Polygenic Heterogeneity Across Obsessive-Compulsive Disorder Subgroups Defined by a Comorbid Diagnosis

Area of Science:

• Psychiatric Genetics
• Neuroscience
• Genomics

Background:

• Obsessive-compulsive disorder (OCD) frequently co-occurs with other psychiatric disorders, with high heritability observed in both OCD and its comorbidities.
• Understanding the genetic underpinnings of these co-occurring conditions is crucial for elucidating OCD's complex etiology.
• Previous research has not fully explored the genetic heterogeneity of OCD in relation to its common comorbidities.

Purpose of the Study:

• To investigate the genetic relationship between OCD and its common comorbidities: major depressive disorder (MDD), attention-deficit hyperactivity disorder (ADHD), and autism spectrum disorder (ASD).
• To examine genetic correlation patterns and polygenic risk score (PRS) associations across different OCD comorbid subgroups.

Main Methods:

• Utilized publicly available genome-wide association study (GWAS) summary statistics to compare genetic correlations between OCD, MDD, ADHD, ASD, and 861 other health phenotypes.
• Employed independent patient data from the Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH) to analyze how PRS of specific traits partitioned across OCD subgroups (OCD only, OCD+MDD, OCD+ADHD, OCD+ASD, OCD+multiple comorbidities).

Main Results:

• Polygenic risk scores (PRS) for most traits, excluding Body Mass Index (BMI), were significantly associated with OCD across all patient subgroups.
• PRS estimates for age at first birth, educational attainment, and insomnia showed significant differences across comorbid OCD subgroups.
• Genetic correlation patterns observed between OCD, MDD, ADHD, and ASD were mirrored in PRS associations within the respective comorbid OCD groups, particularly for anorexia nervosa, age at first birth, educational attainment, insomnia, and neuroticism.

Conclusions:

• The study identified both quantitative and qualitative polygenic heterogeneity across OCD comorbid subgroups.
• These findings suggest distinct genetic architectures underlying OCD when comorbid with MDD, ADHD, or ASD.
• Further research into the genetic basis of OCD comorbidities can inform targeted treatment strategies and improve understanding of psychiatric disorder development.