Obsessive-Compulsive Disorder: An Analysis of Genetic and Biological Pathologies
This paper compiles and analyzes a series of published articles discussing some of the genetic and physiological principles of obsessive-compulsive disorder (OCD), as well as provides insight into potential future investigations for furthering understanding of the underlying mechanisms of the disorder’s pathology. The paper discusses the lack of support for environmental factors contributing to the prevalence of OCD (Grisham et al., 2012), some of the genes under investigation as risk factors (Meira-Lima et al., 2004; Bienvenu et al., 2008; Zike et al., 2017), and details potential for future experimentation to understand pathological changes in neurotransmission using electrophysiological techniques such as fast-scan cyclic voltammetry (Wood and Hashemi, 2013).
Obsessive-compulsive disorder (OCD) is a generalized disorder classified by the presence of two key classifications of symptoms. As defined by the DSM-5, OCD is the concurrence of obsessions and compulsions (American Psychiatric Association, 2013). Obsessions are defined as prevailing thoughts and images that are regarded as abnormal and unwanted, whereas compulsions are the physical, repetitive behaviors that a person acts upon. In popular culture, some of the most common portrayals of OCD display the compulsive habits of excessive handwashing, repetitive opening and closing of doors, or the act of turning lights on and off a specific number of times (Leckman et al., 2010). However, without the presence of obsessive thoughts most of these behaviors would be categorized into a series of related compulsive disorders. Estimates dating back to the early 2000’s place the prevalence of OCD between 1-4 percent of the U.S. population, with a typical age of onset being in the mid-teens (Kessler et al., 2005). Gender has also been shown to impact the onset of OCD, as males typically display symptoms at a younger age and more commonly present symptoms of a tic disorder comorbidity (Monzani et al., 2014).
Once diagnosed, the typical course of treatment is the use of Selective Serotonin Reuptake Inhibitors, which has been shown to aid in symptom remission with varying degrees of success (Fineberg et al., 2007). Estimates put citalopram treatments at about 50 percent effectiveness, but with the lack of more effective treatments this remains the first course of action. As a largely prevalent disorder, the discerning of causes for the disorder is difficult, making the opportunity for generalized treatments difficult (Bruno et al., 2012). Throughout the literature, there have been many proposed genetic causes, biological mechanisms, and treatments proposed to work based on these collected theories with limited degrees of success.
A large number of nongenetic causes have been explored for their relation to the development of OCD. These causes are difficult to measure as determining all the environmental factors that may play a role in disease pathogenesis requires a scrutinizing longitudinal study that accounts for all potential causes. As such, only cases of abuse or extreme trauma have been confirmed as risk factors for OCD (Benedetta et al., 2014). Temporary cases of OCD, while uncommon, have been connected to autoimmune reactions as well as bacterial infections (Swedo et al., 2004). Cultural and societal factors have been found to impact neither the prevalence nor the characteristics of OCD, which further detracts from the impact environmental factors may have (Grisham et al., 2012). Therefore, these factors only account for a small percent of cases and leave the question of how other cases of OCD originate (Lewis-Fernandez et al., 2010).
As a general rule of thumb, pathological studies attempt to define diseases in the simplest terms possible. In the case of many well studied and understood diseases that classify under Mendelian genetics, that is a disease or disorder that stems entirely from gene mutations or polymorphisms, can be defined in terms of dominance and heritability and can be directly related as a causative or a contributor to risk. Unfortunately, most diseases and disorders can be attributed to more than genetics, and this multifactorial nature of pathologies makes predicting disease challenging (Monzani et al., 2014). OCD classifies under this category as several environmental factors have been implicated as risk factors. Several studies have concluded that there is a familial link in OCD risk, which suggests genetics also play a role in OCD risk. Some of the most compelling evidence comes from a study that concluded that direct family members of a person with a childhood onset of OCD are ten times more likely to develop OCD (Pauls, 2010). To date, many small-scale studies of various ethnic groups have been conducted for genetic analysis of genes falling into several classes. The first class is genes implicated in serotonin regulation, the second incorporates genes that regulate glutamate neurotransmission, and the third category is an encompassing category that involves genes discovered through linkage studies with other diseases.
