PLOS Mental Health Conversations: A call for a more holistic understanding of Obsessive-Compulsive Disorder

In the latest edition of our ‘PLOS Mental Health Conversations’ blog we follow high school junior Benjamin J. Blitz as he takes us on his exploration of risk factors for Obsessive-Compulsive Disorder. In our recent limited blog series, ‘PLOS Mental Health Young Voices’ we described the ways in which we are trying to provide a platform for young people to shape the mental health field. This special ‘Conversations’ blog from Benjamin is another example of how we are engaging with young people and supporting them whilst they learn about, and bring their ideas and experience to, the mental health landscape.

The following text has been written by Benjamin J. Blitz. It represents this perspectives and does not necessarily represent the perspectives of PLOS or PLOS Mental Health…

Where are we in understanding the complexity of OCD?

Obsessive Compulsive Disorder (OCD), a long-lasting, usually chronic disorder in which a person has uncontrollable, recurring obsessions, is the fourth most prevalent mental health condition in the United States, with 1.2% of all U.S. adults affected and a lifetime prevalence in U.S adults of 2.3%. Although OCD is the subject of a substantial amount of research, its causation is heavily debated. The literature provides evidence, which suggests that genetic susceptibility, stressful life events, trauma, and immune-related mechanisms may contribute to OCD risk. Although these four factors may influence OCD causation disproportionately to other possible factors, OCD is not caused by a singular factor but rather by a multitude of factors and the time they occur in an individual..

OCD symptoms typically develop in childhood or young adulthood, and in relatively less frequent cases, mature adults. It  is likely underdiagnosed due to misconceptions, complexity and co-occurrence, and stigma during adolescence and adulthood. All negative perinatal events, infections, exposure to toxic pathogens, and traumatic and stressful life events (SLEs) and their associated symptoms can be worsened by behaviors linked to OCD [3]. These worsened symptoms and effects can include, but are not limited to chronic stress, sleep disruption, depression, and more.  In light of existing evidence, I propose contemporary etiological hypotheses of obsessive-compulsive disorder.

Hereditary Predisposition

Many genes have been reported as having an association with OCD, such as the low-activity allele of an enzyme involved in the degradation of dopamine, catechol-O-methyltransferase (COMT). COMT was found frequently in OCD diagnosed patients, particularly in male probands (the first to be diagnosed in their family) . In contrast to other studies that I have analyzed however,  an association between COMT and OCD was found in females rather than t in males, contradicting the previous findings. Similarly, OCD was found to be associated with monoamine oxidase A (MAO-A) in male subjects in one study, but female subjects in another. It is unclear why these differences have been recorded. Recently, there have been reported associations between OCD and the BDNF (chromosome 11p13–14) locus, glutamate (NMDA) subunit receptor gene, and the GABA type B receptor 1 (GABBR1) gene. GABBR1 was found to be over-transmitted at the A-7265G polymorphism. Authors who reviewed this evidence concluded that “OCD is a complex genetic disorder with unknown genetic and environmental bases; There are likely common genetic influences of modest effect (possibly in addition to other less common genetic factors); and many of these genetic determinants have probably not been detected using traditional linkage methodologies”.  Adding to the complex literature, evidence from family, twin, and molecular genetic studies do support a substantial heritable component to OCD. However, evidence suggests that OCD does not appear to follow a simple Mendelian inheritance pattern. Instead, susceptibility is likely influenced by numerous common variants of small effect, alongside rarer genetic variants and their interaction with environmental exposures. In short, the pathophysiology of genetic predisposition in OCD patients is complex and not always uniform, with proposed mechanisms linking genetic susceptibility to OCD including alterations in neurotransmitter signaling, synaptic function, neural circuitry, and neurodevelopment. Taken together, these findings suggest modest but heterogeneous genetic contributions, with potentially sex-specific effects – all of which require further study.

An Exploration of Epigenetics and Family

Many have explored the role of epigenetics in OCD. For instance, PH2 DNA methylation, which has been suggested to be caused by familial punishment, family functioning, and parenting styles have a correlation with prevalence and symptomatic expression. In this study, factors such as the father’s lack of emotional warmth, punishment, rejection, and overprotection, as well as the mother’s excessive interference, rejection, and favoritism, were considered when participants were tested for OCD associated chemical levels such as TPH2 (Tryptophan Hydroxylase 2), a serotonin inhibitor.

What this study found highlights the potential role of the early-life family environment in shaping epigenetic alterations in genes that may be implicated in emotional regulation, psychiatric vulnerability, and may therefore contribute to OCD vulnerability. In terms of parenting styles, compulsion severity differed significantly based on the presence or absence of the father’s punishment whilst Obsessive-Compulsive scores  were higher among those who reported the mother’s excessive interference, rejection, and favoritism . The OCD prevalence scores associated with paternal punishment (emotional warmth concealment, punishment, and rejection) were significant compared to the associations with maternal punishment scores Whilst this study is small,  it highlights a need for further investigation into the relationship between familial environment, epigenetics and OCD.

