Influence of polygenic risk scores for schizophrenia and resilience on the cognition of individuals at-risk for psychosis

Anton Iftimovici,Guy A Rouleau,Boris Chaumette,Gabrielle Houle,Célia Mam-Lam-Fook ,Marie‐Odile Krebs ,Johanna Gradels Hauguel,Patrick A Dion,Calwing Liao,Qiaojun He ,Julie Chaignaud,Oussama Kébir ,Charlotte Danset-Alexandre

doi:10.1038/s41398-021-01624-z

Abstract

Cognitive impairment is a core feature of schizophrenia which precedes the onset of full psychotic symptoms, even in the ultra-high-risk stage (UHR). Polygenic risk scores (PRS) can be computed for many psychiatric disorders and phenotyping traits, including scores for resilience. We explored the correlations between several PRS and neurocognition in UHR individuals. We included 107 UHR individuals; 29.9% of them converted to psychosis (UHR-C) while 57.0% did not (UHR-NC) during the 1-year follow-up. Cognitive performances were assessed with the Wechsler Adult Intelligence Scale estimating the Intelligence Quotient (IQ), the Trail Making Test, the verbal fluency, the Stroop test, and the Wisconsin card sorting test. Linear regression models were used to test their association with the PRS for schizophrenia, bipolar disorder, major depression, ADHD, cross-disorders, cognitive performance, intelligence, education attainment, and resilience to schizophrenia. UHR-C had a lower IQ than UHR-NC. The PRS for schizophrenia negatively correlated with IQ, while the PRS for cognitive performance and for resilience positively correlated with IQ. PRS for schizophrenia showed a significant correlation with working memory and processing speed indices. PRS for schizophrenia showed a higher effect on IQ in UHR-NC, and UHR-NC with high PRS for schizophrenia had a similar IQ as UHR-C. Conversely, UHR-C with a high PRS for resilience performed as well as UHR-NC. Our findings suggest that cognitive deficits may predate the onset of psychosis. The genetic architecture of schizophrenia seems to impacts the cognition in UHR-NC. Cognition is also mediated by PRS for resilience.

Highlights

Schizophrenia is a disabling psychiatric disorder emerging during adolescence and including a large range of positive symptoms, negative symptoms, disorganization of thoughts and behavior, as well as cognitive deficits
The future converters (UHR-C) showed a significant lower Intelligence Quotient (IQ) at baseline than the future non-converters (UHR-NC) (Mean difference = −8 points of IQ; Student T test; P = 0.01, Table 1), the selected genome-wide association studies (GWAS) were not able to predict the conversion to psychosis in ultra-high risk state (UHR) individuals (Supplementary Table 1, uncorrected P = 0.086 for Polygenic risk scores (PRS) for schizophrenia) [40]
The PRS derived from other major psychiatric disorders, intelligence in the general population and educational attainment were not significantly associated with full IQ (FIQ)

Summary

Introduction

Schizophrenia is a disabling psychiatric disorder emerging during adolescence and including a large range of positive symptoms, negative symptoms, disorganization of thoughts and behavior, as well as cognitive deficits These deficits can involve several cognitive domains, including attention, working memory, verbal learning and memory, and executive functions. These deficits may pre-date the onset of schizophrenia and have been reported in early phases of the disorder, namely the ultra-high risk state (UHR) and the first episode of psychosis (FEP). Familial high risk individuals, defined as young people with familial history of schizophrenia, exhibit similar cognitive deficits as UHR, except for a higher impairment on Intelligence Quotient (IQ) [6]. We hypothesize that whole-genome liability for schizophrenia may explain cognitive impairments seen in early phases of psychosis as this is the case in general population [2]

Methods

Results

Conclusion