Genetic and Environmental Influences on Psychotic Disorders

Psychotic disorders arise from a complex interplay between inherited susceptibility and environmental exposures. Twin and family studies estimate heritability of schizophrenia and related conditions at around 70–80%, reflecting contributions of numerous common genetic variants of small effect alongside rare variants of larger effect. Genome-wide association studies have identified hundreds of loci implicating synaptic function, immune signalling and neurodevelopmental pathways. Polygenic risk scores (PRSs) enable quantification of an individual’s aggregate genetic liability, which correlates with clinical severity, cognitive deficits and risk of diagnostic shifts over time. However, genetic predisposition alone does not determine outcome. Exposure to environmental factors such as obstetric complications, childhood trauma, urban living, cannabis use and socioeconomic adversity modulates risk and influences symptom expression. Gene–environment interactions further shape trajectories, with variants in specific genes altering sensitivity to environmental stressors. Advances in neuroimaging and endophenotypic measures illuminate intermediate phenotypes, while longitudinal cohort studies reveal dynamic symptom trajectories in patients, their relatives and general populations. Integrating genetic, epigenetic and exposomic data holds promise for personalized risk prediction and targeted prevention strategies worldwide.

Research from Nature Portfolio

Longitudinal analysis of patients with psychotic disorders, their unaffected siblings and healthy controls identified up to four homogenous symptom-trajectory subgroups for positive and negative dimensions over six years. Group-based trajectory modelling distinguished decreasing, increasing and relapsing courses in patients, and stable or changing schizotypy in siblings and controls. Multinomial logistic regression revealed that non-genetic factors—baseline symptom severity, premorbid adjustment, depressive symptoms and quality of life—rather than polygenic risk scores, were the strongest predictors of long-term trajectories in patients and siblings. These findings underscore the dominant influence of environmental and clinical factors on symptom course and highlight the need for early psychosocial interventions.

Genetic and Environmental Influences on Psychotic Disorders publication trend

The graph below shows the total number of articles in genetic and environmental influences on psychotic disorders across all publications each year (not limited to Nature Index journals).

Technical terms

Polygenic Risk Score (PRS): A quantitative estimate of an individual’s inherited risk for a disorder, calculated by summing the effects of numerous genetic variants identified from genome-wide studies.

Endophenotype: A heritable, measurable intermediate trait—such as cognitive function or brain activation patterns—that lies on the pathway between genes and clinical symptoms.

Genome-Wide Association Study (GWAS): A hypothesis-free approach that scans the genome for common variants associated with a trait or disorder in large populations.

Gene–Environment Interaction: A phenomenon where the effect of an environmental exposure on disease risk depends on an individual’s genetic makeup, or vice versa.

Group-Based Trajectory Modelling: A statistical method for identifying distinct longitudinal patterns of symptom development within a heterogeneous population.

Psychotic-Like Experiences (PLEs): Subclinical perceptual and cognitive phenomena that resemble psychosis symptoms, assessed dimensionally in the general population.

References

1. Association of neurotransmitter pathway polygenic risk with specific symptom profiles in psychosis. Molecular Psychiatry (2024).
2. Common genetic variants contribute to heritability of age at onset of schizophrenia. Translational Psychiatry (2023).
3. Gene–environment pathways to cognitive intelligence and psychotic-like experiences in children. eLife (2024).
4. Six-year trajectories and associated factors of positive and negative symptoms in schizophrenia patients, siblings, and controls: Genetic Risk and Outcome of Psychosis (GROUP) study. Scientific Reports (2023).