Polygenic risk for schizophrenia and neurocognitive performance in patients with schizophrenia

Abstract

Both neurocognitive deficits and schizophrenia are highly heritable. Genetic overlap between neurocognitive deficits and schizophrenia has been observed in both the general population and in the clinical samples. This study aimed to examine if the polygenic architecture of susceptibility to schizophrenia modified neurocognitive performance in schizophrenia patients. Schizophrenia polygenic risk scores (PRSs) were first derived from the Psychiatric Genomics Consortium (PGC) on schizophrenia, and then the scores were calculated in our independent sample of 1130 schizophrenia trios, who had PsychChip data and were part of the Schizophrenia Families from Taiwan project. Pseudocontrols generated from the nontransmitted parental alleles of the parents in these trios were compared with alleles in schizophrenia patients in assessing the replicability of PGC-derived susceptibility variants. Schizophrenia PRS at the P-value threshold (PT) of 0.1 explained 0.2% in the variance of disease status in this Han-Taiwanese samples, and the score itself had a P-value 0.05 for the association test with the disorder. Each patient underwent neurocognitive evaluation on sustained attention using the continuous performance test and executive function using the Wisconsin Card Sorting Test. We applied a structural equation model to construct the neurocognitive latent variable estimated from multiple measured indices in these 2 tests, and then tested the association between the PRS and the neurocognitive latent variable. Higher schizophrenia PRS generated at the PT of 0.1 was significantly associated with poorer neurocognitive performance with explained variance 0.5%. Our findings indicated that schizophrenia susceptibility variants modify the neurocognitive performance in schizophrenia patients.

Let’s Talk about the Association between Schizophrenia Polygenic Risk Scores and Cognition in Patients and the General Population: A Review

“…Since attention is strongly impaired in individuals with SZ, most studies considered this domain in their analyses. Significant associations between SZ-PRS and attention are only reported by Nakahara et al [27] , while other studies did not reveal any significant association between SZ-PRS and attention [28,33] . Post hoc analysis by Xavier et al [35] revealed a significant association between SZ-PRS and vigilance but the finding did not survive correction for multiple testing.…”

“…In summary, most studies with affected individuals did not find an association between SZ-PRS and cognition i.e., general cognitive abilities, specific cognitive domains or intelligence quotient (IQ). Only a few were able to find an association for general cognitive abilities [27,33] and for specific cognitive domains [27,33] . The picture from studies in the general population is similarly blurry.…”

“…Wang et al, 2018 [33] Schizophrenia Trio Genomic Research in Taiwan Whalley et al, 2016 [34] Generation Scotland:the Scottish Family Health Study: Xavier et al, 2018 [35] Clinical Antipsychotics Trials of Intervention Effectiveness-schizophrenia trial:…”

“…The Wisconsin Card Sorting Test (WCST) is also part of the MCCB as a valid measurement for reasoning and problem solving as subfunctions of executive functioning and has been applied in the study of Wang et al [33] . They report a significant association between the outcome measures perseverative responses, perseverative errors, conceptual level response and failure to maintain set and SZ-PRS, even though the overall outcome measure for the WCST did not reveal any significant association with SZ-PRS [33] . For problem solving Nakahara et al [27] report a significant negative correlation with SZ-PRS.…”

“…This composite score however, must be interpreted with caution since each study investigated different cognitive areas and applied different neurocognitive tests, leading to inconsistent findings. Wang et al [33] based their outcome measure for general cognitive abilities on the neurocognitive tests for sustained attention (CPT) and executive functioning (WCST; see Table 1) and reported a significant association with SZ-PRS. The composite score of the CMINDS, applied by Nakahara et al [27] , also showed a significant negative correlation between SZ-PRS and general cognitive abilities.…”