Schizophrenia, a debilitating mental disorder marked by disruptions in thought processes, perceptions, emotional responsiveness, and social interactions, has a complex aetiology (NIMH, 2023). To date, twin studies have proved invaluable in determining the heritability of this illness, otherwise defined as the proportion of a disorder’s variability within a population attributable to genetic factors. These studies estimate heritability by examining discrepancies in the concordance rate (the probability that a second will twin will develop a disorder if the first examined has the disorder) between monozygotic twins, who share 100% of their DNA, and dizygotic twins, who share 50% of their DNA. This essay will first discuss the conclusions drawn from twin studies regarding the heritability of schizophrenia. It will then explore the limitations of these heritability estimates, focussing on two key elements. First, the reliance of twin studies on the Equal Environments Assumption (EEA), and how violations of this assumption limit the reliability of any conclusions drawn. Second, the notion of heritability erroneously partitions phenotypic variation of schizophrenia into genetic and environmental components, neglecting the relevance of gene-environment interactions on the disorder’s variability.

Gottesman and Shield’s seminal 1966 study with 57 pairs of twins showed a 48% concordance rate in monozygotic (MZ) twins, and 17% in dizygotic (DZ) twins, leading to a determined heritability rate of ~80% for schizophrenia (Gottesman & Shields, 1966). This co-twin MZ study design allowed for determinations of heritability by providing valuable controls for genetic proximity and (early) environmental effects. This has proved to be a reliable and robust finding, having been replicated in more recent and methodologically rigorous studies in countries such as Denmark and Finland (Klaning, 1996; Cannon, 1998), western European countries such as Germany and the UK (Franzek, 1998) as well as Eastern countries, such as Japan (Imamura, 2020). The heritable genetic risk is reaffirmed in studies observing the similar rates of the disorder amongst offspring of both unaffected and affected MZ twins, implying that unaffected MZ twins still carry the genetic risk even without expressing the disease (Gottesman, 1989). Although the generalisability of findings from twin studies has been considered a potential limitation, evidence suggests that the prevalence of psychiatric symptoms among twins does not differ significantly from that of the general population (Kendler et al., 1995).

While twin studies have been central to the determination that schizophrenia is ~80% heritable, the reliability of this statistic is limited due to its presupposition of the Equal Environment Assumption (EEA). This assumes that MZ and DZ twin pairs experience equivalent trait-relevant environmental exposures (Fosse et al., 2015). Violations of the EEA assumption may lead to an overemphasis on the genetic basis for MZ correlations due to the lack of consideration of the more similar environments experienced by MZ twins compared to DZ twins. This results in an overestimation of the genetic effect and an underestimation of the shared environmental effect. Importantly, robust evidence indicates greater environmental similarity amongst MZ twins compared to DZ twins, both in terms of their interactions (Dalgard, 1976) and their treatment (Joseph, 2004)

To illustrate how the EEA may skew heritability estimates from twin studies, consider how more similar early psychosocial stressors may contribute to increased schizophrenia concordance in MZ twins. Strong and robust correlations have been found between childhood psychosocial stressors and increased risk of schizophrenia (Alemany et al., 2012; Varese, 2012). However, a study exploring the EEA in the general twin population found that correlations in child social adversity was larger in identical than fraternal twins (Fosse et al., 2015). In each of five categories typically associated with child social adversity and schizophrenia (bullying, sexual abuse, physical maltreatment, emotional neglect, and general trauma) significantly higher correlations were observed in identical twin pairs than fraternal twin pairs (z > 3.53, p < 0.001). This finding remained consistent across gender, country, and sample size.

While the literature has yet to explore additional violations of the EEA, it is plausible that they exist regarding other environmental predictors of schizophrenia. Factors such as drug use, prenatal maternal infection, advanced parental age, migration, urbanicity, isolation, and others, have all emerged as significant environmental predictors of schizophrenia (Stilo et al., 2019). Thus, given the violation of the EEA with regards to early psychosocial adversities and schizophrenia, coupled with more general evidence towards the more analogous environments of MZ twins compared to DZ twins, it is reasonable to infer that heritability estimates from twin studies, due to their reliance on this assumption, overemphasise the role of genetics in the variability of schizophrenia and underestimate the role of more similar environmental conditions among MZ twins.