The first class of genes proposed to be involved in OCD pathogenesis, serotonin regulators, is perhaps the most promising. Seeing as citalopram treatments have some degree of effectiveness for OCD management, the first suspicion falls on serotonin regulation (Fineberg et al., 2007). In previous studies, monoamine oxidases, serotonin transporter genes, and a variety of supporting genes have been investigated for a relationship with OCD. The champion candidates under this category are currently SLC6A4 and HTR2A (Meira-Lima et al., 2004). SLC6A4 is a gene coding for a solute carrier protein that is part of a group of transporters with a high affinity for serotonin, while HTR2A codes for a serotonin specific receptor protein. Specific polymorphisms in the solute carrier have been tied to OCD with varying degrees of certainty, and it is most likely that these discrepancies are linked to ethnic and gender differences within the study populations (Sinopoli et al., 2017). The HTR2A gene has also had varying degrees of success in its implication, but studies are still hopeful. The importance of noting these genes as candidates is the concept of differential expression. As many of the symptoms of OCD can be tied to the frontal lobe and striatum, if elevated expression of these genes can be proven in future studies, there would be evidence supporting these polymorphisms as risk alleles. Currently there are several existing mouse models that may work for in vivo studies (Wang et al., 2009). Use of immunostaining techniques can identify areas of high expression for these genes to corroborate this theory, while other techniques such as fluorescence assays can further test these claims.
Various other serotonin regulators have been tested for association but have been disproven as risk genes for OCD (Pauls, 2010). Many of the genetic studies on OCD have attempted to propose novel mutations and single nucleotide polymorphisms (SNPs) as well as epigenetic alterations that may lead to onset. Research by Grünblatt et al. (2018) found that changes in methylation of the SLC6A4 gene may contribute to gene silencing that triggers the onset of OCD. While the statistical significance for their study was not ideal, their preliminary study shows promise for exploring biochemical alterations to gene expression as a pathological mechanism.
The proposed mechanism of glutamate regulation alterations shows another set of promising genetic findings in recent studies. As glutamate is a more difficult neurotransmitter to study, less about its operating mechanisms are known. However, the SLC1A1 gene has been largely implicated by several studies in OCD risk (Wu et al., 2012). As another solute carrier similar to SLC6A4, the gene codes for a protein that acts as a highly effective glutamate transporter. Researchers in Korea have reported a strong correlation of SNPs in SLC1A1 with OCD (Kim et al., 2018). Differing reports have challenged this conclusion and a great deal of conclusive research is still needed before these (Abdolhosseinzadeh et al., 2018). Again, tracking expression of this gene within the brain can greatly improve upon our understanding of the disorder’s mechanisms and may expand upon our understanding of glutamate as a neurotransmitter. Other genes important in glutamate regulation have been observed for ties to OCD, including the glutamate receptor gene GRIA1, which is theorized to interact with variants of serotonin regulation to create a complex series of mechanisms by which OCD arises (Ortiz et al., 2016).
Further studies of glutamate signaling have introduced novel genes that have strong implications in OCD pathology. The most conclusive study focused on the SAPAP3 gene, which is part of a group of proteins in the postsynaptic density of the dendrite that forms the functional scaffolding for glutamate reception (Bienvenu et al., 2008). In this study, four separate SNPs within the gene showed a positive association with OCD. Through genome analysis, this specific gene was tied to excessive grooming in humans, which solidified the argument for the importance of glutamate in OCD. The most important finding of the research, however, is that these specific SNPs can be targeted for treatment by the drug fluoxetine. While the authors acknowledged that these findings are preliminary and need further verification from future studies, they provided one of the few conclusive reports on a genetic cause of OCD and other grooming disorders. More research by Zike et al. (2017) has provided further insight on the glutamatergic mechanisms of OCD pathology by showing that a loss of SLC1A1 function leads to changes in basal ganglia function. Several repetitive behaviors have previously been linked to changes in the basal ganglia, which supports the claims by the authors that the gene can be implicated in OCD pathology.
The last category that researchers have taken an interest in is genes that could be cross-linked between OCD and its common comorbidities. As roughly 30 percent of people with OCD have some form of tic disorder, Tourette Syndrome is a common disorder studied alongside OCD (Grados, 2010). Many of the genes previously discussed, including SLC1A1, HTR2A, and monoamine oxidase genes, have been observed in these cross-linkage analyses. A variety of other genes that play roles in glutamate and serotonin signaling have also been observed, including other solute carrier, receptor, and supporting genes (Yu et al., 2015). While most of these genes have only been seen as having a modest association between the two disorders, creating these links is important in establishing an understanding of the interconnectivity of the mechanisms of the brain. As serotonin is a major neurotransmitter throughout the brain, it serves as a prime starting point for linkage studies, but there are other neurotransmitters that should be investigated. Dopamine, for example, is highly tied to Tourette’s and as a neurotransmitter important in behaviors is another potential tie between the two disorders (Singer et al., 1982). Even glutamate has modest ties to Tourette’s, which has highlighted SLC1A1 as a candidate gene and suggests that a plethora of neurotransmitters are implicated in OCD (Naaijen et al., 2016). Besides Tourette’s, the implication of serotonin implicates depression’s comorbidity with OCD, and potential dopamine dysregulation could imply a modest association with schizophrenia and Parkinson’s disease. In some cases, deep brain stimulation has been shown to be an effective treatment for severe cases of OCD by targeting various regions of the brain (Alonso et al., 2015). Most notably, the subthalamic nucleus is a common region targeted for this procedure in both OCD and Parkinson’s patients. The subthalamic nucleus is heavily linked with dopaminergic cell death in Parkinson’s patients and successful reports of this treatment in OCD patients further strengthens the theory that dopamine regulation is disturbed in some types of OCD. Cross-link studies on these disorders could hold the key to furthering our understanding of many neurological disorders as well as some of the mechanisms that commonly underly them.
