Associations of schizophrenia with arrhythmic disorders and electrocardiogram traits: an in-depth genetic exploration of population samples

Background: An important contributor to the decreased life expectancy of individuals with schizophrenia is sudden cardiac death. While arrhythmic disorders play an important role in this, the nature of the relation between schizophrenia and arrhythmia is not fully understood. Methods: We leveraged summary-level data of large-scale genome-wide association studies of schizophrenia (53,386 cases 77,258 controls), arrhythmic disorders (atrial fibrillation, 55,114 cases 482,295 controls; Brugada syndrome, 2,820 cases 10,001 controls) and electrocardiogram traits (heart rate (variability), PR interval, QT interval, JT interval, and QRS duration, n=46,952-293,051). First, we examined shared genetic liability by assessing global and local genetic correlations and conducting functional annotation. Next, we explored bidirectional causal relations between schizophrenia and arrhythmic disorders and electrocardiogram traits using Mendelian randomization. Outcomes: There was no evidence for global genetic correlations, except between schizophrenia and Brugada (rg=0.14, p=4.0E-04). In contrast, strong positive and negative local genetic correlations between schizophrenia and all cardiac traits were found across the genome. In the strongest associated regions, genes related to immune system and viral response mechanisms were overrepresented. Mendelian randomization indicated a causal, increasing effect of liability to schizophrenia on Brugada syndrome (OR=1.15, p=0.009) and heart rate during activity (beta=0.25, p=0.015). Interpretation: While there was little evidence for global genetic correlations, specific genomic regions and biological pathways important for both schizophrenia and arrhythmic disorders and electrocardiogram traits emerged. The putative causal effect of liability to schizophrenia on Brugada warrants increased cardiac monitoring and potentially early medical intervention in patients with schizophrenia. Funding: European Research Council Starting Grant. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement JLT is supported by a European Research Council (ERC) Starting grant (UNRAVEL-CAUSALITY, grant number 101076686). KJHV and JLT are supported by Foundation Volksbond Rotterdam. CRB is supported by the Dutch Heart Foundation (PREDICT2 project, CVON 2018-30) and the Leducq Foundation (project 17CVD02). JAP was supported by the US National Institutes of Mental Health (R01MH123724). JAP and JBerg were supported by European Unions Horizon 2020 Research and Innovation Programme (CoMorMent project; Grant #847776). RT is supported by the Canada Research Chairs program. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: GWAS catalog (https://www.ebi.ac.uk/gwas/) or through request by e-mail to the corresponding authors of any GWAS not available there. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes The findings of this study are based on summary-level data of published GWAS, all of which are publicly available or can be requested from the corresponding author, JLT.