Aetiology
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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.

<p>True</p> Signup and view all the answers

Systematic reviews indicate a lifetime prevalence of about 7 per 1000 for schizophrenia.

<p>False</p> Signup and view all the answers

The lifetime morbid risk of developing schizophrenia is reported to be about 7.2 per 1000.

<p>True</p> Signup and view all the answers

Recent studies support the belief that schizophrenia has a similar incidence in all populations.

<p>False</p> Signup and view all the answers

The incidence of early-onset schizophrenia has reportedly decreased over the past four decades.

<p>False</p> Signup and view all the answers

Schizophrenia is more common in men than women, with a male:female ratio of 1.4:1.

<p>True</p> Signup and view all the answers

The difference in schizophrenia prevalence between men and women is not due to differences in referral, identification, or age of onset.

<p>True</p> Signup and view all the answers

A meta-analysis showed an increase in fertility in people with schizophrenia, with men experiencing the most substantial increase.

<p>False</p> Signup and view all the answers

Acute psychosis in schizophrenia is associated with excessive dopamine neurotransmission in the basal ganglia.

<p>True</p> Signup and view all the answers

Environmental factors that act early in life have no influence on the development of schizophrenia.

<p>False</p> Signup and view all the answers

The mode of inheritance for schizophrenia is straightforward, and genes deterministically cause the illness.

<p>False</p> Signup and view all the answers

Schizophrenia is considered to have a neurodevelopmental disturbance that increases vulnerability to symptom emergence.

<p>True</p> Signup and view all the answers

The neuroprotective effects of estrogen in reducing schizophrenia prevalence in women are well-supported by strong evidence.

<p>False</p> Signup and view all the answers

Single nucleotide polymorphisms in genes like ZNF804A are genetic factors associated with schizophrenia.

<p>True</p> Signup and view all the answers

The lifetime risk of schizophrenia for a monozygotic twin of a proband is 17%.

<p>False</p> Signup and view all the answers

Maternal malnutrition is an environmental factor that can contribute to the development of schizophrenia.

<p>True</p> Signup and view all the answers

According to Rudin's studies, the rate of dementia praecox was lower among the siblings of probands than in the general population.

<p>False</p> Signup and view all the answers

Early cannabis use is a social factor associated with schizophrenia.

<p>False</p> Signup and view all the answers

Copy number variation, such as the 22q11 deletion, is a genetic factor associated with schizophrenia.

<p>True</p> Signup and view all the answers

The concept of a schizophrenia spectrum is supported by the increased risk of schizophrenia-related disorders in first-degree relatives of patients with schizophrenia.

<p>True</p> Signup and view all the answers

The lifetime risk of schizophrenia for a child with one affected parent is higher than for a monozygotic twin of a proband.

<p>False</p> Signup and view all the answers

Ethnic minority status is a social factor that contributes to the development of schizophrenia.

<p>True</p> Signup and view all the answers

The dopamine hypothesis is one of the theoretical models for the etiology of schizophrenia.

<p>True</p> Signup and view all the answers

Schizophrenia follows a simple Mendelian pattern of inheritance.

<p>False</p> Signup and view all the answers

Genetic liability to schizophrenia is expressed when a certain threshold of genetic susceptibility is exceeded.

<p>True</p> Signup and view all the answers

Schizophrenia can be inherited as a single-gene dominant disorder in some families.

<p>False</p> Signup and view all the answers

Genome-wide association studies (GWAS) have been useful in identifying SNPs related to schizophrenia.

<p>True</p> Signup and view all the answers

Copy number variants (CNVs) do not contribute to schizophrenia risk.

<p>False</p> Signup and view all the answers

Epistasis is uncommon in complex genetic disorders like schizophrenia.

<p>False</p> Signup and view all the answers

Genetic studies of schizophrenia often investigate epistasis.

<p>False</p> Signup and view all the answers

Identifying schizophrenia genes has been difficult due to the genetic heterogeneity of the disorder.

<p>True</p> Signup and view all the answers

Single nucleotide polymorphisms (SNPs) typically have large effect sizes in schizophrenia.

<p>False</p> Signup and view all the answers

Linkage studies were highly successful in identifying the genetic basis of schizophrenia.

<p>False</p> Signup and view all the answers

Velocardiofacial syndrome (VCFS) is caused by deletion of one copy of chromosome 22q11.

<p>True</p> Signup and view all the answers

VCFS occurs in approximately 1 in 400 live births.

<p>False</p> Signup and view all the answers

About 50% of individuals with VCFS experience psychosis.

<p>False</p> Signup and view all the answers

DISC 1 was identified through studies of a large Scottish family involving a translocation between chromosomes 1 and 11.

<p>True</p> Signup and view all the answers

It is clear that DISC 1 has the same role in schizophrenia outside the Scottish family where it was first identified.

<p>False</p> Signup and view all the answers

SNPs collectively explain about 60% of the genetic risk for schizophrenia.

<p>False</p> Signup and view all the answers

Epigenetic factors are a potential source for the missing heritability of schizophrenia.

<p>True</p> Signup and view all the answers

Crow’s lateralization hypothesis, proposed in 2002, is widely supported in the scientific community.

