Aetiology

Epidemiology of Schizophrenia

• Schizophrenia has a low incidence and high prevalence, with varying estimates due to methodology and diagnostic criteria.
• The annual incidence is 0.16-1.00 per 1000 population, with a median incidence of 0.15 per 1000.
• The lifetime prevalence is about 5 per 1000, with a lifetime morbid risk of 7.2 per 1000.

Age at Onset

• Schizophrenia can begin at any stage of life, from childhood to old age.
• The usual onset is between 15 and 35 years old.

Gender

• Schizophrenia is more common in men than women, with a male:female ratio of 1.4:1.
• The difference is more marked for severe cases.
• The difference may be attributed to neuroprotective effects of estrogen or genetic and epigenetic risk factors.

Fertility

• Patients with schizophrenia show decreased fertility, with a substantial reduction in fertility (about 40% of that expected).
• The figures are difficult to interpret due to historical limitations and side effects of treatment.

Aetiology

• The most important influence is genetic, with about 80% of the risk being inherited.
• Environmental factors contribute too, many of which act early in life and interact with the genetic predisposition.
• Schizophrenia is a disorder of brain connectivity, with acute psychosis associated with excessive dopamine neurotransmission in the basal ganglia.

Aetiological Factors and Theories

• Genetic factors include single nucleotide polymorphisms, copy number variation, and rare variants.
• Early environmental factors include maternal malnutrition, infection, birth complications, and urban birth.
• Social factors include migration and ethnic minority status.
• Other factors include early cannabis use and various hypotheses such as neurodevelopmental, gene-environment interactions, dopamine, glutamate, dysconnectivity, and immune/inflammatory factors.

Family Studies

• Family studies show a higher incidence of schizophrenia among relatives of probands, with a lifetime risk of schizophrenia in various classes of relatives.
• The estimates suggest a familial aetiology, primarily due to shared genes, and also support a role for shared environmental factors.

Twin Studies

• Twin studies show unequivocal evidence of heritability, with concordance rates several-fold higher in monozygotic twins than in dizygotic twins.
• Heritability estimates range from 40-50% for monozygotic twins and 10% for dizygotic twins.

Adoption Studies

• Adoption studies provide evidence of a genetic contribution to schizophrenia, with a higher incidence among adopted-away children of mothers with schizophrenia.

Mode of Inheritance

• The mode of inheritance is polygenic, with multiple genes contributing to the risk of schizophrenia.
• No single gene is necessary or sufficient, and they act as risk factors rather than determinants.

Schizophrenia Susceptibility Genes

• Despite high heritability, identifying schizophrenia genes has been difficult due to factors such as the complexity of the disorder and the lack of a single or major gene.
• Recent advances in genomics and methods have led to the identification of three types of genetic variation contributing to schizophrenia risk: single nucleotide polymorphisms, copy number variants, and rare variants.

Copy Number Variants Associated with Schizophrenia Risk

• Copy number variants (CNVs) are associated with schizophrenia, with examples including deletions and duplications on chromosomes 1q21.1, 15q11.2, and 22q11.2.
• CNVs can act as a schizophrenia risk factor, with some being inherited and others present de novo.

Rare Variants

• Rare variants can also increase the risk of schizophrenia, with examples including variants in the gene SETD1A.
• These rare variants can be either inherited or present de novo.### Schizophrenia Genetics
• 22q11 is a locus for schizophrenia genes, and several genes within this region have been identified
• 22q11 hemideletion is associated with neurodevelopmental and neuropsychiatric syndromes, such as intellectual disability and ADHD
• One copy number variation (CNV) can produce different phenotypes (pleiotropy)

DISC 1

• Disrupted in schizophrenia 1 (DISC 1) is a gene linked to a high incidence of schizophrenia and other disorders in a large Scottish family
• The role of DISC 1 in schizophrenia outside this family is unclear, and its significance is debated

The "Missing Heritability"

