Notes on Genetics and Treatment of Schizophrenia

Genetics and Treatment of Schizophrenia

What is CNV?

• CNV stands for Copy Number Variants, which are segments of DNA that vary in copy number among individuals in a population.
• Extensive research has shown the prominence of CNVs in the human genome, with contributions from various studies (Sebat et al., 2007; Szatmari et al., 2007; etc.).

Formation of CNVs

• CNVs often arise in genomic regions flanked by Low Copy Repeats (LCR) which are prone to Non-Allelic Homologous Recombination (NAHR).
• These events can lead to a recurrent nature of CNVs and are often found as de novo mutations upon inspection.

Risk Genes for Schizophrenia Identified by GWAS

• Notable risk genes include:
  • DISC1 (Chromosome 1)
  • ZNF804A (Chromosome 2)
  • NRXN1 (Chromosome 11)
  • NRGN (Chromosome 8)
  • TCF4 (Chromosome 22)
  • MHC (Chromosome 6)
• The list includes other genes associated with bipolar disorder and autism spectrum disorders.

De Novo CNVs

• Characteristically, these mutations are not inherited from either parent.
  • Frequency of de novo CNVs:
    • 10% in simplex schizophrenia families.
    • 3% in multiplex schizophrenia families.
    • <1% in non-disease samples.
• Specific large CNVs at chromosomes 1q21.1, 15q11.2, and 15q13.3 correlate with approximately 1% of schizophrenia cases.

Detection of CNV

Techniques

• Single-cell Sequencing: Uses Multiple Displacement Amplification (MDA) with hexamer primers for higher fidelity detection of CNVs in single neurons.
• Next Generation Sequencing (NGS): Utilizes modern technologies for high-throughput sequencing, enabling the detection of rare mutations and CNVs at a larger scale.

Next Generation Sequencing vs. Sanger Sequencing

• Sanger sequencing (1977) uses dideoxynucleotides for chain termination, while NGS implements micro/nanotechnologies to sequence millions of fragments concurrently.
• NGS is characterized by:
  • Highly multiplexed sequencing.
  • Reduced reagent costs.
  • Capable of outputting hundreds of millions of DNA reads in a single run.

Multiplexing

• This method allows simultaneous analysis of multiple samples through barcoding during library construction, enhancing throughput in sequencing and analysis.

Sequencing Cost Trends

• Notable examples include:
  • The Human Genome Project took 13 years and cost around $3 billion.
  • Modern techniques have drastically reduced costs, e.g., $10,000 for a genome in just 8 days using Illumina technologies.

Treatment of Schizophrenia

Dopamine Hypothesis

• Evidence for dopamine involvement in schizophrenia:
  • Autopsy studies show increased dopamine receptors.
  • Dopamine agonists exacerbate psychosis.
  • Effective neuroleptics block post-synaptic dopamine actions.

Alternative Hypotheses

• Some researchers recommend considering other roles of neurotransmitters like glutamate (e.g., NMDA receptor involvement).

antipsychotic Medications

• Two main classes:
  • Typical Antipsychotics: Primarily dopamine antagonists; known for causing extrapyramidal side effects.
  • Atypical Antipsychotics: Affect serotonin and dopamine pathways; tend to have lower risk for extrapyramidal symptoms.

Side Effects of Antipsychotics

• Common side effects include:
  • Extrapyramidal symptoms: Parkinsonism, Dystonia, Akathisia.
  • Weight gain, sexual dysfunction, and seizures (rare).

Atypical Antipsychotics**

• CLOZAPINE is effective for treatment-resistant schizophrenia and has minimal extrapyramidal side effects.
• OLANZAPINE is known for its multi-receptor action, controlling mood symptoms but associated with weight gain and sedation.

Conclusion - Key Takeaways

• Knowledge of DE NOVO mutations, CNVs, and the mechanisms behind drug actions are crucial for treatment approaches in schizophrenia.
• Differentiating between typical and atypical antipsychotic treatments can help tailor treatment plans effectively to individual patient needs, addressing both positive and negative symptoms of the disorder.