Questions and Answers
Schizophrenia is a disorder with a high incidence and a low prevalence.
False
Using current diagnostic criteria, the annual incidence of schizophrenia is 0.16-1.00 per 1000 population with a broad definition.
True
A meta-analysis reported that the mean incidence of schizophrenia is 1.24 per 1000 population.
False
The incidence of schizophrenia is reportedly higher in developed countries than in developing countries.
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Systematic reviews indicate a lifetime prevalence of about 7 per 1000 for schizophrenia.
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The lifetime morbid risk of developing schizophrenia is reported to be about 7.2 per 1000.
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Recent studies support the belief that schizophrenia has a similar incidence in all populations.
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The incidence of early-onset schizophrenia has reportedly decreased over the past four decades.
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Schizophrenia is more common in men than women, with a male:female ratio of 1.4:1.
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The difference in schizophrenia prevalence between men and women is not due to differences in referral, identification, or age of onset.
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A meta-analysis showed an increase in fertility in people with schizophrenia, with men experiencing the most substantial increase.
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Acute psychosis in schizophrenia is associated with excessive dopamine neurotransmission in the basal ganglia.
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Environmental factors that act early in life have no influence on the development of schizophrenia.
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The mode of inheritance for schizophrenia is straightforward, and genes deterministically cause the illness.
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Schizophrenia is considered to have a neurodevelopmental disturbance that increases vulnerability to symptom emergence.
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The neuroprotective effects of estrogen in reducing schizophrenia prevalence in women are well-supported by strong evidence.
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Single nucleotide polymorphisms in genes like ZNF804A are genetic factors associated with schizophrenia.
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The lifetime risk of schizophrenia for a monozygotic twin of a proband is 17%.
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Maternal malnutrition is an environmental factor that can contribute to the development of schizophrenia.
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According to Rudin's studies, the rate of dementia praecox was lower among the siblings of probands than in the general population.
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Early cannabis use is a social factor associated with schizophrenia.
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Copy number variation, such as the 22q11 deletion, is a genetic factor associated with schizophrenia.
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The concept of a schizophrenia spectrum is supported by the increased risk of schizophrenia-related disorders in first-degree relatives of patients with schizophrenia.
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The lifetime risk of schizophrenia for a child with one affected parent is higher than for a monozygotic twin of a proband.
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Ethnic minority status is a social factor that contributes to the development of schizophrenia.
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The dopamine hypothesis is one of the theoretical models for the etiology of schizophrenia.
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Schizophrenia follows a simple Mendelian pattern of inheritance.
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Genetic liability to schizophrenia is expressed when a certain threshold of genetic susceptibility is exceeded.
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Schizophrenia can be inherited as a single-gene dominant disorder in some families.
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Genome-wide association studies (GWAS) have been useful in identifying SNPs related to schizophrenia.
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Copy number variants (CNVs) do not contribute to schizophrenia risk.
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Epistasis is uncommon in complex genetic disorders like schizophrenia.
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Genetic studies of schizophrenia often investigate epistasis.
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Identifying schizophrenia genes has been difficult due to the genetic heterogeneity of the disorder.
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Single nucleotide polymorphisms (SNPs) typically have large effect sizes in schizophrenia.
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Linkage studies were highly successful in identifying the genetic basis of schizophrenia.
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Velocardiofacial syndrome (VCFS) is caused by deletion of one copy of chromosome 22q11.
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VCFS occurs in approximately 1 in 400 live births.
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About 50% of individuals with VCFS experience psychosis.
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DISC 1 was identified through studies of a large Scottish family involving a translocation between chromosomes 1 and 11.
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It is clear that DISC 1 has the same role in schizophrenia outside the Scottish family where it was first identified.
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SNPs collectively explain about 60% of the genetic risk for schizophrenia.
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Epigenetic factors are a potential source for the missing heritability of schizophrenia.
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Crow’s lateralization hypothesis, proposed in 2002, is widely supported in the scientific community.
