Schizophrenia Lecture 10: Aetiology Overview

Schizophrenia Lecture 10

• Core Textbook Reading: Kalat, J.W. (2019). Biological Psychology, 13th edition. Boston, Massachusetts: Cengage Learning; Chapter 14: Module 14.3.

Aetiology of Schizophrenia

• Both genetic and environmental factors contribute to the cause of schizophrenia.
• Studies indicate a genetic predisposition to schizophrenia can be passed down.
• Research evidence for genetic transmission comes from family studies, twin studies, and adoption studies.

Twin Studies

• Concordance rates in identical twins (MZ) show a predisposition to schizophrenia is heritable.
• However, concordance rates are not 100%, proving environmental factors also play a crucial role.
• Some individuals can carry genes for schizophrenia but do not develop the disorder.
• Analyses of medical records (Norway and Denmark) support a genetic interpretation of high concordance rates in MZ twins.
• Gottesman & Bertelson (1989) research asks about children of discordant MZ twins, to understand risk of schizophrenia, considering twins eventually become parents.
• Data from MZ twins show children of twins without schizophrenia have similar risk as those with schizophrenia, but different rates were shown in DZ twins.
• These studies suggest genetic vulnerability that offspring inherit, even if individuals weren't diagnosed themselves.
• Twin studies have limitations - twins are not representative of the general population, experiencing different birth complications and varying mortality rates.
• Twins spend more time together and have similar social networks, increasing likelihood of shared environmental experiences, thus potentially confounding the results.
• Parental treatment differences exist between MZ and DZ twin pairs.
• All these factors lead to confounding environmental variables.

Large-scale Twin Study

• The large-scale Danish twin study (Hilker et al., 2018) reported concordance rates of 33% in MZ twins and 7% in DZ twins.
• Genetic heritability was estimated at 79%.
• The proband-wise method used in this study increases concordance rates, but it was criticized for the possibility to double-count cases
• The study highlights that only 15% of MZ twin pairs became concordant
• The 33% rate reported was a result of using this method partially.
• The modelling used to calculate genetic heritability in twin studies faces criticism (Torrey et al., 2019).
• The models rely on inaccurate assumptions – twins being similar to general populations and the same shared environment effects on both MZ & DZ pairs and minimal gene-environment interactions.

Adoption Studies

• Adoption studies examine adopted children who develop schizophrenia, which support a genetic basis for schizophrenia.
• Genetic and rearing factors can be analyzed in adoption studies.
• Hypothesis: Adults with schizophrenia adopted as children are more likely to have biological relatives with schizophrenia compared with those not affected.
• Kety (1994) compared relatives of adoptees with and without schizophrenia and found that first-degree biological relatives of adoptees with schizophrenia had a 12.5% rate of schizophrenia.
• This was corroborated by similarities in findings with other adoption studies with findings from Heston (1966) and Kety (1988)
• Tienari et al. (2004) did a long-term follow-up Finnish nationwide sample of adoptees.
• Families were studied for presence or absence of schizophrenia, comparing high and low genetic risk groups in family environments
• Clinical observations and interviews were used to understand family functioning by using the Oulu Family Rating Scale (OPAS)
• Tienari found a higher probability of schizophrenia among children with biological mothers with schizophrenia, but did not see the same in the low genetic risk group.
• The probability of schizophrenia was higher for children from mothers with schizophrenia and dysfunctional families.

Diathesis-Stress Model

• A model explaining increased susceptibility to schizophrenia by converging prenatal health issues with later stressors in adolescence/childhood.

Heritability of Schizophrenia

• Questions remain unanswered about the transmission, what is being inherited, genes related to the disorder and their control processes.

Efforts to Locate a Gene

• Schizophrenia is not caused by a single gene but likely multiple susceptibility genes with small effects, interacting with epigenetic and environmental factors (Cannon, 2015; Van Os & Kapur, 2009; Mueser & McGurk, 2004).
• Relevant genes include:
• COMT (catechol-O-methyltransferase) is involved in dopamine metabolism.
• G72 is thought to influence glutamatergic activity
• Neuregulin 1 is linked to NMDA, GABA, and ACh receptor regulation.
• Dysbindin influences presynaptic glutamate.
• DISC1 (disrupted in schizophrenia 1) gene impacts neuron differentiation and migration and also dendritic spine production and new neuron generation in the hippocampus.

GWAS Study

• An ambitious genome-wide association study (GWAS) by the Schizophrenia Working Group of the Psychiatric Genomics Consortium (2014) analyzed >35,000 individuals with schizophrenia and >110,000 controls.

• This identified 108 distinct loci, including 83 not previously linked to schizophrenia.

• Notable gene locations include genes for dopamine receptor D2 implicated in dopamine neurotransmission, genes for glutamatergic neurotransmission, and genes expressed in immune tissues, which supports a link between schizophrenia and the immune system.

• Ma et al. (2018) identified 6 crucial genes linked to increased schizophrenia risk, five relating to neurodevelopment.

In Summary

• Many genes are involved in schizophrenia, with small effects, and unknown transmission and expression (Coelewij & Curtis, 2018).
• A polygenic risk score can explain at least 7% of schizophrenia liability (Kendler, 2016).
• Around 5% of schizophrenia cases are linked to rare copy number variants (CNVs).
• Some CNVs significantly increase schizophrenia risk (Lowther et al., 2017).