Schizophrenia and cardiometabolic abnormalities: A Mendelian randomization study

Noushin Saadullah Khani; Marius Cotic; Baihan Wang; Rosemary Abidoph; Georgina Mills; Alvin Richards-Belle; Benjamin I Perry; Golam M Khandaker; Elvira Bramon

doi:10.3389/fgene.2023.1150458

Schizophrenia and cardiometabolic abnormalities: A Mendelian randomization study

Front Genet. 2023 Apr 6:14:1150458. doi: 10.3389/fgene.2023.1150458. eCollection 2023.

Authors

Noushin Saadullah Khani¹, Marius Cotic^{1

2}, Baihan Wang¹, Rosemary Abidoph^{1

3}, Georgina Mills¹, Alvin Richards-Belle^{1

4}, Benjamin I Perry^{5

6}, Golam M Khandaker^{7

8

9}, Elvira Bramon^{1

3}

Affiliations

¹ Division of Psychiatry, Mental Health Neuroscience Department, University College London, London, United Kingdom.
² Department of Genetics and Genomic Medicine, UCL Great Ormond Street Institute of Child Health, University College London, London, United Kingdom.
³ Camden and Islington NHS Foundation Trust, London, United Kingdom.
⁴ Division of Psychiatry, Epidemiology and Applied Clinical Research Department, University College London, London, United Kingdom.
⁵ Department of Psychiatry, University of Cambridge, Cambridge, United Kingdom.
⁶ Cambridgeshire and Peterborough NHS Foundation Trust, Cambridge, United Kingdom.
⁷ MRC Integrative Epidemiology Unit, Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, United Kingdom.
⁸ NIHR Bristol Biomedical Research Centre, Bristol, United Kingdom.
⁹ Avon and Wiltshire Mental Health Partnership NHS Trust, Bristol, United Kingdom.

Abstract

Background: Individuals with a diagnosis of schizophrenia are known to be at high risk of premature mortality due to poor physical health, especially cardiovascular disease, diabetes, and obesity. The reasons for these physical health outcomes within this patient population are complex. Despite well-documented cardiometabolic adverse effects of certain antipsychotic drugs and lifestyle factors, schizophrenia may have an independent effect. Aims: To investigate if there is evidence that schizophrenia is causally related to cardiometabolic traits (blood lipids, anthropometric traits, glycaemic traits, blood pressure) and vice versa using bi-directional two-sample Mendelian randomization (MR) analysis. Methods: We used 185 genetic variants associated with schizophrenia from the latest Psychiatric Genomics Consortium GWAS (n = 130,644) in the forward analysis (schizophrenia to cardiometabolic traits) and genetic variants associated with the cardiometabolic traits from various consortia in the reverse analysis (cardiometabolic traits to schizophrenia), both at genome-wide significance (5 × 10^-8). The primary method was inverse-variance weighted MR, supported by supplementary methods such as MR-Egger, as well as median and mode-based methods. Results: In the forward analysis, schizophrenia was associated with slightly higher low-density lipoprotein (LDL) cholesterol levels (0.013 SD change in LDL per log odds increase in schizophrenia risk, 95% CI, 0.001-0.024 SD; p = 0.027) and total cholesterol levels (0.013 SD change in total cholesterol per log odds increase in schizophrenia risk, 95% CI, 0.002-0.025 SD; p = 0.023). However, these associations did not survive multiple testing corrections. There was no evidence of a causal effect of cardiometabolic traits on schizophrenia in the reverse analysis. Discussion: Dyslipidemia and obesity in schizophrenia patients are unlikely to be driven primarily by schizophrenia itself. Therefore, lifestyle, diet, antipsychotic drugs side effects, as well as shared mechanisms for metabolic dysfunction and schizophrenia such as low-grade systemic inflammation could be possible reasons for the apparent increased risk of metabolic disease in people with schizophrenia. Further research is needed to examine the shared immune mechanism hypothesis.

Keywords: Mendelian randomization; cardiometabolic traits; metabolic syndrome; schizophrenia; single-nucleotide polymorphism.

Abstract

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