• Much of the heritability of schizophrenia is still unexplained, despite the identification of many SNPs, CNVs, and rare variants
• SNPs collectively will explain about 30% of the genetic risk, and CNVs perhaps another 5-10%
• The remainder likely arises from additional genetic variants, epistasis, gene-environment interactions, and epigenetic factors

Crow's Lateralization Hypothesis

• Crow proposed that schizophrenia is due to a single gene responsible for cerebral asymmetry and language
• The theory is not widely supported

The Biology of Schizophrenia Genes

• Schizophrenia genes converge on functional networks and biochemical pathways
• Key pathways include N-methyl-D-aspartate (NMDA) receptor-mediated signaling and synaptic plasticity, and immune function

Immune Function

• The major histocompatibility complex (MHC) locus on chromosome 6 shows the strongest statistical association to schizophrenia
• Two interpretations of this finding are:
  • Immune, autoimmune, or inflammatory factors play a role in schizophrenia
  • "Immune genes" influence brain development, influencing synaptogenesis and other processes
• The genetic signal to the MHC locus arises mainly from the complement component 4 (C4) gene
• Individuals with risk forms of C4 express the gene at higher levels, leading to more pruning of synapses during brain development

NMDA Receptor Signaling

• Genes involved in NMDA receptor signaling and synaptic function are overrepresented among schizophrenia risk SNPs and CNVs
• Glutamate and NMDA receptor hypofunction have long been postulated in schizophrenia

Environmental Risk Factors

• Despite the prominent genetic component, environmental factors also play an important role in the etiology of schizophrenia
• Prenatal and perinatal factors have been identified, including maternal infections, malnutrition, birth complications, and others
• Many environmental risk factors are not specific to schizophrenia and are shared by other disorders
• The distinction between genetic and environmental factors is an oversimplification, and interactions are common

Clinical and Therapeutic Implications

• There is no direct clinical role of genetic testing for schizophrenia in clinical practice
• Genetic discoveries are providing new potential drug targets, but seem unlikely to lead directly to new pharmacotherapies

Environmental Risk Factors

• Maternal infections: ?
• Maternal malnutrition: 2
• Birth complications: 2
• Winter birth: 1.1
• Advanced paternal age: 1.7
• Urban birth and upbringing: 1.9
• Childhood trauma and adversity: 2.8
• Being an immigrant: 2.9
• Cannabis smoking: 2
• Tobacco smoking: 2.2
• Life events: 3.2

Obstetric Complications

• Rates of schizophrenia are increased in individuals with obstetric complications
• Odds ratio: 2
• Complications include antepartum hemorrhage, diabetes, low birth weight, asphyxia, and Rhesus incompatibility
• Complications are more relevant in individuals with a genetic predisposition to schizophrenia

Infective and Inflammatory Factors

• Fetuses exposed to influenza during the second trimester may have an increased risk of schizophrenia
• Prenatal influenza affects fetal brain development
• Maternal infections associated with schizophrenia include toxoplasmosis, herpes simplex virus 2, and rubella

Maternal Malnutrition

• Children born to mothers who experienced famine early in pregnancy have an increased risk of schizophrenia
• Odds ratio: 2
• Mechanism proposed: epigenetic, with malnutrition altering DNA methylation and gene expression regulation

Winter Birth

• Schizophrenia is slightly more frequent among people born in the late winter than among those born in the summer
• Season of birth effect observed in both northern and southern hemispheres
• Explanation unknown, with possible reasons including:
  • Prevalence of influenza earlier in the winter
  • Sunshine and vitamin D levels around the time of birth
  • Factors related to the time of conception, via seasonal fluctuations in gamete genetic makeup

Paternal Age

• Schizophrenia is associated with paternal age, especially in those without a family history of psychosis
• Relative risk: 1.66 for fathers over 50 years old compared to those aged 25-29
• Favored explanation: increased frequency of mutations in sperm with age
• Phenomenon only observed for a man's first-born child, and not for subsequent ones

Estimates and methodology of schizophrenia incidence and prevalence, with a focus on diagnostic criteria and population differences.