Can Obsessive-Compulsive Traits in the General Population Help Identify Genes for OCD?

What you need to know

• Researchers identified a genetic variant associated with obsessive-compulsive (OC) traits in children from the general population that was also linked to clinical OCD.
• OC traits measured in the community shared genetic risk with OCD diagnosis, suggesting OCD may represent the extreme end of normally distributed traits.
• Using a measure that captured the full range of OC traits from strengths to weaknesses improved ability to detect genetic associations compared to typical symptom measures.

Background on OCD and genetics

Obsessive-compulsive disorder (OCD) is a psychiatric condition characterized by recurrent, intrusive thoughts (obsessions) and repetitive behaviors or mental acts (compulsions). It affects about 1-2% of the population and often begins in childhood or adolescence. Twin studies have shown that OCD runs in families and is moderately heritable, meaning genetics plays a role in its development.

However, identifying specific genes involved in OCD has been challenging. Previous genome-wide association studies (GWAS), which scan the entire genome to find genetic variants associated with a disorder, have not found any variants that reached genome-wide significance for OCD. The most promising findings have been in regions on chromosome 9 and in genes involved in glutamate signaling in the brain.

One reason it has been difficult to find OCD genes may be that most studies have looked at diagnosed OCD cases compared to controls. An alternative approach is to study obsessive-compulsive (OC) traits in the general population. The idea is that the same genes that influence milder OC traits may also be involved in clinical OCD when present in more extreme forms.

Using a novel OC trait measure in children

This study took a new approach by examining OC traits in over 5,000 children from the general community, rather than only looking at diagnosed OCD cases. The researchers used a novel measure called the Toronto Obsessive-Compulsive Scale (TOCS) that assesses OC traits on a spectrum from strengths to weaknesses. For example, it includes items asking if a child is “never upset when belongings are rearranged” (a strength) to “very upset when belongings are rearranged” (a weakness).

This is different from typical OCD symptom measures that only assess the presence and severity of symptoms. The advantage of the TOCS is that it captures more variation in the general population, where most people do not have clinical symptoms. This may make it easier to detect genetic effects.

Key findings

The main findings of the study were:

1. A genetic variant in the PTPRD gene was significantly associated with OC traits measured by the TOCS in children from the community. This is the first genome-wide significant finding for OC traits.

2. The same PTPRD variant was also associated with diagnosed OCD in a separate sample of OCD cases and controls, although not at genome-wide significance.

3. Overall genetic risk for OC traits overlapped with genetic risk for OCD. Children with more genetic variants associated with OC traits were more likely to have an OCD diagnosis.

4. The genetic correlation between OC traits and OCD was high (0.71), although not statistically significant likely due to sample size limitations.

5. Using the full range TOCS measure improved power to detect genetic associations compared to typical symptom measures that produce more skewed distributions in community samples.

What does the PTPRD gene do?

The PTPRD gene provides instructions for making a protein called protein tyrosine phosphatase delta. This protein is found primarily in the brain and is involved in the development and function of neurons. Specifically, it plays a role in:

• Axon guidance - helping neurons extend projections to connect with other neurons during brain development
• Synapse formation - establishing connections between neurons
• Regulating excitatory and inhibitory signaling between neurons

Interestingly, PTPRD interacts with other proteins that have been implicated in OCD-related behaviors in previous studies. While more research is needed, this finding provides a potential biological link to OCD risk.

Implications of shared genetic risk

The overlap in genetic influences on OC traits and OCD diagnosis has several important implications:

1. It supports the idea that OCD may represent the extreme end of OC traits that are normally distributed in the population. There may not be a clear dividing line between “normal” and “clinical” obsessions and compulsions.

2. Studying OC traits in large community samples may be a powerful way to identify genes involved in OCD. This approach allows for larger sample sizes and captures more variation than only studying diagnosed cases.

3. Genetic findings from OC traits are likely relevant to understanding the biology of clinical OCD. The same genes seem to be involved across the spectrum from mild to severe.

4. OC traits measured in childhood may indicate genetic risk for developing OCD later in life. However, longitudinal studies are needed to confirm this.

Advantages of the trait-based approach

This study demonstrated some key advantages of using a trait-based approach to study the genetics of psychiatric disorders:

1. Improved statistical power - By capturing more variation in the population, trait measures can detect smaller genetic effects that may be missed when only studying diagnosed cases.

2. Larger sample sizes - It’s easier to collect data on traits in large community samples than to recruit thousands of patients with a specific diagnosis.

3. Developmental perspective - Trait measures in children may reveal genetic risks before the onset of clinical disorders.

4. Mechanistic insights - Understanding how genes influence traits across the normal range may reveal biological pathways involved in both typical and atypical development.

Limitations and future directions

Some limitations of this study include:

• The sample was primarily of European ancestry, so findings may not generalize to other populations.
• The genetic correlation between OC traits and OCD, while high, was not statistically significant. Larger samples are needed to confirm the extent of genetic overlap.
• This study looked at traits at one time point in childhood. Longitudinal studies are needed to examine how genetic risks unfold over development.

Future research directions could include:

• Replicating these findings in independent samples
• Examining how OC trait-associated genes affect brain structure and function
• Investigating whether polygenic scores based on OC traits can predict OCD onset
• Using OC trait measures to identify more genes involved in OCD biology

Conclusions

• A novel measure of OC traits in children revealed a genetic variant associated with both traits and OCD diagnosis, providing new insights into the biology of obsessive-compulsive behaviors.
• There appears to be substantial overlap in the genes that influence OC traits in the general population and clinical OCD.
• Studying quantitative traits in large community samples is a promising approach for understanding the genetics of complex psychiatric disorders.