Genetics in Schizophrenia

1. Evidence for a Genetic Basis: Family, Twin, and Adoption Studies

• Heritability: Twin studies consistently estimate heritability at roughly 60-81% - Kaplan and Sadock's Synopsis of Psychiatry, p. 1109; Kaplan & Sadock's Comprehensive Textbook of Psychiatry.
• Family studies: Risk correlates with genetic closeness to an affected relative.
  • First-degree relatives: ~5-15% empirical risk (vs. ~1% in the general population)
  • Second-degree relatives: ~2-8% risk, with a clear drop-off in risk as genetic relatedness decreases
  • Increased risk also extends to "spectrum" conditions - schizoaffective disorder, schizotypal and paranoid personality disorder - Kaplan & Sadock's Comprehensive Textbook of Psychiatry, Table 30.2-1.
• Twin studies:
  • Monozygotic (MZ) twin concordance: ~40-60% (some sources cite up to 50%)
  • Dizygotic (DZ) twin concordance: ~10-16%
  • Because MZ concordance is well below 100%, environmental factors clearly also contribute - Kaplan & Sadock's Comprehensive Textbook of Psychiatry, p. 4474.
• Adoption studies: Biological relatives of adoptees who develop schizophrenia show much higher rates of the illness than the adoptive (non-biological) relatives who raised them, and children of biological parents with schizophrenia carry at least a 10% risk of developing the disorder or a related condition - even when raised apart. This strongly supports a genetic (rather than purely environmental/rearing) contribution - Kaplan & Sadock's Comprehensive Textbook of Psychiatry, p. 4474; Synopsis of Psychiatry, p. 1109.
• Paternal age: Advanced paternal age (father >60 years) is associated with increased risk, possibly reflecting age-related epigenetic damage during spermatogenesis - Synopsis of Psychiatry, p. 1109.

2. Molecular Genetics: Common Variants (GWAS)

• Genome-wide association studies (GWAS), driven largely by the Psychiatric Genomics Consortium (PGC), have identified hundreds of common single nucleotide polymorphisms (SNPs) associated with schizophrenia risk.
• The largest PGC meta-analyses have combined tens of thousands of cases and controls (e.g., ~67,000 cases/94,000 controls in recent discovery cohorts), identifying over 300 independent genome-wide significant loci.
• Individually, these common variants carry very small effect sizes (odds ratios typically 1.01-1.3), meaning no single gene "causes" schizophrenia.
• Polygenic risk scores (PRS) combine thousands of these variants into a composite score. Current PRS explains only about 11% of overall liability, with an estimated theoretical upper limit of around 25% - meaning PRS cannot reliably predict who will or won't develop schizophrenia and has limited clinical utility at present - Kaplan & Sadock's Comprehensive Textbook of Psychiatry, p. 7915.
• Implicated biological pathways converge on synaptic transmission, glutamatergic signaling, calcium channel function, and immune/complement pathways (e.g., complement component 4, C4, linked to synaptic pruning).

3. Rare, High-Impact Variants

• Copy number variants (CNVs) - deletions or duplications of chromosomal segments - are rarer than common SNPs but carry much larger individual risk, accounting for perhaps 2-5% of schizophrenia cases.
• The best-characterized example is 22q11.2 deletion syndrome (DiGeorge syndrome), which confers roughly a 25-30% lifetime risk of psychotic illness, making it one of the strongest known single genetic risk factors for schizophrenia - Kaplan & Sadock's Comprehensive Textbook of Psychiatry, p. 7915-7916; Synopsis of Psychiatry, p. 1110.
• Other CNVs (e.g., at 1q21.1, 15q13.3, 16p11.2) and rare protein-altering variants identified via exome sequencing also converge on genes involved in synaptic function and neurodevelopment.

4. Candidate Genes

• COMT (catechol-O-methyltransferase) - involved in dopamine metabolism
• Genes affecting glutamate release/signaling and various monoamine receptors
• BDNF (brain-derived neurotrophic factor) - a recent meta-analysis found the BDNF rs6265 polymorphism associated with schizophrenia susceptibility (Vajagathali & Ramakrishnan, 2024, PMID: 38616064).

5. Epigenetics and Gene-Environment Interaction

6. Recent Advances (2024-2025)

• A 2025 gene-level analysis (Dang et al., Nature Human Behaviour, PMID: 39753749) used Mendelian randomization and quantitative trait loci to refine the genetic architecture and identify therapeutic targets for schizophrenia.
• A 2024 meta-analytical review (Choudhary et al., Schizophrenia Research, PMID: 36443183) integrates genomics with induced pluripotent stem cell (iPSC) models to study disease mechanisms functionally.
• Broader reviews (e.g., in Molecular Psychiatry, 2023-2024) confirm schizophrenia as highly polygenic, with common variants now explaining up to ~40% of heritability (compared to the ~80% estimated from twin studies), leaving a substantial "missing heritability" gap attributed to rare variants, gene-gene interactions, and epigenetic factors.

Summary Table

Genetics in Schizophrenia — 10 Marks

Introduction (1 mark)

1. Evidence for Genetic Basis (3 marks)

• First-degree relatives: 5-15% risk (vs ~1% general population)
• Second-degree relatives: 2-8% risk (decreasing with genetic distance)
• Risk also raised for spectrum conditions: schizoaffective disorder, schizotypal/paranoid personality disorder

• Monozygotic (MZ) concordance: 40-60%
• Dizygotic (DZ) concordance: 10-16%
• MZ >> DZ confirms strong genetic component; MZ <100% confirms role of environment

• Biological relatives of adopted-away schizophrenic probands show higher rates than adoptive relatives
• Children of affected biological parents carry ~10% risk even when reared by unaffected adoptive parents
• Confirms transmission is genetic, not purely due to rearing environment

2. Molecular Genetics (4 marks)

• Psychiatric Genomics Consortium (PGC) GWAS have identified 300+ genome-wide significant loci
• Each variant has small effect (OR 1.01-1.3) — "polygenic" architecture
• Polygenic Risk Score (PRS) currently explains only ~11% of liability (theoretical max ~25%) — limited clinical utility for prediction

• Account for 2-5% of cases; larger individual effect than common SNPs
• 22q11.2 deletion syndrome is the best example — confers ~25-30% risk of psychosis, strongest known single genetic risk factor
• Others: 1q21.1, 15q13.3, 16p11.2 deletions/duplications

• COMT (dopamine metabolism)
• Genes affecting glutamate signaling and monoamine receptors
• BDNF (neurotrophic signaling)
• Complement C4 (linked to excessive synaptic pruning)

3. Epigenetics and Gene-Environment Interaction (1 mark)

• Most risk variants act by altering gene expression rather than protein structure
• Environmental factors (obstetric complications, prenatal infection, cannabis use, urban birth/migration, advanced paternal age) interact with genetic vulnerability to determine phenotypic expression (diathesis-stress model)

Conclusion (1 mark)