A second limitation of heritability estimates from twin studies is the neglect of gene-environment interactions, as traditional interpretations of heritability tend to stress either the role of genetics or the environment. Gottesman, who conducted the original 1966 twin study, suggested a Diathesis-Stress model for schizophrenia, in that twin discordance emerges when environmental stressors trigger an underlying (genetic) diathesis (Gottesman, 1989). Evidence towards this notion is visible in a number of the most prevalent environmental predictors of schizophrenia.

 As discussed, robust evidence implicates the role of early psychosocial stressors on the future risk of schizophrenia. However, newer research has identified genes (e.g., COMT, BDNF, CACNA1C, NRG1, FKBP5) that mediate the relationship between childhood adversity and an increased risk of schizophrenia (Mihaljevic, 2017; Tessner, 2011). Similarly, in an investigation of genetic and early psychosocial stressors and their role in determining the variability of schizophrenia, significant, additive interactions were found across the spectrum of phenotypic expression (Pries et al., 2020).

Drug use in early adolescence is another environmental factor that has been strongly associated with an increased risk of schizophrenia. However, newer research has found that psychosis as a result of cannabis use, for example, was linked to family histories of psychosis (Henquet et al., 2008). A number of genes have since been identified to mediate the relationship between psychoses-symptoms and cannabis, such as COMT, DRD2, FAAH, AKT1 (Caspi et al., 2005).

The role of prenatal environmental conditions in determining schizophrenia variability is also complicated by gene-environment interactions. For example, prenatal maternal infection with Toxoplasma, a neuro-invasive protozoan parasite, has been found to cause an 80% increased risk of schizophrenia (Brown et al., 2005). However, a genome-wide association study showed that susceptibility and immune response to TOXO infection is influenced by the presence of particular genes, such as CNTNAP2 and GABAR2 (Wang et al., 2019). Similar genetic modulators for prenatal infections have been observed with herpes simplex virus, cytomegalovirus, and rubella, all of which have been shown to increase the risk of developing schizophrenia (Dickerson, 2020; Prasad, 2012). Early psychosocial stressors, drug use, and prenatal maternal infection are just three of many environmental predictors for schizophrenia. Considering the interplay of genetics and environments in these predictors, it is reasonable to infer the substantial importance of gene-environment interactions in other factors influencing schizophrenia, an importance which heritability estimates from twin studies fails to adequately capture.

Twin study heritability estimates are further complicated by epigenetics, in which gene expression is modified by the environment without any modifications of the DNA code itself. This modification can result from external factors such as diet, disease, stress, and smoking (Al Aboud, 2022) Epigenetic theory challenges the notion that MZ twin discordance is an indicator of solely environmental effects, suggesting that phenotypic expression is influenced, in part, by epigenetic modifications. Methylation differences, a robust indicator of epigenetic processes, have been observed in MZ twins from infancy and only increase with age (Fraga et al., 2005). Notably, it has been shown that the epigenetic profile of a schizophrenic twin from a pair of discordant twins is more similar to the epigenetic profile of affected concordant twins than to their own unaffected co-twin (Petronis, 2003). This suggests that schizophrenic discordance among MZ twins is not solely due to exposure to different environmental risk factors, but because the expression of relevant schizophrenic traits are determined by epigenetic regulation (Castellani, 2015). While this does not undermine the ~80% heritability estimate for schizophrenia, it underscores the substantial role of epigenetics in the disorder’s variability, prompting a reconsideration of  traditional genetic interpretations of heritability estimates.

To conclude, while twin studies have provided an invaluable estimate for the heritability of schizophrenia, it is an estimate that must be approached with caution. The EEA, inherent in twin studies, risks attributing higher concordance in MZ twins solely to genetics, overlooking the role of their more similar environments. Violations of the EEA have been demonstrated with regards to early psychosocial stressors, and inferring similar violations regarding other environmental factors, thus weakens the reliability of heritability estimates from twin studies. Furthermore, the gene-environment dichotomy inherent to traditional interpretations of heritability faces increasing scrutiny. Substantial evidence indicates that environmental factors, such as early psychosocial stressors, drug use, and prenatal maternal infection, interact with genetic predispositions to shape schizophrenia variability,. Furthermore, the emergence of epigenetic evidence for schizophrenia variability, such as discordant methylation patterns in MZ twins, adds further complexity to heritability estimates derived from twin studies. Thus, while twin studies have been instrumental in our understanding of the genetic component in schizophrenia heritability, given the limitations discussed, any conclusions drawn should be treated with the appropriate caution.

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