Impact of schizophrenia genetic liability on the association between schizophrenia and physical illness: a data linkage study

Background Individuals with schizophrenia are at higher risk of physical illnesses, which are a major contributor to their 20-year reduced life expectancy. It is currently unknown what causes the increased risk of physical illness in schizophrenia. Aims To link genetic data from a clinically ascertained sample of individuals with schizophrenia to anonymised NHS records. To assess (i) rates of physical illness in those with schizophrenia, and (ii) whether physical illness in schizophrenia is associated with genetic liability. Method We linked genetic data from a clinically ascertained sample of individuals with schizophrenia (CardiffCOGS, n=896) to anonymised NHS records held in the Secure Anonymised Information Linkage (SAIL) databank. Physical illnesses were defined from the General Practice Database and Patient Episode Database for Wales. Genetic liability for schizophrenia was indexed by (i) rare CNVs, and (ii) polygenic risk scores. Results Individuals with schizophrenia in SAIL had increased rates of epilepsy (standardised rate ratio (SRR)=5.34), intellectual disability (SRR=3.11), type 2 diabetes (SRR=2.45), congenital disorders (SRR=1.77), ischaemic heart disease (SRR=1.57) and smoking (SRR=1.44) in comparison to the general SAIL population. In those with schizophrenia, carrier status for schizophrenia-associated CNVs and neurodevelopmental disorderassociated CNVs was associated with height (P=0.015–0.017), with carriers being 7.5– 7.7cm shorter than non-carriers. We did not find evidence that the increased rates of poor physical health outcomes in schizophrenia are associated with genetic liability for the disorder. Conclusions This study demonstrates the value of and potential for linking genetic data from clinically ascertained research studies to anonymised health records. The increased risk