Polygenic Resilience Scores are Associated With Lower Penetrance of Schizophrenia Risk Genes, Protection Against Psychiatric and Medical Disorders, and Enhanced Mental Well-Being and Cognition

Abstract

Background and Hypothesis In the past decade, significant advances have been made in finding genomic risk loci for schizophrenia (SCZ). This, in turn, has enabled the search for SCZ resilience loci that mitigate the impact of SCZ risk genes. We identified the first genomic resilience profile for SCZ, completely independent from known risk loci for SCZ, though it remains unclear whether resilience loci foster protection against adverse states associated with SCZ involving clinical, cognitive, and brain-structural phenotypes. Study Design We analyzed genomic and phenotypic data from 459 784 participants from the UK Biobank, using regression models to estimate interaction effects of resilience and SCZ risk scores on phenotypes spanning multiple scales. Study Results We found that resilience loci for SCZ afforded protection against lifetime psychiatric (schizophrenia, bipolar disorder, anxiety, and depression) and medical disorders (such as type 2 diabetes, cardiovascular, and digestive and metabolic disorders). Resilience loci also moderated the impact of SCZ loci, associated with protection against self-harm behavior and greater fluid intelligence scores. The main effects of resilience are also observed in the absence of a moderating effect in some instances, such as associations with larger brain structures. Conclusions Overall, this study highlights a wide range of phenotypes that are significantly associated with resilience loci within the general population, revealing distinct patterns separate from those associated with SCZ risk loci. Resilience loci may protect against serious psychiatric and medical outcomes, comorbidities, and cognitive impairment. Therefore, it is conceivable that resilience loci facilitate adaptive processes linked to improved health and life expectancy.