Genetics of obsessive-compulsive disorder (OCD)
INTRODUCTION of OCD
Heterogeneity
Definition
History
**Obsessions** are intrusive thoughts, images, or urges causing anxiety.
- Four broad dimensions symptoms: contamination and cleaning, symmetry; (repeating, ordering, and counting); forbidden thoughts; hoarding
- First description in psychiatric literature in 1838 by Jean-Étienne Esquirol
- Ever since, heredity has been regarded to play an important
role in the development of OCD - Recently, OCD has been classified as an anxiety disorder because of changes in classification of DSM-5
- Reclassified as Obsessive-Compulsive and Related Disorders in 2013.
- Added related disorders like body dysmorphic disorder, skin picking disorder, trichotillomania, and hoarding disorder
- In (ICD)-11, this classification also includes olfactory reference syndrome and hypochondria. DSM-5 was the removal of the requirement of insight and added specifiers for insight (fair, poor, absent) and past tic disorders.
Treatment
Treatment option : i) Pharmacological, psychotherapeutic, and surgical options
ii) Selective serotonin reuptake inhibitors and cognitive behavioral therapy.
iii) Second-line options include clomipramine, risperidone, and aripiprazole.
Challenges in Treatment : - Not all individuals respond sufficiently to interventions.
- Additional efforts needed for understanding underlying mechanisms, improving outcomes, early detection, and understanding etiology.
Epidemiology
Prevalence and Onset - Females are affected in adolescence and adulthood, while males affected in childhood.
Severity - impairs quality of life, increases the risk of mortality and suicidal ideation
Risk Factors - including genetic and environmental factors such as childhood trauma and stressful life events. A persistent low-grade inflammation and autoimmune response.
Dysfunction in cortico-striato-thalamo-cortical (CSTC) circuitry leading to hyperactivity in brain regions associated with repetitive thoughts and compulsions.
Epidemiology
- Genetic Epidemiology
A. Familial clustering of OCD
Familial Clustering - OCD tends to run in families, with first-degree relatives
Onset and Symptom Dimension Familiality: The prevalence of OCD is substantially higher in relatives of individuals with early onset OCD compared to later onset.
Overlap with Other Disorders: OCD shares genetic and phenomenological features with Tourette syndrome, ADHD, anxiety disorders, and autism spectrum disorders (ASDs).
B. Heritability from family and twin studies
Heritability of OCD: Twin studies show a substantial heritability of OCD and obsessive-compulsive symptoms.
Twin Correlations: Monozygotic (MZ) twin correlations are consistently higher than dizygotic (DZ) twin correlations, suggesting a genetic influence on the disorder.
- Molecelular genetics
Compulsions are repetitive behaviors or mental rituals to reduce anxiety and aim to prevent, reduce anxiety or impede feared events caused by obsessions
D. Common variants
. Initial genome-wide studies failed to identify significant variants, though subsequent meta-analyses highlighted potential loci near genes like BTBD3 and PTPRD.
C. Genetic architecture
Single-nucleotide polymorphism (SNP)-based heritability studies provide insights into the genetic architecture of (OCD)
Overall, common genetic variants contribute significantly to the variance of OCD, suggesting a substantial genetic component.
E. Rare Variants
B.Epigenetics and gene expression
mainly focusing on DNA methylation.
F. Genetic relationship with comorbid disorders
(OCD) often occurs alongside various psychiatric disorders like anxiety disorders, Autism Spectrum Disorder (ASD), Tourette syndrome, anorexia nervosa, and Attention-Deficit/Hyperactivity Disorder (ADHD).
However, while OCD and ASD share some behavioral traits, they don't seem to have a significant genetic correlation. Similarly, although OCD and ADHD frequently coexist, they have limited shared genetic factors.
A. Sex differences
However, two genes (GRID2 and GRP135) associated with OCD were only found to be linked to females, not males
Clinical and therapeutic implications
Future studies may focus on polygenic risk scores (PRS) to inform personalized therapeutic interventions.
Pharmacogenetic studies investigate genetic factors influencing variable treatment responses in OCD, with a recent GWAS identifying a significant locus associated with treatment response to SRIs.
Based on genetic findings, drugs targeting glutamatergic neurotransmission, such as memantine, lamotrigine, topiramate, and riluzole, show promise as potential treatments for OCD.
aim to identify specific genetic risk factors and biological underpinnings of OCD to improve prevention and treatment
Conclusions and future directions
Future research should explore alternative phenotyping strategies beyond case/control status, such as measuring obsessive-compulsive symptoms broadly and considering transdiagnostic dimensions.
Investigating gene-environment interactions, structural variants, and epigenetic mechanisms will contribute to understanding the underlying biological mechanisms of OCD.
Current genetic studies on OCD are limited by sample sizes, but larger meta-analyses are underway to identify robust genetic variants and understand its genetic architecture.
Understanding the genetic basis of OCD may lead to the development of new treatment strategies and personalized interventions, including psychological treatment outcomes.
(OCD) is a heritable, polygenic disorder influenced by both common and rare genetic variants, as well as environmental factors.