliable than genome wide approach, which might explain the existence of inconsistent findings. In conclusion, our understanding of mental disorders is preliminary and lack of evidence, so further researches are required and necessary.

1.4 Gene-gene Interaction and Gene-environment Interaction

Instead of relating single genes to disease condition recent studies started to attribute disease condition to complex forms of mechanism which include gene-gene interaction. Two examples of such interaction are found between serotonin 2C receptor (5-HT2C) and TPH2[10], and between 5-HTTPR short allele and low activity form of catechol-O-methyl-transferase (COMT Met158) [11]. Studies also report other interactions, such as interactions among 5-HTT, 5-HT2C and MAOA [10].

From current view of point, single gene or gene-gene interaction is not sufficient to explain the etiology of mental disorders. We also need to take consideration of environmental factors. A typical example is stress, which influences NMDA neurotransmission and alters HPA axis. NMDARs play important role in neuronal plasticity and memory formation. Studies showed that deficits on glutamate system are associated with some BPD traits including dissociation [12]. Moreover, BPD patients showed a delayed cortical recovery from psychosocial stress compared to controls [13]. All these evidences suggested that environmental factors influence the vulnerability of various mental disorders.

Bibliography
1. Ross, C. A., Ferrell, L. & Schroeder, E. Co-Occurrence of Dissociative Identity Disorder and Borderline Personality Disorder. Journal of Trauma & Dissociative 15, 79-90 (2014).
2. Reichborn-Kjennerud, T. et al. The genetic epidemiology of personality disorder. Dialogues in Clinical Neuroscience 12, 103-114 (2010).
3. Hankin, B. L., Barrocas, A. L., Jenness, J., Oppenheimer, C. W., Badanes, L. S., Abela, J. R. Z., Young, J. & Smolen, A. Association between 5-HTTLPR and borderline personality disorder traits among youth. Frontiers in psychiatry 2, 1-7 (2011).
4. Maurex, L., Zaboli, G., Ohman, A., Asberg, M. & Leopardi, R. The serotonin transporter gene polymorphism (5-HTTLPR) and affective symptoms among women diagnosed with borderline personality disorder. European Psychiatry 25, 19-25 (2010).
5. Parsey, R. V., Hastings, R. S., Oquendo, M. A., Hu, X., Goldman, D. & Huang, Y. Y. Effect of a triallelic functional polymorphism of the serotonintransporter-linked promoter region on expression of serotonin transporter in the human brain. Am J Psychiatry 163, 48–51 (2006).
6. Zalsman, G., Huang, Y. Y., Oquendo, M. A., Burke, A. K., Hu, X. Z. & Brent, D.A. Association of a triallelic serotonin transporter gene promoter region (5-HTTLPR) polymorphism with stressful life events and severity of depression. Am J Psychiatry 163, 1588–93 (2006).
7. Ni, X., Sicard, T., Bulgin, N., Bismil, R., Chan, K., McMain, S. & Kennedy, L. Monoamine oxidase A gene is associated with borderline personality disorder. Psychiatric Genetics 17, 153-157 (2007).
8. Wilson, S. T., Stanley, B., Brent, D. A., Oquendo, M. A., Huang, Y. & Mann, J. J. The tryptophan hydroxylase-1 A218C polymorphism is associated with diagnosis, but not suicidal behavior, in borderline personality disorder. Am J Med Genet B Neuropsychiatr Genet 150B, 202-208 (2009).
9. Calati, R., Gressier, F., Balestri, M. & Serretti, A. Genetic modulation of borderline personality disorder: Systematic review and meta-analysis. Journal of Psychiatric Research 47, 1275-1287 (2013).
10. Ni, X., Chan, D., Chan, K., McMain, S. & Kennedy, J. L. Serotonin genes and gene-gene interactions in borderline personality disorder in a matched case-control study. Progress in Neuro-Psychopharmacology & Biological Psychiatry 33, 128-133 (2009).
11. Tadic, A., Victor, A., Baskaya, O., Cuber, R., Hoch, J., Kouti, I., Anicker, N. J., Hoppner, W., Lieb, K. & Dahmen, N. Interaction between gene variants of the serotonin transporter promoter region (5-HTTLPR) and Cthechol O-Methyltransferase (COMT) in borderline personality disorder. American J Med Genet 150B, 487-495 (2008).
12. Grosjean, B. & Tsai, G. E. NMDA neurotransmission as a critical mediator of borderline personality disorder. J Psychiatry Neurosci 32,103–15(2007).
13. Walter, M., Bureau, J. F., Holmes, B. M., Bertha, E. A., Hollander, M. & Wheelis, J. Cortisol response to interpersonal stress in young adults with borderline personality disorder: a pilot study. Eur Psychiatry 23:201–204 (2008).

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