Trauma

A meta-analysis from 2025, that explored data from seven published and peer-reviewed papers attempt to answer the long-standing question of if different types of SLEs and trauma are major precipitants to OCD occurrence. The study quantified the effect size of each of the seven studies In short, the data indicated that in OCD diagnosed individuals, SLEs were significantly more common than in people who did not have a diagnosis. Indeed, this is consistent with a historical study by McKeon et al., in which it had been noted that the mean number of SLEs was noticeably higher in OCD diagnosed people. The same trend was consistently shown across all studies examined in the above meta-analysis. Of note,  SLEs occurring within one year pre-diagnosis, had a positive effect size Indeed, in a 2012 study conducted with 329 people diagnosed with OCD it was found that 60.8% had experienced at least one significant SLE preceding OCD diagnosis. It is worth noting however, that many of the studies examined as part of the above meta-analysis are over a decade old and although the data and criteria are still valid by today’s standards in many cases, our understanding as a society and the recall bias of participants may have changed and therefore the results would be very different today. Taken together, the existing evidence demonstrates a consistent association between stressful life events and OCD onset, although the strength and direction of causality remain areas of ongoing investigation..

Autoimmune Diseases and Strep Throat?

In an interesting case study in Saudi Arabia, a 13-year-old boy with strep throat resulted in Pediatric autoimmune neuropsychiatric disorder associated with streptococcal infections (PANDAS), which was then followed by a diagnosis of OCD over the course of approximately 5-6 months. PANDAS is recognized as a significant causative element in the emergence of childhood-onset OCD but this detailed case provides more circumstance and background information and research. It had been noted that the child had a history of streptococcal pharyngitis prior to six months pre-diagnosis and that he has been fixated on cleanliness and sickness. According to the authors, streptococcal pharyngitis had caused an immune response (Autoimmune Basal Ganglia Encephalitis (BGE)) mistakenly targeting basal ganglia, which results in the noted symptoms such as behavioral regulation issues in the form of irritability, apparent anxiety circuits, and motor control difficulties described as “clumsiness, decreased concentration, and restlessness.” A variety of diagnostic tests, including an MRI, CT scan, CSF culture, electrocardiogram, and GABHS culture presented as negative or unremarkable. Although this single case cannot establish causation and may indeed be a misinterpretation, the findings presented, together with previous clinical and laboratory evidence, could further support the hypothesis that some hold that streptococcal pharyngitis contributes to the onset of OCD through PANDAS-related autoimmune mechanisms, potentially interacting with developmental changes occurring during puberty.. Although debate remains and more understanding is needed, this is an intriguing pathway that warrants further exploration.

Emerging and Understudied Risk Factors

Although OCD risk factors have been well established for decades now, there are still some hypothetical risk factors that are currently being investigated for a possible role in OCD causation. Some theorized risk factors include substance abuse and gastro-intestinal (GI) problems. Previous research on the relationship of OCD and substance abuse have produced conflicting results, with some studies suggesting OCD might work against substance misuse due to the nature of OCD cleanliness and cautiousness. Recently it was found through a large population study of over 6 million individuals in Sweden that OCD was, in contrast to previous findings, associated with a greater likelihood of substance abuse and that OCD diagnosed individuals are 3.7 times more likely to have substance abuse issues than the general population. Furthermore, in a cross-sectional study conducted in 2025 utilizing machine learning and logistic regression, it was shown that there is a potential link between GI issues and OCD. More potential risk factors noted in this machine learning study included sleep disorders and smoking. The attempt to prove the relation between these risk factors and OCD was measured through the association of GI issues and symptoms present in the same individuals who had symptoms representative of clear OCD diagnoses. Even though regression was used there may still be inherent flaws in the study including but not limited to stress level confounding both sleep and GI symptoms, diet reflecting socioeconomic status rather than biology, and reverse causation in many aspects of the questionnaire given. The cross-sectional design paired with self-report bias may also cause this study to be flawed in nature.

Conclusions – we need holistic understanding and management

A limitation of all of the above is that the evidence used to formulate this blog relied on relatively small or highly specific samples, which makes it impossible to generalize their findings to the broader OCD population. Trauma and stressful-life-event research also relies on self-reported experiences, which are vulnerable to memory errors and personal interpretation. Because of this, the exact timing or severity of certain events may not be fully accurate. There is also a wide range of study designs represented here for instance, case reports, cross-sectional studies, meta-analyses, and a few longitudinal studies, all of which measure OCD onset and risk factors differently. This variation makes it difficult to compare results directly or draw firm conclusions about cause-and-effect relationships.

In terms of identifying a cause, evidence supports the fact that OCD causation is extremely complex and multifactorial but likely attributed to external infection, SLEs and trauma, and genetic predisposition. It is generally accepted that OCD is not the result of one factor, but a multitude of different interacting factors , resulting in what is generally accepted as obsessive-compulsive disorder. Although this may be the case, to successfully develop new, more holistic treatments and to further our understanding of OCD and other similar neuropsychiatric/neurobiological conditions, we must further investigate all possible risk factors such as sleep disorders, GI issues, substance abuse, and their intersection with each risk factor mentioned above before we are equipped to fully support those living with OCD

About the author:

Benjamin Blitz is a high school junior at Hawken School with a particular interest in clinical and forensic neurology. His interest in neurology developed through his experience volunteering as a canine handler at the Louis Stokes Cleveland VA Medical Center, where he supported veterans living with a range of mental health conditions, including obsessive-compulsive and related disorders. This experience sparked his interest in understanding the neurological and psychological factors underlying these conditions and in pursuing further research in the field