Abstract
Event-related potential (ERP) components have been used to assess cognitive functions in patients with psychotic illness. Evidence suggests that among patients with psychosis there is a distinct heritable neurophysiologic phenotypic subtype captured by impairments across a range of ERP measures. In this study, we investigated the genetic basis of this “globally impaired” ERP cluster and its relationship to psychosis and cognitive abilities. We applied K-means clustering to six ERP measures to re-derive the globally impaired (n = 60) and the non-globally impaired ERP clusters (n = 323) in a sample of cases with schizophrenia (SCZ = 136) or bipolar disorder (BPD = 121) and healthy controls (n = 126). We used genome-wide association study (GWAS) results for SCZ, BPD, college completion, and childhood intelligence as the discovery datasets to derive polygenic risk scores (PRS) in our study sample and tested their associations with globally impaired ERP. We conducted mediation analyses to estimate the proportion of each PRS effect on severity of psychotic symptoms that is mediated through membership in the globally impaired ERP. Individuals with globally impaired ERP had significantly higher PANSS-positive scores (β = 3.95, P = 0.005). The SCZ-PRS was nominally associated with globally impaired ERP (unadjusted P = 0.01; R2 = 3.07%). We also found a significant positive association between the college-PRS and globally impaired ERP (FDR-corrected P = 0.004; R2 = 6.15%). The effect of college-PRS on PANSS positivity was almost entirely (97.1%) mediated through globally impaired ERP. These results suggest that the globally impaired ERP phenotype may represent some aspects of brain physiology on the path between genetic influences on educational attainment and psychotic symptoms.
Highlights
In recent years, traditional psychiatric diagnostic constructs have been increasingly challenged
All participants were of self-reported European ancestry, between 18 and 65 years of age, with no history of neurological disorders, no history of head injury, no substance abuse or dependence in the preceding 12 months, normal hearing confirmed by audiometric testing, and normal intelligence based on the North American Adult Reading Test (NAART)
In the analysis restricted to cases only, there was no significant difference in age or other demographic variables between the two event-related potential (ERP) clusters
Summary
Traditional psychiatric diagnostic constructs have been increasingly challenged. In line with shared genetic susceptibility, the endophenotype–biomarker literatures on BPD–SCZ indicate differences in degree, rather than differences in kind, across various domains of brain function, both in patients and in their clinically unaffected relatives[6,7,8,9,10,11,12] These observations challenge the traditional dichotomous model of SCZ and BPD and support a dimensional approach to understanding how genetic and. Auditory event-related potential (ERP) components— including P50 sensory gating, N1, P2, and P3—have been extensively investigated in the psychoses and are putative endophenotypes for psychotic spectrum disorders[7,13,14,15,16,17] Each of these ERP components measures specific aspects of brain function and is reliably quantifiable across diverse clinical and laboratory settings[11,18]. We have shown that ERP phenotypes are heritable and genetically correlated with BPD and SCZ8,9,15
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