<p>False</p> Signup and view all the answers

Around 0.14% of schizophrenia cases have a deletion at 15q13.3.

<p>True</p> Signup and view all the answers

An odds ratio of 3 is observed for duplications at locus 16p13.11.

<p>False</p> Signup and view all the answers

Schizophrenia genes often converge on N-methyl-D-aspartate (NMDA) receptor-mediated signaling pathways.

<p>True</p> Signup and view all the answers

Deletion of 22q11 is only associated with schizophrenia, not with any other neurodevelopmental or neuropsychiatric syndromes.

<p>False</p> Signup and view all the answers

The NRXN1 deletion has an odds ratio of 9 for schizophrenia.

<p>True</p> Signup and view all the answers

About 90% of copy number variants seen in schizophrenia are inherited.

<p>False</p> Signup and view all the answers

A duplication at 1q21.1 is associated with an odds ratio of 2 for schizophrenia.

<p>False</p> Signup and view all the answers

The deletion at 1q21.1 is associated with microcephaly and heart defects as other phenotypes.

<p>True</p> Signup and view all the answers

Rare variants in the gene SETD1A have an odds ratio of 11 for schizophrenia.

<p>False</p> Signup and view all the answers

A significant copy number variant for schizophrenia is a duplication at 22q11.2 with multiple phenotypes including cardiac issues.

<p>False</p> Signup and view all the answers

Luxenberger's study found concordance in 11 of 19 dizygotic twins for schizophrenia.

<p>False</p> Signup and view all the answers

The rate of concordance for schizophrenia is several times higher in monozygotic twins than in dizygotic twins.

<p>True</p> Signup and view all the answers

Heritability for schizophrenia from population studies is estimated to be around 81%.

<p>False</p> Signup and view all the answers

Among discordant monozygotic twins, the risk of schizophrenia does not increase in the children of the unaffected co-twin.

<p>False</p> Signup and view all the answers

Modern twin studies separate environmental factors into those that are unique to the individual and those shared with others.

<p>True</p> Signup and view all the answers

Adopted-away children of mothers with schizophrenia have similar schizophrenia rates to children raised by their biological schizophrenic parents.

<p>True</p> Signup and view all the answers

The meta-analysis of twin studies concluded that individual-specific environmental influences contribute more to the environmental risk for schizophrenia than shared environmental influences.

<p>False</p> Signup and view all the answers

The rate for schizophrenia among children of adopted schizophrenic parents is higher than among those raised without schizophrenic parents.

<p>True</p> Signup and view all the answers

The substantial heritability of schizophrenia is confirmed by genome-wide studies alone.

<p>False</p> Signup and view all the answers

Unaffected identical co-twins of individuals with schizophrenia can still exhibit some mild features of the disorder.

<p>True</p> Signup and view all the answers

Rates of schizophrenia are increased in individuals with obstetric complications compared to their unaffected siblings.

<p>True</p> Signup and view all the answers

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.

<p>False</p> Signup and view all the answers

Maternal malnutrition affecting DNA methylation is proposed as a mechanism increasing the risk of schizophrenia in offspring.

<p>True</p> Signup and view all the answers

Schizophrenia is less frequent among people born in the late winter compared to those born in the summer.

<p>False</p> Signup and view all the answers

Schizophrenia has the same risk association with paternal age regardless of whether the offspring is the first-born child or not.

<p>False</p> Signup and view all the answers

A meta-analysis of the 1957 influenza pandemic yielded positive results establishing a clear relationship between influenza and schizophrenia.

<p>False</p> Signup and view all the answers

Prenatal exposure to rubella has been associated with an increased risk of schizophrenia.

<p>True</p> Signup and view all the answers

Children born after the Dutch 'Hunger Winter' of 1944 exhibited a decreased risk of schizophrenia.

<p>False</p> Signup and view all the answers

The major histocompatibility complex (MHC) locus on chromosome 6 shows the strongest statistical association with schizophrenia.

<p>True</p> Signup and view all the answers

Sekar et al. (2016) found that the genetic signal to the MHC locus arises mainly from the complement component 5 (C5) gene.

<p>False</p> Signup and view all the answers

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.

<p>False</p> Signup and view all the answers

Genes involved in NMDA receptor signaling and synaptic function are significantly affected by schizophrenia risk SNPs and CNVs.

<p>True</p> Signup and view all the answers

Environmental factors have no significant role in the etiology of schizophrenia.

<p>False</p> Signup and view all the answers

The relative risk of schizophrenia associated with maternal malnutrition is three times higher than with winter birth.

<p>True</p> Signup and view all the answers

Genetic testing for schizophrenia is commonly used in clinical practice for diagnostic purposes.

<p>False</p> Signup and view all the answers

The relative risk of schizophrenia from childhood trauma and adversity is higher than that from being an immigrant.

<p>False</p> Signup and view all the answers

Genetic discoveries in schizophrenia are leading directly to new pharmacotherapies.

<p>False</p> Signup and view all the answers

The item with the highest relative risk for schizophrenia in Table 11.6 is life events.

<p>True</p> Signup and view all the answers

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

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