In summary

The development of schizophrenia involves a complex interplay of both genetic, environmental, and other risk factors
The discovery of highly expressed schizophrenia-related genes and associated biological neurodevelopmental processes have not yet directly led to any novel therapies
An improved understanding of the link between genetic, environmental, and other risk factors and their associated implications for underlying biology may be key for developing novel therapies and tailored treatment

Schizophrenia develops as a result of patient-specific interactions between genetic, environmental, and broader risk factors, from urban living to recreational drug use. While no one factor is considered more important than another, physicians require a deep appreciation of how they interact in order to better assess how vulnerable a patient is to schizophrenia and to ensure that adequate support is in place for their well-being.^1,2

Starting with the genetics

A growing body of evidence is defining a complex picture of schizophrenia-related genes. Genome-wide association studies, borne out of international collaborative efforts with extensive datasets, have so far identified nearly 300 schizophrenia-related loci.^3‒6

While understanding the relative contributions of these many loci is a daunting task, groups are employing novel multi-omic approaches to meet this challenge. The use of such approaches, combined with an improved understanding of the function of protein-coding regions, has revealed novel insights into the molecular mechanisms underlying schizophrenia.⁷

Genetic risk loci identified so far implicate biological processes related to the neurodevelopment of schizophrenia.¹ Furthermore, transcription analysis has demonstrated increased expression of many of these schizophrenia-related alleles in the prefrontal cortex during early mid-fetal development, as well as further changes in genetic expression during the transition from late childhood into adolescence.⁸

The additional impact of the environment

While the impact of genetic risk factors cannot be ignored, these must be considered within the context of the patient's environment. Several non-genetic risk factors have been identified that may contribute to schizophrenia, including obstetric complications, infections, urban living, childhood adversity, and cannabis use.²

Several groups have started to examine the additive effects of multiple environmental factors, and new data provide intriguing evidence of associations between non-genetic risk factors and aspects of brain function.² While delineating the association between environmental factors and brain function is proving to be a complex challenge, it is beginning to highlight that psychotic syndromes can be viewed as an adaptive response to the environment.⁹ Exposure to different factors, particularly early in life, may have an impact on the developing “social” brain. Therefore, alone or in combination with genetic risk factors, an individual's environment plays an important role in their risk of developing schizophrenia.^2,9

Risk factors further amplify susceptibility

Genetic and environmental factors, of course, are not solely responsible for differences between individuals. Instead, characteristics arise due to a complex interplay between genetics, the environment, and other risk factors.^10,11 These may include nutrition, perinatal vitamin D levels, infection with human endogenous retroviruses, smoking, intelligence quotient, and social cognition among others.^10,11

The effect of such factors, while individually weak, can be cumulatively significant and have the effects amplified by underlying genetic and wider environmental factors. If these combinations occur at critical periods of development, they can have a sufficient magnitude to drive the development of schizophrenia.¹⁰ Therefore, this raises the possibility of applying appropriate and targeted interventions to those who are at the greatest risk, the challenge being to identify such individuals or groups early enough to prevent the cumulative impact of risk factors.

Tying it all together to improve patient care

An improved understanding of the underlying neuropathological mechanism of schizophrenia in conjunction with a greater insight into the impact of risk profile may support identification of novel targets for treatment and drug development.¹ Advances in phenotyping by underlying biology in multiple sclerosis provide an aspirational example of a move towards more personalized treatments in the central nervous system therapy area.¹²