Gene–environment interaction is a concept in genetic epidemiology postulating that exposure to certain environmental conditions elicits expression of a phenotype (i.e., a disease state) in persons with specific gene alleles. Indeed, most diseases, including mental disorders, stem from an interaction between genes and the environment, rather than one or more genes alone. Uchiyama et al. observe that the gene–environment interaction is not yet an optimal equation to reliably predict disease occurrence. They argue that gene and environment are impactfully regulated by cultural evolution, or the density of cultural subgroups within a population that, along with diverse culturally dependent behaviors, significantly affect heritability estimates. In simpler terms, if environmental factors including pollution, pathogen, and pesticide levels, or dietary choices, affect the expression of susceptibility genes (Hunter, Reference Hunter2005; Rojas-Rueda et al., Reference Rojas-Rueda, Morales-Zamora, Alsufyani, Herbst, AlBalawi, Alsukait and Alomran2021), then according to Uchiyama et al. different culturally driven approaches to the environment along with the use of advanced technologies that are protective against environmental risk factors can further regulate gene responses. As an example, application of sunscreen alleviates the risk conferred by ultraviolet (UV) exposure on development of skin cancer in genetically at-risk populations. Thus cultural evolution can mitigate the impact of environmental risk on disease prevalence.

The need to describe additional factors underlying disease onset is implicitly recognized in studies of mental disorders. For example, schizophrenia is a mental illness resulting from a highly heritable albeit poorly understood genetic component. In the case of schizophrenia genetic risk variants include both rare genes and multiple common risk alleles with small effect sizes (Schizophrenia Working Group of the Psychiatric Genomics, 2014). Despite this genetic contribution, the majority (~90%) of individuals with schizophrenia have no parents with schizophrenia, and ~40% of monozygotic twins of schizophrenia patients remain healthy (Akdeniz, Tost, & Meyer-Lindenberg, Reference Akdeniz, Tost and Meyer-Lindenberg2014a; Svrakic, Zorumski, Svrakic, Zwir, & Cloninger, Reference Svrakic, Zorumski, Svrakic, Zwir and Cloninger2013). This evidence illustrates the power of environmental factors, including prenatal maternal stress, poor nutrition, infection or birth complications, as well as adolescent and adulthood behaviors such as addictive drug consumption and social factors such as emigration and minority status (van Os, Kenis, & Rutten, Reference van Os, Kenis and Rutten2010), in influencing gene expression leading to schizophrenia. These important risk factors share the potential to function as triggers to reveal the behavioral expression of mental illness, but they do not explain why only about 1% of the global population is consistently impacted by these non-genetic factors.

It is understood that reducing environmental variation increases the calculated heritability of disease (Stoolmiller, Reference Stoolmiller1999) and that populations living in geographical areas with high cultural homogeneity will exhibit higher heritability outcomes compared with culturally diverse populations. Conversely, areas with diversified cultural landscapes are expected to be exposed to more diverse culturally informed behavioral models that, if rapidly diffused, may confer protection against vulnerable genes and environmental risk factors. Thus, while many factors may underlie geographical differences in the prevalence of schizophrenia (Charlson et al., Reference Charlson, Ferrari, Santomauro, Diminic, Stockings, Scott and Whiteford2018; He et al., Reference He, Liu, Li, Guo, Gao, Bai and Lyu2020; Jablensky et al., Reference Jablensky, Sartorius, Ernberg, Anker, Korten, Cooper and Bertelsen1992), including socioeconomics, population density, and healthcare practices, based on the argument elaborated here perhaps cultural evolution, as defined by Uchiyama et al. should also be considered as a contributing factor in the gene–environment equation.

