Etiology in psychiatry: embracing the reality of poly‐gene‐environmental causation of mental illness

Abstract

Intriguing findings on genetic and environmental causation suggest a need to reframe the etiology of mental disorders. Molecular genetics shows that thousands of common and rare genetic variants contribute to mental illness. Epidemiological studies have identified dozens of environmental exposures that are associated with psychopathology. The effect of environment is likely conditional on genetic factors, resulting in geneenvironment interactions. The impact of environmental factors also depends on previous exposures, resulting in environment-environment interactions. Most known genetic and environmental factors are shared across multiple mental disorders. Schizophrenia, bipolar disorder and major depressive disorder, in particular, are closely causally linked. Synthesis of findings from twin studies, molecular genetics and epidemiological research suggests that joint consideration of multiple genetic and environmental factors has much greater explanatory power than separate studies of genetic or environmental causation. Multi-factorial gene-environment interactions are likely to be a generic mechanism involved in the majority of cases of mental illness, which is only partially tapped by existing gene-environment studies. Future research may cut across psychiatric disorders and address poly-causation by considering multiple genetic and environmental measures across the life course with a specific focus on the first two decades of life. Integrative analyses of poly-causation including gene-environment and environmentenvironment interactions can realize the potential for discovering causal types and mechanisms that are likely to generate new preventive and therapeutic tools.

What causes psychosis? An umbrella review of risk and protective factors

“…On an etiopathological level, our findings corroborate the notion that psychotic disorders can be related to adversities in an individual's social milieu, whereby environmental exposures during critical developmental periods impact brain, neurocognition, affect, and social cognition 13,138 . It is also apparent that most of these factors are likely not specific to psychosis, but also associated with other mental disorders 139 . From a transdiagnostic perspective, the current study can provide a benchmark for comparing the magnitude of association of these factors with other nonpsychotic mental disorders.…”

“…To date, the integration of multiple non-purely genetic factors into "polyrisk" scores has been limited by the lack of established and robust a priori knowledge on their association with psychotic disorders 139 . The current umbrella review attempted to fill this knowledge gap by providing the most robust estimates of association (ORs) between several non-purely genetic risk (or protective) factors and psychotic disorders.…”

“…Recently, geneticists have advocated the development of polyrisk scores encompassing socio-demographic, parental, perinatal, later factors, antecedents, and genetic risk profiling 139,142 . Such an approach may ultimately reveal new, clinically useful predictors, because even the risk factors that we found to be weakly associated with psychotic disorders may eventually contribute to the predictive accuracy of the model, as previously observed for genetic associations 44 .…”

“…Such an approach may ultimately reveal new, clinically useful predictors, because even the risk factors that we found to be weakly associated with psychotic disorders may eventually contribute to the predictive accuracy of the model, as previously observed for genetic associations 44 . The current umbrella review lays the groundwork for testing the predictive accuracy of integrated polyrisk scores in independent samples 139 . Finally, on a pragmatic level, the current stratification of evidence can be used by clinicians, policy makers and regulatory bodies to inform and strategically target outreach campaigns, to promote the prevention of mental disorders in the youth population, and to raise awareness of risk factors for psychotic disorders.…”

Psychiatry and developmental psychopathology: Unifying themes and future directions

“…We focus on four interrelated principles, all of which acknowledge and embrace etiological complexity , an important theme in modern child, adolescent, and adult psychiatry [25,26]. These principles include calls for (1) multi disciplinary translational research [27,28], (2) specification of multi causal pathways to seemingly single diagnostic syndromes [26,29], (3) description of divergent multi final outcomes from common etiological starting points [29,30], and (4) research conducted across multiple levels of analysis spanning genes to environments [31,32]. After discussing these principles, we turn our attention to the importance of disrupted neuromaturational processes in developing psychopathology.…”