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Around 0.14% of schizophrenia cases have a deletion at 15q13.3.
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An odds ratio of 3 is observed for duplications at locus 16p13.11.
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Schizophrenia genes often converge on N-methyl-D-aspartate (NMDA) receptor-mediated signaling pathways.
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Deletion of 22q11 is only associated with schizophrenia, not with any other neurodevelopmental or neuropsychiatric syndromes.
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The NRXN1 deletion has an odds ratio of 9 for schizophrenia.
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About 90% of copy number variants seen in schizophrenia are inherited.
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A duplication at 1q21.1 is associated with an odds ratio of 2 for schizophrenia.
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The deletion at 1q21.1 is associated with microcephaly and heart defects as other phenotypes.
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Rare variants in the gene SETD1A have an odds ratio of 11 for schizophrenia.
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A significant copy number variant for schizophrenia is a duplication at 22q11.2 with multiple phenotypes including cardiac issues.
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Luxenberger's study found concordance in 11 of 19 dizygotic twins for schizophrenia.
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The rate of concordance for schizophrenia is several times higher in monozygotic twins than in dizygotic twins.
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Heritability for schizophrenia from population studies is estimated to be around 81%.
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Among discordant monozygotic twins, the risk of schizophrenia does not increase in the children of the unaffected co-twin.
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Modern twin studies separate environmental factors into those that are unique to the individual and those shared with others.
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Adopted-away children of mothers with schizophrenia have similar schizophrenia rates to children raised by their biological schizophrenic parents.
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The meta-analysis of twin studies concluded that individual-specific environmental influences contribute more to the environmental risk for schizophrenia than shared environmental influences.
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The rate for schizophrenia among children of adopted schizophrenic parents is higher than among those raised without schizophrenic parents.
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The substantial heritability of schizophrenia is confirmed by genome-wide studies alone.
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Unaffected identical co-twins of individuals with schizophrenia can still exhibit some mild features of the disorder.
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Rates of schizophrenia are increased in individuals with obstetric complications compared to their unaffected siblings.
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The 1957 influenza A2 pandemic is the strongest example demonstrating that fetuses exposed during the second trimester to influenza have an increased risk of tuberculosis.
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Maternal malnutrition affecting DNA methylation is proposed as a mechanism increasing the risk of schizophrenia in offspring.
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Schizophrenia is less frequent among people born in the late winter compared to those born in the summer.
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Schizophrenia has the same risk association with paternal age regardless of whether the offspring is the first-born child or not.
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A meta-analysis of the 1957 influenza pandemic yielded positive results establishing a clear relationship between influenza and schizophrenia.
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Prenatal exposure to rubella has been associated with an increased risk of schizophrenia.
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Children born after the Dutch 'Hunger Winter' of 1944 exhibited a decreased risk of schizophrenia.
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The major histocompatibility complex (MHC) locus on chromosome 6 shows the strongest statistical association with schizophrenia.
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Sekar et al. (2016) found that the genetic signal to the MHC locus arises mainly from the complement component 5 (C5) gene.
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Individuals with the risk forms of C4 express the gene at higher levels, and this is associated with less pruning of synapses during brain development.
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Genes involved in NMDA receptor signaling and synaptic function are significantly affected by schizophrenia risk SNPs and CNVs.
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Environmental factors have no significant role in the etiology of schizophrenia.
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The relative risk of schizophrenia associated with maternal malnutrition is three times higher than with winter birth.
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Genetic testing for schizophrenia is commonly used in clinical practice for diagnostic purposes.
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The relative risk of schizophrenia from childhood trauma and adversity is higher than that from being an immigrant.
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Genetic discoveries in schizophrenia are leading directly to new pharmacotherapies.
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The item with the highest relative risk for schizophrenia in Table 11.6 is life events.
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Study Notes
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
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Description
Estimates and methodology of schizophrenia incidence and prevalence, with a focus on diagnostic criteria and population differences.