Examples of behaviors that have been shown to vary by culture globally include infant–caregiver attachment styles (Agishtein & Brumbaugh, Reference Agishtein and Brumbaugh2013) and maternal and/or infant healthcare (Beck et al., Reference Beck, Wojdyla, Say, Betran, Merialdi, Requejo and Van Look2010; Lee, Talegawkar, Merialdi, & Caulfield, Reference Lee, Talegawkar, Merialdi and Caulfield2013; Wang et al., Reference Wang, Wang, Darling, Perumal, Liu, Danaei and Fawzi2020; Yaya & Ghose, Reference Yaya and Ghose2019). In these examples, increased social engagement within families and/or communities and improved maternal and infant health would be expected to protect against risk factors known to increase the incidence of schizophrenia such as social isolation (Michalska da Rocha, Rhodes, Vasilopoulou, & Hutton, Reference Michalska da Rocha, Rhodes, Vasilopoulou and Hutton2018; Veling, Hoek, Selten, & Susser, Reference Veling, Hoek, Selten and Susser2011), birth complications, maternal stress (Davies et al., Reference Davies, Segre, Estrade, Radua, De Micheli, Provenzani and Fusar-Poli2020; Lipner, Murphy, & Ellman, Reference Lipner, Murphy and Ellman2019), and nutrition in infants and young children (Wahlbeck, Forsen, Osmond, Barker, & Eriksson, Reference Wahlbeck, Forsen, Osmond, Barker and Eriksson2001). Interestingly, this culturally driven biological protection may operate: (1) at the behavioral level (i.e., through healthier behavioral approaches to cope with environmental risks factors) and/or (2) through specific forms of neural plasticity. Moreover, protective behaviors established during childhood could alleviate the risk of detrimental behaviors including poor sleep practices or use of addictive substances, which may be linked to psychotic symptoms later in life (Evins, Green, Kane, & Murray, Reference Evins, Green, Kane and Murray2012; Waite, Sheaves, Isham, Reeve, & Freeman, Reference Waite, Sheaves, Isham, Reeve and Freeman2020). Similarly, a healthier social structure within families and societies, and improved support for children and caregivers could reduce the incidence of psychological and physical traumas linked to development of psychotic symptoms (Popovic et al., Reference Popovic, Schmitt, Kaurani, Senner, Papiol, Malchow and Falkai2019). Brain mechanisms through which culturally conditioned behaviors may modulate the expression of psychosis include changes in brain structure or compensatory alterations in molecular mechanisms of synaptic transmission. This hypothesis is bolstered by the fact that deficits in social interaction and communication are core pathologies in patients with schizophrenia (Fett et al., Reference Fett, Viechtbauer, Dominguez, Penn, van Os and Krabbendam2011; Green, Reference Green1996; Green, Horan, & Lee, Reference Green, Horan and Lee2015; Green, Waldron, & Coltheart, Reference Green, Waldron and Coltheart2007; van Os et al., Reference van Os, Kenis and Rutten2010) and that cortical and subcortical brain structure and function are altered by mild or chronic stress such as social deprivation or exclusion (Akdeniz et al., Reference Akdeniz, Tost, Streit, Haddad, Wust, Schafer and Meyer-Lindenberg2014b; Gianaros et al., Reference Gianaros, Jennings, Sheu, Greer, Kuller and Matthews2007; Liston, McEwen, & Casey, Reference Liston, McEwen and Casey2009; Luethi, Meier, & Sandi, Reference Luethi, Meier and Sandi2008).

Based on this hypothesis, application of healthier cultural models of communication and social engagement could deter the strengthening of neural pathways that permit psychosis (Canli & Lesch, Reference Canli and Lesch2007; Casey, Giedd, & Thomas, Reference Casey, Giedd and Thomas2000; Chiao & Blizinsky, Reference Chiao and Blizinsky2010; Cook & Black, Reference Cook and Black2012; Miller et al., Reference Miller, Chen, Fok, Walker, Lim, Nicholls and Kobor2009). Cultural factors, such as tolerance for diversity and diffusion of beneficial habits and scientific knowledge may significantly compensate for both genetic risk variants and exposure to environmental risks, conferring resilience through culturally informed behaviors. Consideration of cultural evolution theory could help to explain the consistent incidence of schizophrenia at ~1%, resulting from the presence of both genetic and environmental risks and the absence of protective behaviors. It is tempting to hypothesize that globalization, and rapid knowledge transfer through modern internet and telecommunications platforms could aid in more efficient cultural evolution across geographical distance.