Genetics of Psychiatric Disorders

Genetics of Psychiatric Disorders - Genes & Minds

• Heritability ($H^2 = V_G / V_P$): Genetic contribution to trait variance.

  • High: Schizophrenia ~80%; Bipolar ~70-80%; ADHD ~75%; ASD ~70-90%.

• Inheritance:

  Type	Genes	Effect	Relevance in Psychiatry
  Monogenic	Single	Large	Rare
  Polygenic	Multiple	Small, additive	Common (most disorders)

• Gene-Environment Interaction (GxE): Diathesis-stress model (genes + stress → disorder).

• Epigenetics: Altered gene expression, not DNA sequence (DNA methylation, histone modification).

  • 📌 Epi: Methylates Histones (Epigenetics: Methylation, Histone modification).

• ⭐ > Twin studies (MZ vs. DZ) are crucial for estimating heritability of psychiatric disorders.

Genetics of Psychiatric Disorders - Unraveling Roots

Psychiatric disorders have a significant genetic basis, influenced by multiple genes and environmental interactions.

• High Heritability: Many disorders show strong familial aggregation and high heritability estimates.
• Polygenic Risk: Most disorders arise from the combined effects of many common variants (Single Nucleotide Polymorphisms - SNPs), each with a small effect.
• Rare Variants: Copy Number Variations (CNVs) (e.g., 22q11.2 deletion) can confer substantial risk, especially for neurodevelopmental disorders.

Key Psychiatric Disorders: Genetic Insights

⭐ > Copy Number Variations (CNVs) are increasingly recognized as important risk factors for neurodevelopmental disorders like ASD and schizophrenia, often conferring higher risk than common SNPs.

Genetics of Psychiatric Disorders - Tailored Treatments

Pharmacogenomics: Genetic variations influence drug response, guiding personalized psychiatric treatments.

• Pharmacokinetics (PK):
  • Key CYP enzymes (CYP2D6, CYP2C19, CYP2C9, CYP1A2) metabolize psychotropics (SSRIs, TCAs, antipsychotics).
  • Metabolizer phenotypes (Poor, Intermediate, Extensive, Ultra-rapid) impact drug levels, efficacy, and side effects.

    Enzyme	Common Psychotropic Substrates	Clinical Implications of Polymorphisms (e.g., Poor Metabolizers)
    CYP2D6	TCAs, fluoxetine, paroxetine, risperidone, aripiprazole	↑ drug levels, ↑ side effects
    CYP2C19	Citalopram, escitalopram, sertraline, TCAs, diazepam	↑ drug levels, ↑ side effects (PMs); ↓ efficacy (UMs for active drugs)
    CYP2C9	Valproate (minor), phenytoin	↑ drug levels, ↑ toxicity
    CYP1A2	Clozapine, olanzapine, duloxetine	↑ drug levels (PMs); ↓ levels with inducers (e.g., smoking)

• Pharmacodynamics (PD):
  • Genetic variations in drug targets (e.g., HTR2A receptors, SLC6A4 transporters) also affect treatment outcomes.
• Specific Examples:
  • HLA-B*1502 allele: ↑ risk of carbamazepine-induced SJS.
  • HLA variants (e.g., HLA-DQB1): Linked to clozapine agranulocytosis & response.

⭐ Individuals who are CYP2D6 poor metabolizers may experience increased side effects or toxicity from standard doses of many antidepressants and antipsychotics.

Genetics of Psychiatric Disorders - Syndrome Spotlights

• Down Syndrome: Trisomy 21; Psychiatric: Alzheimer's (early onset), depression.
• Fragile X Syndrome: FMR1 gene mutation; Psychiatric: ASD, anxiety, ADHD.
• Velocardiofacial Syndrome (22q11.2 Deletion): 22q11.2 deletion; Psychiatric: High psychosis risk (schizophrenia), anxiety.
• Prader-Willi Syndrome: Paternal 15q11-q13 del/UPD; Psychiatric: Behavioral issues, hyperphagia, mood disorders.
• Angelman Syndrome: Maternal 15q11-q13 del/UPD; Psychiatric: Severe developmental delay, happy demeanor, sleep issues.

⭐ Velocardiofacial syndrome (22q11.2 deletion) is one of the strongest known genetic risk factors for schizophrenia, with up to 30% of affected individuals developing psychosis.

High‑Yield Points - ⚡ Biggest Takeaways

• Most psychiatric disorders follow polygenic inheritance, not Mendelian patterns.
• High heritability seen in schizophrenia (~80%), bipolar disorder (~75%), and autism spectrum disorder.
• Specific genes (e.g., COMT, BDNF, 5-HTTLPR) contribute, but with small individual effects.
• Gene-environment interactions (GxE) are critical for disease development.
• Epigenetic modifications, like DNA methylation, regulate gene expression.
• Copy Number Variations (CNVs) are significant risk factors for several disorders.
• Twin studies (higher MZ vs DZ concordance) strongly support genetic contributions.