Autism spectrum disorders (ASD) are also currently being explored for ties with OCD. Drawing the connection between the two disorders is difficult as both are classified as spectrums, and the relatively high prevalence of the two increases the odds of a chance correlation, but in the report by Guo et al. (2017) the researchers posited a five-gene polygenic linkage between the two disorders. The most convincing allele found was for the TUBB3 gene, which is known to play an important role in axonal elongation and maturation. The validity of this study comes from the relatively large sample size used as well as a series of computational and statistical analyses to improve the significance of their findings. The authors suggest this is evidence of a stronger link between OCD and ASD than between OCD and Tourette’s, but more data is needed before this can be confirmed. Research by Samuels et al. (2007) has also yielded potential as they identified a region on chromosome 14 is associated with hoarding compulsions in familial cases of OCD. Since no specific genes were identified in this study, a great deal of investigation beyond this report is necessary to identify the genes potentially involved.
Attention deficit hyperactivity disorder (ADHD) has also been tied with OCD through the co-occurrence of hoarding behaviors with ADHD. In the meta-analysis conducted by Park et al. (2016), they concluded that there was a significant comorbidity of 29 percent between ADHD and compulsive hoarding behaviors. While they did not perform genetic analyses to find related genes, their large sample size gives compelling support for their claims. A major hindrance to this however is the fact that the connection can only be drawn between ADHD and hoarding compulsions, which are only a few examples of the behaviors someone with OCD may display. Further confirmation of their findings may clarify the relation between these behaviors and ADHD and may aid in connecting yet another mental disorder with OCD, and further illuminates the complexity of these multifactorial disorders.
Given the complexity of the nervous system, many of the proposed mechanisms for how these genes impact OCD pathology have been difficult to explore. Researchers have struggled with ways to quantify the exact changes that occur within the brain of someone with a mental disorder. Well established analytical techniques typically are highly invasive and difficult to use on human patients. As recently mentioned, the mouse models have been used to represent many different mental pathologies, including OCD (Wang et al., 2009). One of the best techniques for observing physiological changes in these models is fast-scan cyclic voltammetry, where microelectrodes are inserted into specific regions of the brain to measure real time release and reuptake of neurotransmitters (Wood and Hashemi, 2013). By using specific electric stimulations applied as waveforms, the electrodes can selectively measure specific neurotransmitters such as dopamine and serotonin. While this is most commonly used in the study of depression, the technique has potential to quantify the neurochemical changes that transpire in an OCD model. By using the established OCD mouse models, fast-scan cyclic voltammetry can be used to compare neurotransmission between the control and disease models. While this does not determine exactly where in the signaling pathway the disorder originates, it may provide hints about where to look by revealing what parts of the pathways are impacted.
Despite a broad exploration of various genetic causes and mechanisms for OCD pathogenesis, more research is needed before most of the conclusions made can be accepted as reliable and clinically useful. Most of the previously mentioned studies only present preliminary data within small sample populations, and there are many discrepancies on the statistical significance of the results between researchers. Before these findings can be implicated, conformational studies with highly replicable results must be presented and corroborated. There is potential for exploratory treatments once these findings are confirmed, including different drug treatments and gene therapies (Hirschtritt et al., 2017). It is important to note that since OCD presents in a variety of ways with a range of symptoms it is likely impossible to find an underlying cause that ties to every case. While this certainly will serve as an obstacle for finding treatments for OCD and similar disorders, it is possible that uncovering the mechanisms by which OCD develops will allow for more individualized treatments with increased efficacy.
The multifactorial nature of OCD further complicates our understanding of the onset of the disorder. The most optimistic study claims that OCD pathogenesis relies on two liability factors, but even the authors of this study acknowledge that these two factors, genetics and environment, are too general to imply that OCD is a simple disorder to understand (Monzani et al., 2014). By exploring the various neurotransmitters that may play a role in developing obsessive-compulsive disorder, we can truly appreciate the complexities and nuances of the nervous system, particularly when relating OCD to other neurological disorders such as Tourette’s and ADHD (Kessler et al., 2005). As previously mentioned, further studies must expand upon these proposed mechanisms, and solid quantification of the biochemical changes must be established before clinical treatments can be explored.
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