Schizophrenia Etiology: Genetic Architecture and Environmental Triggers

Schizophrenia (lifetime prevalence ~0.7%) arises from complex gene-environment interplay:

Genetics

• Heritability ~80% (twin studies).
• Polygenic: thousands of common variants (GWAS: >300 loci) + rare copy-number variants (22q11.2 del, 16p11.2 dup, SETD1A, C4A).
• Risk increases with number of affected relatives (1st-degree: 10%; both parents: 40%).

Environmental Risk Factors

• Prenatal: Maternal infection (influenza, rubella), malnutrition, hypoxia, stress → microglial priming.
• Perinatal: Obstetric complications, winter/spring birth (vitamin D, infection).
• Childhood: Trauma (abuse, neglect), urbanicity, migration, social adversity.
• Adolescence: Cannabis (high-THC, early use), amphetamines, social stress.

No single factor is sufficient. The "two-hit" (or multi-hit) model posits genetic vulnerability + environmental stressors during neurodevelopmental windows → circuit dysfunction → psychosis. Epigenetic mechanisms (DNA methylation, miRNA) mediate gene-environment dialogue.