Abstract Background and Hypothesis Elucidating the neurobiological and psychological mechanisms that promote resilience to the adverse effects of schizophrenia’s genetic and environmental risk architecture may reveal new avenues for advancing treatment and prevention. Identification of genetic loci associated with schizophrenia resilience enables links between protective polygenic variation, non-genetic resilience factors, and intermediate phenotypes. This approach may help identify protective traits and delineate potentially evolutionarily shaped resilience mechanisms that attenuate schizophrenia pathophysiology across biological levels. Study Design This narrative review integrates current concepts in psychiatric resilience research with findings from schizophrenia resilience genetics and evolutionary medicine. Within a decompositional, dimensional framework, we summarize evidence for trait-level resilience factors that may be linked to schizophrenia resilience variants and discuss candidate neurobiological mechanisms. Study Results Schizophrenia’s substantial fitness costs and evolutionary dynamics may have favored common genetic variants that buffer elevated polygenic liability and promote resilience to the disorder. Existing evidence implicates protective traits across obstetric, immunological, cognitive, and visual-system domains as candidate mediators of resilience to schizophrenia pathophysiology. Conclusions Current findings suggest that common genetic variants may confer resilience to schizophrenia by enhancing neural plasticity, fluid intelligence, and visual cognition. Immune-related and obstetric pathways remain promising candidates, although direct links to resilience variants have not been established. Such mechanisms may reflect evolutionarily shaped adaptations that attenuate risk-allele penetrance and could also modify clinical expression, course, and somatic comorbidity. Their characterization may provide initial insights into the neurobiology of schizophrenia resilience and identify targets for preventive and disease-modifying interventions.
Abstract The resilience paradigm offers a complementary perspective to risk-focused models of psychosis by asking how favorable outcomes can be maintained or regained despite substantial vulnerability, adversity, or illness-related burden. Schizophrenia resilience research encompasses both processes that buffer antecedent risk and reduce the likelihood that vulnerability leads to psychotic illness, and those that support adaptation and recovery after illness onset. Drawing on clinical, psychological, social, and biological research, we consider the relationship between resilience and recovery, resilience-promoting processes, structural and societal influences, and genetic and neurobiological factors. A resilience perspective can extend current approaches by placing greater emphasis on mechanisms and conditions that support adaptation to adversity across the course of illness.
Abstract Background and Hypothesis Air pollution exposure has been associated with altered neurodevelopment and increased risk of schizophrenia. Individuals at high genetic risk may be more vulnerable to these effects. Here, we examined how air pollution relates to brain structure and functional connectivity in adolescents, and we tested for the first time whether genetic risk for schizophrenia exacerbates these effects. Study Design We included n = 1580 individuals with information on genetic risk for schizophrenia, air pollution at 9-10 years, and structural and resting-state functional magnetic resonance imaging at 13-14 years from the Adolescent Brain Cognitive Development Study. We used linear mixed-effects models to examine the association between air pollution (ambient particulate matter (PM₂.5), nitrogen dioxide (NO₂), and ozone (O₃)) and brain measures, and test whether genetic risk for schizophrenia moderated these effects. Study Results Higher PM₂.5 was associated with smaller right frontal pole surface area (p-FDR = 0.039). Individuals with low polygenic risk scores for schizophrenia (PRS-SCZ) and medium PM₂.5 had smaller left caudate volumes compared with those with medium PRS-SCZ and medium PM₂.5 (p-FDR = 0.019). In individuals with low PRS-SCZ, higher PM₂.5 was associated with larger left (p-FDR = 0.019) and right (p-FDR = 0.018) caudate volumes. Higher NO₂ was associated with stronger negative functional connectivity between default mode and dorsal attention networks (p-FDR = 0.034) and weaker positive functional connectivity between dorsal attention and frontoparietal networks (p-FDR = 0.034). Conclusions Air pollution and its interplay with genetic risk for schizophrenia are associated with structural and functional changes in areas implicated in schizophrenia pathophysiology. This underscores the potential of lowering air pollution during critical periods of neurodevelopment and informing proactive environmental policies.
