Genetics of schizophrenia

Genetics of schizophrenia

Genetics of schizophrenia

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Heritability & Risk - It Runs in the Family

  • Schizophrenia has a strong genetic component, demonstrated by family, twin, and adoption studies. It follows a polygenic inheritance model, not a simple Mendelian pattern.
  • Lifetime risk is directly proportional to the degree of genetic relatedness:
    • General Population: 1%
    • Sibling with schizophrenia: 9%
    • Child with one parent with schizophrenia: 13%
    • Dizygotic twin: ~17%
    • Monozygotic twin: ~48-50%

⭐ The fact that monozygotic twin concordance is only ~50%, not 100%, is a classic exam point. It strongly implicates non-genetic factors (e.g., environment, epigenetics) in the disease's etiology.

Gene Hotspots - Chromosomal Culprits

  • Highly polygenic, with heritability estimated at ~80%. No single gene is causative.
  • Key chromosomal microdeletions confer the highest risk:
    • 22q11.2 Deletion Syndrome: The single strongest genetic predictor. Also known as Velocardiofacial or DiGeorge syndrome.
    • 16p11.2 Duplication/Deletion
    • 1q21.1 & 3q29 Deletions
  • Specific gene associations:
    • MHC region on Chromosome 6: Genes like C4 are implicated in excessive synaptic pruning.
    • DISC1 (Disrupted in Schizophrenia 1)
    • NRG1 (Neuregulin 1)

⭐ The risk of schizophrenia in individuals with 22q11.2 deletion is 25-30%, a nearly 30-fold increase over the general population's 1% risk.

  • 22q11.2 Deletion Syndrome (VCFS/DiGeorge): The most significant known syndromic cause linked to schizophrenia.
    • Individuals have a ~25-30% lifetime risk of developing schizophrenia.
    • 📌 CATCH-22 Mnemonic: Cardiac defects, Abnormal facies, Thymic hypoplasia, Cleft palate, Hypocalcemia.
  • Other Associated Syndromic Risks:
    • Fragile X Syndrome: FMR1 gene premutation carriers show ↑ rates of psychosis.
    • Klinefelter Syndrome (XXY): Associated with a 4-fold ↑ risk of psychotic disorders.

Chromosome 22 with 22q11.2 deletion

High-Yield: Psychosis in 22q11.2 deletion syndrome often presents earlier than idiopathic schizophrenia and may have more prominent negative and cognitive symptoms.

Epigenetics & Models - Nature Meets Nurture

  • Gene-Environment Interaction: Genetic predisposition isn't destiny. Environmental factors modulate gene expression via epigenetic changes.
  • Key Mechanisms:
    • DNA Methylation: ↑ methylation can silence protective genes.
    • Histone Modification: Acetylation/deacetylation alters chromatin, affecting gene access.
  • Environmental Triggers:
    • Prenatal: Maternal infection (influenza), malnutrition.
    • Adolescence: Cannabis use, urban upbringing, social stress.
  • "Two-Hit" Hypothesis:
    • First Hit: Genetic or developmental disruption (prenatal).
    • Second Hit: Environmental stressor (e.g., adolescent drug use) triggers psychosis onset. Schizophrenia: Gene x Environment Model

⭐ Advanced paternal age (>50) is linked to a higher risk of de novo mutations in sperm, contributing to schizophrenia risk in offspring.

  • Schizophrenia has a strong genetic component with heritability estimated at ~80%.
  • Monozygotic twin concordance is ~40-50%, while dizygotic twin concordance is ~10-15%.
  • Having a first-degree relative with schizophrenia is the single strongest risk factor for developing the illness.
  • The disorder is polygenic; it is not caused by a single gene but multiple genes of small effect.
  • Specific genetic syndromes like 22q11.2 deletion are associated with an increased risk.

Practice Questions: Genetics of schizophrenia

Test your understanding with these related questions

A mother from rural Louisiana brings her 4-year-old son to a pediatrician. Her son is intellectually disabled, and she hopes that genetic testing will help determine the cause of her son's condition. She had previously been opposed to allowing physicians to treat her son, but his impulsive behavior and learning disabilities are making it difficult to manage his care on her own. On exam, the child has a long, thin face with a large jaw, protruding ears, and macroorchidism. The physician also hears a high-pitched holosystolic murmur at the apex of the heart that radiates to the axilla. Which of the following trinucleotide repeats is most likely affected in this individual?

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Flashcards: Genetics of schizophrenia

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Schizophrenia/psychosis in teens is associated with frequent _____ use

TAP TO REVEAL ANSWER

Schizophrenia/psychosis in teens is associated with frequent _____ use

cannabis

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