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

Abstract

<jats:title>Abstract</jats:title> <jats:sec> <jats:title>Background</jats:title> <jats:p>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.</jats:p> </jats:sec> <jats:sec> <jats:title>Methods</jats:title> <jats:p>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.</jats:p> </jats:sec> <jats:sec> <jats:title>Results</jats:title> <jats:p>We found evidence for weak genome-wide negative correlation of schizophrenia with T2D (rg=-0.07; 95% C.I., -0.03,0.12; p=0.002) and BMI (rg=-0.09; 95% C.I., -0.06,-0.12; p=1.83x10 -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.</jats:p> </jats:sec> <jats:sec> <jats:title>Conclusions</jats:title> <jats:p>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.</jats:p> </jats:sec>