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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.

SUBMITTER: Xavier RM

PROVIDER: S-EPMC5852279 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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

Xavier Rose Mary RM Dungan Jennifer R JR Keefe Richard S E RSE Vorderstrasse Allison A

Schizophrenia research. Cognition 20180128

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 loc ...[more]

PMID: 29552508

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Project description:ImportanceSchizophrenia is a clinically heterogeneous disorder. It is currently unclear how variability in symptom dimensions and cognitive ability is associated with genetic liability for schizophrenia.ObjectiveTo determine whether phenotypic dimensions within schizophrenia are associated with genetic liability to schizophrenia, other neuropsychiatric disorders, and intelligence.Design, setting, and participantsIn a genetic association study, 3 cross-sectional samples of 1220 individuals with a diagnosis of schizophrenia were recruited from community, inpatient, and voluntary sector mental health services across the UK. Confirmatory factor analysis was used to create phenotypic dimensions from lifetime ratings of the Scale for the Assessment of Positive Symptoms, Scale for the Assessment of Negative Symptoms, and the MATRICS Consensus Cognitive Battery. Analyses of polygenic risk scores (PRSs) were used to assess whether genetic liability to schizophrenia, other neuropsychiatric disorders, and intelligence were associated with these phenotypic dimensions. Data collection for the cross-sectional studies occurred between 1993 and 2016. Data analysis for this study occurred between January 2019 and March 2021.Main outcomes and measuresOutcome measures included phenotypic dimensions defined from confirmatory factor analysis relating to positive symptoms, negative symptoms of diminished expressivity, negative symptoms of motivation and pleasure, disorganized symptoms, and current cognitive ability. Exposure measures included PRSs for schizophrenia, bipolar disorder, major depression, attention-deficit/hyperactivity disorder, autism spectrum disorder, and intelligence.ResultsOf the 1220 study participants, 817 were men (67.0%). Participants' mean (SD) age at interview was 43.10 (12.74) years. Schizophrenia PRS was associated with increased disorganized symptom dimension scores in both a 5-factor model (β = 0.14; 95% CI, 0.07-0.22; P = 2.80 × 10-4) and a 3-factor model across all samples (β = 0.10; 95% CI, 0.05-0.15; P = 2.80 × 10-4). Current cognitive ability was associated with genetic liability to schizophrenia (β = -0.11; 95% CI, -0.19 to -0.04; P = 1.63 × 10-3) and intelligence (β = 0.23; 95% CI, 0.16-0.30; P = 1.52 × 10-10). After controlling for estimated premorbid IQ, current cognitive performance was associated with schizophrenia PRS (β = -0.08; 95% CI, -0.14 to -0.02; P = 8.50 × 10-3) but not intelligence PRS.Conclusions and relevanceThe findings of this study suggest that genetic liability for schizophrenia is associated with higher disorganized dimension scores but not other symptom dimensions. Cognitive performance in schizophrenia appears to reflect distinct contributions from genetic liabilities to both intelligence and schizophrenia.

Project description:MicroRNA-137 (miRNA-137; miR-137) is one of the important post-transcriptional regulators of the nervous system development, and its MIR137 gene rs1625579 polymorphism was reported to be a potential regulator for schizophrenia susceptibility. However, schizophrenia characteristics controlled by MIR137 rs1625579 polymorphism are still insufficiently understood. There were 3 groups included in the study: (a) subjects with diagnosis of schizophrenia (n = 150; 81-females, 69-males), (b) mentally healthy people (control group; n = 102; 66-females, 36-males) and (c) Belarusian indigenous male group (n = 295). Associations of rs1625579 with schizophrenia, symptom's severity and cognitive performance [by using Positive and Negative Syndrome Scale (PANSS) and Wisconsin Card Sorting Test (WCST), respectively] were studied, when compared to controls. Allele and genotype frequencies were investigated in Belarusian indigenous males. Rs1625579 displayed no association with schizophrenia in Belarusian population. Significant "symptom severity-genotype" interactions were revealed for schizophrenia patients. Patients with T/G genotype displayed lower severity of positive symptoms and general psychopathology compared to homozygous subjects. T/T genotype was associated with the highest symptom's severity. The negative symptom scores and the total PANSS-score were significantly higher in females carrying genotype T/T vs. T/G+G/G; no significant gene-phenotype associations were found in males. WCST parameters did not show any association with rs1625579 polymorphism. MIR137 rs1625579 polymorphism might be an important sex-dependent factor influencing severity of schizophrenia psychopathological manifestations. These findings also contribute to the knowledge on candidate gene effects on characteristics related to schizophrenia phenotype. As miR 137 is considered to be cancer therapeutic target, miR-137 may also explain the lower incidence of cancer in schizophrenia patients. Further studies with larger sample size are needed to confirm these novel findings.

Project description:Multiple sources of evidence suggest that genetic factors influence variation in clinical features of schizophrenia. The authors present the first genome-wide association study (GWAS) of dimensional symptom scores among individuals with schizophrenia.Based on the Lifetime Dimensions of Psychosis Scale ratings of 2,454 case subjects of European ancestry from the Molecular Genetics of Schizophrenia (MGS) sample, three symptom factors (positive, negative/disorganized, and mood) were identified with exploratory factor analysis. Quantitative scores for each factor from a confirmatory factor analysis were analyzed for association with 696,491 single-nucleotide polymorphisms (SNPs) using linear regression, with correction for age, sex, clinical site, and ancestry. Polygenic score analysis was carried out to determine whether case and comparison subjects in 16 Psychiatric GWAS Consortium (PGC) schizophrenia samples (excluding MGS samples) differed in scores computed by weighting their genotypes by MGS association test results for each symptom factor.No genome-wide significant associations were observed between SNPs and factor scores. Most of the SNPs producing the strongest evidence for association were in or near genes involved in neurodevelopment, neuroprotection, or neurotransmission, including genes playing a role in Mendelian CNS diseases, but no statistically significant effect was observed for any defined gene pathway. Finally, polygenic scores based on MGS GWAS results for the negative/disorganized factor were significantly different between case and comparison subjects in the PGC data set; for MGS subjects, negative/disorganized factor scores were correlated with polygenic scores generated using case-control GWAS results from the other PGC samples.The polygenic signal that has been observed in cross-sample analyses of schizophrenia GWAS data sets could be in part related to genetic effects on negative and disorganized symptoms (i.e., core features of chronic schizophrenia).

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

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

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