Polygenic signal for symptom dimensions and cognitive performance in patients with chronic schizophrenia

Abstract

Genetic etiology of psychopathology symptoms and cognitive performance in schizophrenia is supported by candidate gene and polygenic risk score (PRS) association studies. Such associations are reported to be dependent on several factors - sample characteristics, illness phase, illness severity etc. We aimed to examine if schizophrenia PRS predicted psychopathology symptoms and cognitive performance in patients with chronic schizophrenia. We also examined if schizophrenia associated autosomal loci were associated with specific symptoms or cognitive domains.Case-only analysis using data from the Clinical Antipsychotics Trials of Intervention Effectiveness-Schizophrenia trials (n = 730). PRS was constructed using Psychiatric Genomics Consortium (PGC) leave one out genome wide association analysis as the discovery data set. For candidate region analysis, we selected 105-schizophrenia associated autosomal loci from the PGC study.We found a significant effect of PRS on positive symptoms at p-threshold (PT) of 0.5 (R2 = 0.007, p = 0.029, empirical p = 0.029) and negative symptoms at PT of 1e-07 (R2 = 0.005, p = 0.047, empirical p = 0.048). For models that additionally controlled for neurocognition, best fit PRS predicted positive (p-threshold 0.01, R2 = 0.007, p = 0.013, empirical p = 0.167) and negative symptoms (p-threshold 0.1, R2 = 0.012, p = 0.004, empirical p = 0.329). No associations were seen for overall neurocognitive and social cognitive performance tests. Post-hoc analyses revealed that PRS predicted working memory and vigilance performance but did not survive correction. No candidate regions that survived multiple testing corrections were associated with either symptoms or cognitive performance. Our findings point to potentially distinct pathogenic mechanisms for schizophrenia symptoms.

Rare copy number variants in individuals at clinical high risk for psychosis: Enrichment of synaptic/brain‐related functional pathways

“…A prior study in schizophrenia patients found that negative symptoms were significantly more severe in cases with a higher number of CNV‐disrupted genes ( n ≥ 13) than a fewer number of CNV‐disrupted genes ( n ≤ 6) (Lee, Liu, Wen, Chang, & Hwu, ). Recent studies have reported that polygenic risk scores can strongly predict symptom dimensions in schizophrenia, namely both positive and negative symptoms (Xavier et al, ), and only negative symptoms (Bigdeli et al, ), suggesting that many schizophrenia risk loci may influence dimensions of symptomatology and clinical presentations of schizophrenia. Higher levels of self‐disturbance were found in CHR‐P individuals compared to controls and predicted time to transition to psychosis (Nelson, Thompson, & Yung, ).…”

“…Recent studies found significant associations between polygenic risk scores and symptom dimensions of schizophrenia (e.g., positive and negative symptoms, neurocognition) suggesting that many schizophrenia risk loci may influence the clinical presentation (Bigdeli et al, ; Xavier, Dungan, Keefe, & Vorderstrasse, ). A recent study supported the hypothesis that the common‐variant, genome‐wide association findings for schizophrenia point to a limited set of involved neurons, namely, medium spiny neurons, pyramidal neurons in hippocampal CA1, pyramidal neurons in the somatosensory cortex as well as cortical interneurons, and the gene sets also point to the same cells (Skene et al, ).…”

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

“…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.…”

“…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:…”

CHIMGEN: a Chinese imaging genetics cohort to enhance cross-ethnic and cross-geographic brain research

“…These studies have been primarily conducted using candidate-gene approaches and small samples, and they have been criticized based on the minimal effect size of a single variant and their lack of statistical power. In view of polygenic profiles of neuroimaging and cognitive phenotypes [61,62], genomic data should be integrated to identify normal and abnormal gene-brain-behavior pathways. Since environmental factors alone and gene-environment interactions affect neuroimaging and cognitive phenotypes [6,63,64], it is important to identify the environmental factors associated with these phenotypes, which would help better guide clinical practice to address these adverse environmental factors.…”