A polygenic risk score analysis of psychosis endophenotypes across brain functional, structural, and cognitive domains

Abstract

This large multi‐center study investigates the relationships between genetic risk for schizophrenia and bipolar disorder, and multi‐modal endophenotypes for psychosis. The sample included 4,242 individuals; 1,087 patients with psychosis, 822 unaffected first‐degree relatives of patients, and 2,333 controls. Endophenotypes included the P300 event‐related potential (N = 515), lateral ventricular volume (N = 798), and the cognitive measures block design (N = 3,089), digit span (N = 1,437), and the Ray Auditory Verbal Learning Task (N = 2,406). Data were collected across 11 sites in Europe and Australia; all genotyping and genetic analyses were done at the same laboratory in the United Kingdom. We calculated polygenic risk scores for schizophrenia and bipolar disorder separately, and used linear regression to test whether polygenic scores influenced the endophenotypes. Results showed that higher polygenic scores for schizophrenia were associated with poorer performance on the block design task and explained 0.2% (p = 0.009) of the variance. Associations in the same direction were found for bipolar disorder scores, but this was not statistically significant at the 1% level (p = 0.02). The schizophrenia score explained 0.4% of variance in lateral ventricular volumes, the largest across all phenotypes examined, although this was not significant (p = 0.063). None of the remaining associations reached significance after correction for multiple testing (with alpha at 1%). These results indicate that common genetic variants associated with schizophrenia predict performance in spatial visualization, providing additional evidence that this measure is an endophenotype for the disorder with shared genetic risk variants. The use of endophenotypes such as this will help to characterize the effects of common genetic variation in psychosis.

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.…”

“…While the studies of Ranlund and Whalley [28,34] were not able to find any association between SZ-PRS and verbal learning, Nakahara et al [27] showed a significant association between verbal learning and SZ-PRS. Also, in this case the post hoc analysis by Xavier et al [35] on a possible association between SZ-PRS and memory did not survive correction for multiple testing.…”

“…Nakahara et al, 2018 [27] • C: N = 136 Ranlund et al, 2017 [28] • Shafee et al, 2018 [29] Bipolar-Schizophrenia Network for Intermediate Phenotypes: van Os et al, 2017 [30] Genetic Risk and Outcome of Psychosis: • IQ (information, block design, digit symbol coding, arithmetic (WAIS); baseline & 3-year follow-up) • IQ (information (every third item), block design (uneven items), digit symbol coding, arithmetic (uneven items) (WAIS-III short form); 6-year follow-up)…”

“…Since there is an (endo-)phenotypic as well as genotypic overlap between bipolar disorder (BD), major depressive disorder (MDD), schizoaffective disorder (SA) and schizophrenia (SZ), some studies used mixed samples in their analyses [28,29,31,34] . In all studies SZ-PRS significantly differentiated between the different diagnostic groups.…”

Causal Inference on Pathophysiological Mediators in Psychiatry

“…Thus, the PRS provides a continuous, quantitative measure of an individual's overall genetic burden that can be associated with pathophysiological measures, such as gene/protein expression and brain activity/connectivity. For instance, PRSs have been recently associated with functional/structural brain imaging measures as well as cognitive performance in psychosis (Ranlund et al 2018). Likewise, the quantification of PRSs coupled with intermediate pathophysiological mediators can facilitate the translation of genetic findings into biological insights.…”