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. 2024 Jul 1;81(7):681-690.
doi: 10.1001/jamapsychiatry.2024.0200.

Genetic and Phenotypic Features of Schizophrenia in the UK Biobank

Sophie E Legge  1 , Antonio F Pardiñas  1 , Grace Woolway  1 , Elliott Rees  1 , Alastair G Cardno  2 , Valentina Escott-Price  1 , Peter Holmans  1 , George Kirov  1 , Michael J Owen  1 , Michael C O'Donovan  1 , James T R Walters  1
Affiliations

Genetic and Phenotypic Features of Schizophrenia in the UK Biobank

Sophie E Legge et al. JAMA Psychiatry. .

Abstract

Importance: Large-scale biobanks provide important opportunities for mental health research, but selection biases raise questions regarding the comparability of individuals with those in clinical research settings.

Objective: To compare the genetic liability to psychiatric disorders in individuals with schizophrenia in the UK Biobank with individuals in the Psychiatric Genomics Consortium (PGC) and to compare genetic liability and phenotypic features with participants recruited from clinical settings.

Design, setting, and participants: This cross-sectional study included participants from the population-based UK Biobank and schizophrenia samples recruited from clinical settings (CLOZUK, CardiffCOGS, Cardiff F-Series, and Cardiff Affected Sib-Pairs). Data were collected between January 1993 and July 2021. Data analysis was conducted between July 2021 and June 2023.

Main outcomes and measures: A genome-wide association study of UK Biobank schizophrenia case-control status was conducted, and the results were compared with those from the PGC via genetic correlations. To test for differences with the clinical samples, polygenic risk scores (PRS) were calculated for schizophrenia, bipolar disorder, depression, and intelligence using PRS-CS. PRS and phenotypic comparisons were conducted using pairwise logistic regressions. The proportions of individuals with copy number variants associated with schizophrenia were compared using Firth logistic regression.

Results: The sample of 517 375 participants included 1438 UK Biobank participants with schizophrenia (550 [38.2%] female; mean [SD] age, 54.7 [8.3] years), 499 475 UK Biobank controls (271 884 [54.4%] female; mean [SD] age, 56.5 [8.1] years), and 4 schizophrenia research samples (4758 [28.9%] female; mean [SD] age, 38.2 [21.0] years). Liability to schizophrenia in UK Biobank was highly correlated with the latest genome-wide association study from the PGC (genetic correlation, 0.98; SE, 0.18) and showed the expected patterns of correlations with other psychiatric disorders. The schizophrenia PRS explained 6.8% of the variance in liability for schizophrenia case status in UK Biobank. UK Biobank participants with schizophrenia had significantly lower schizophrenia PRS than 3 of the clinically ascertained samples and significantly lower rates of schizophrenia-associated copy number variants than the CLOZUK sample. UK Biobank participants with schizophrenia had higher educational attainment and employment rates than the clinically ascertained schizophrenia samples, lower rates of smoking, and a later age of onset of psychosis.

Conclusions and relevance: Individuals with schizophrenia in the UK Biobank, and likely other volunteer-based biobanks, represent those less severely affected. Their inclusion in wider studies should enhance the representation of the full spectrum of illness severity.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Rees reported grants from Akrivia Health outside the submitted work. Dr Owen reported grants from Akrivia Health and Takeda Pharmaceuticals outside the submitted work. Dr O’Donovan reported grants from the UK Medical Research Council and the National Institutes of Health during the conduct of the study as well as grants from Takeda Pharmaceuticals and Akrivia Health outside the submitted work. Dr Walters reported grants from Akrivia Health and Takeda Pharmaceuticals outside the submitted work. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Genetic Correlations
Genetic correlations between the schizophrenia genome-wide association study in UK Biobank and Psychiatric Genomics Consortium (PGC) schizophrenia, bipolar disorder, major depressive disorder (MDD), attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), anorexia nervosa, and intelligence. Comparison correlations with PGC schizophrenia are given in second row. The color of each box indicates the magnitude of the correlation. Statistics and statistical comparison between the correlations are provided in eTable 5 in Supplement 1.
Figure 2.
Figure 2.. Polygenic Risk Comparisons Between Cohorts
A, Odds ratios (ORs) from the polygenic risk score (PRS) comparisons between UK Biobank participants with schizophrenia and the other cohorts (eTable 5 in Supplement 1). The vertical dotted line corresponds to 1 (null association). Error bars indicate 95% CIs. B-E, Distribution of each PRS for each cohort. The vertical dotted line represents the mean PRS in UK Biobank participants with schizophrenia. Diamonds represent the mean PRS for each sample.
Figure 3.
Figure 3.. Phenotypic Comparisons Between Cohorts
Cleveland plot of proportion (binary variables) or mean (continuous variables) values for each phenotype for each study. GCSE indicates General Certificate of Secondary Education; ICD-10, International Statistical Classification of Diseases and Related Health Problems, Tenth Revision.
See this image and copyright information in PMC

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