Evidence for Shared Genetic Aetiology Between Schizophrenia, Cardiometabolic, and Inflammation-Related Traits: Genetic Correlation and Colocalization Analyses

Benjamin I Perry; Nicholas Bowker; Stephen Burgess; Nicholas J Wareham; Rachel Upthegrove; Peter B Jones; Claudia Langenberg; Golam M Khandaker

doi:10.1093/schizbullopen/sgac001

Evidence for Shared Genetic Aetiology Between Schizophrenia, Cardiometabolic, and Inflammation-Related Traits: Genetic Correlation and Colocalization Analyses

Schizophr Bull Open. 2022 Jan 11;3(1):sgac001. doi: 10.1093/schizbullopen/sgac001. eCollection 2022 Jan.

Authors

Benjamin I Perry^{1

2}, Nicholas Bowker³, Stephen Burgess⁴, Nicholas J Wareham³, Rachel Upthegrove⁵, Peter B Jones^{1

2}, Claudia Langenberg³, Golam M Khandaker^{1

2}

Affiliations

¹ Department of Psychiatry, University of Cambridge School of Clinical Medicine, Cambridge, UK.
² Cambridgeshire and Peterborough NHS Foundation Trust, Cambridge, UK.
³ MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Cambridge, UK.
⁴ MRC Biostatistics Unit, University of Cambridge, Cambridge, UK.
⁵ Institute for Mental Health, University of Birmingham, Birmingham, UK.

Abstract

Background: Schizophrenia commonly co-occurs with cardiometabolic and inflammation-related traits. It is unclear to what extent the comorbidity could be explained by shared genetic aetiology.

Methods: We used GWAS data to estimate shared genetic aetiology between schizophrenia, cardiometabolic, and inflammation-related traits: fasting insulin (FI), fasting glucose, glycated haemoglobin, glucose tolerance, type 2 diabetes (T2D), lipids, body mass index (BMI), coronary artery disease (CAD), and C-reactive protein (CRP). We examined genome-wide correlation using linkage disequilibrium score regression (LDSC); stratified by minor-allele frequency using genetic covariance analyzer (GNOVA); then refined to locus-level using heritability estimation from summary statistics (ρ-HESS). Regions with local correlation were used in hypothesis prioritization multi-trait colocalization to examine for colocalisation, implying common genetic aetiology.

Results: We found evidence for weak genome-wide negative correlation of schizophrenia with T2D (r_g = -0.07; 95% C.I., -0.03,0.12; P = .002) and BMI (r_g = -0.09; 95% C.I., -0.06, -0.12; P = 1.83 × 10^-5). We found a trend of evidence for positive genetic correlation between schizophrenia and cardiometabolic traits confined to lower-frequency variants. This was underpinned by 85 regions of locus-level correlation with evidence of opposing mechanisms. Ten loci showed strong evidence of colocalization. Four of those (rs6265 (BDNF); rs8192675 (SLC2A2); rs3800229 (FOXO3); rs17514846 (FURIN)) are implicated in brain-derived neurotrophic factor (BDNF)-related pathways.

Conclusions: LDSC may lead to downwardly-biased genetic correlation estimates between schizophrenia, cardiometabolic, and inflammation-related traits. Common genetic aetiology for these traits could be confined to lower-frequency common variants and involve opposing mechanisms. Genes related to BDNF and glucose transport amongst others may partly explain the comorbidity between schizophrenia and cardiometabolic disorders.

Keywords: cardiometabolic disorders; colocalization; common aetiology; correlation; genetic; schizophrenia.

Abstract

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