Associations between schizophrenia polygenic liability, symptom dimensions and cognitive ability in schizophrenia

Sophie E Legge, Stanley Zammit, James T R Walters, et al.

Research output: Contribution to journalArticle (Academic Journal)peer-review

Abstract

Importance
Schizophrenia is a clinically heterogeneous disorder. It is currently unclear how variability in symptom dimensions and cognitive ability is related to genetic liability for schizophrenia.

Objective
To determine whether phenotypic dimensions within schizophrenia are associated with genetic liability to schizophrenia, other neuropsychiatric disorders and intelligence.

Design
Confirmatory factor analysis (CFA) was used to create phenotypic dimensions from lifetime ratings of the Scale for the Assessment of Positive Symptoms (SAPS), Scale for the Assessment of Negative Symptoms (SANS), and the MATRICS cognitive battery. Analyses of polygenic risk scores (PRS) were used to assess whether genetic liability to schizophrenia, other neuropsychiatric disorders, and intelligence were associated with these phenotypic dimensions.

Setting
Three cross-sectional samples of individuals with a diagnosis of schizophrenia recruited from secondary mental health services in the UK.

Participants
The study included a total of 1220 individuals with schizophrenia, 817 of whom were male (66.97%). Participants’ mean age at interview was 43.10 years (SD=12.74).

Main outcomes and measures
Outcome measures included phenotypic dimensions defined from CFA relating to positive symptoms, negative symptoms of diminished expressivity, negative symptoms of motivation and pleasure, disorganised symptoms, and current cognitive ability. Exposure measures included PRS for schizophrenia, bipolar disorder, major depression, ADHD, autism spectrum disorder, and intelligence.

Results
Schizophrenia PRS was associated with increased disorganised symptom dimension scores in both a 5-factor model (β[95% CI]=0.14[0.07,0.22];P=2.80x10-4) and a 3-factor model across all samples (β[95% CI]=0.10[0.05,0.15];P=2.80x10-4). Current cognitive ability was associated with genetic liability to schizophrenia (β[95% CI]=-0.11[-0.19,-0.04];P=1.63x10-3) and intelligence (β[95% CI]=0.23[0.16,0.30];P=1.52x10-10). After controlling for estimated premorbid IQ, current cognitive performance was associated with schizophrenia PRS (β[95% CI]=-0.08[-0.14,0.02];P=8.50x10-3) but not intelligence PRS.

Conclusions and relevance
Genetic liability for schizophrenia is associated with higher disorganised dimension scores, but not other symptom dimensions. Cognitive performance in schizophrenia reflects distinct contributions from genetic liabilities to both intelligence and schizophrenia.
Original languageEnglish
Pages (from-to)1143-1151
Number of pages9
JournalJAMA Psychiatry
Volume78
Issue number10
Early online date4 Aug 2021
DOIs
Publication statusE-pub ahead of print - 4 Aug 2021

Bibliographical note

Funding Information:
Funding/Support: This project was supported by

Funding Information:
the following grants: Medical Research Council Centre (MR/L010305/1), Program (G0800509),

Funding Information:
reported receiving research grant NPRP7-1174-3-302 from the Qatar National Research Fund. Dr Owen reported receiving grants from Takeda Pharmaceuticals outside the submitted work. Dr O'Donovan reported receiving grants from the Medical Research Council and grants from the National Institute for Mental Health during the conduct of the study and grants from Takeda Pharmaceuticals outside the submitted work. Dr Walters reported receiving grants from the Medical Research Council during the conduct of the study and grants from Takeda Pharmaceuticals outside the submitted work. No other disclosures were reported.

Publisher Copyright:
© 2021 American Medical Association. All rights reserved.

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