Characterizing the Shared Genetic Underpinnings of Schizophrenia and Cardiovascular Disease Risk Factors
Linn Rødevand1, Zillur Rahman1, Guy F L Hindley1
1Norwegian Center for Mental Disorders Research (NORMENT), Division of Mental Health and Addiction, Institute of Clinical Medicine, Oslo University Hospital, University of Oslo, Oslo (Rødevand, Rahman, Hindley, Smeland, Frei, Tekin, Kutrolli, Bahrami, Hoseth, Shadrin, Lin, Steen, Andreassen); Department of Psychosis Studies, Institute of Psychiatry, Psychology, and Neuroscience, King's College London (Hindley); Center for Bioinformatics, Department of Informatics, University of Oslo, Oslo (Frei); Division of Mental Health, Helse Møre Romsdal HF, Kristiansund, Norway (Hoseth); Department of Medical Genetics, Oslo University Hospital, Oslo, and NORMENT, Department of Clinical Science, University of Bergen, Bergen, Norway (Djurovic); Multimodal Imaging Laboratory and Departments of Radiology, Psychiatry, and Neurosciences, University of California San Diego, La Jolla (Dale).
Objective:
Schizophrenia is associated with increased risk of cardiovascular disease (CVD), although there is variation in risk among individuals. There are indications of shared genetic etiology between schizophrenia and CVD, but the nature of the overlap remains unclear. The aim of this study was to fill this gap in knowledge.
Methods:
Overlapping genetic architectures between schizophrenia and CVD risk factors were assessed by analyzing recent genome-wide association study (GWAS) results. The bivariate causal mixture model (MiXeR) was applied to estimate the number of shared variants and the conjunctional false discovery rate (conjFDR) approach was used to pinpoint specific shared loci.
Results:
Extensive genetic overlap was found between schizophrenia and CVD risk factors, particularly smoking initiation (N=8.6K variants) and body mass index (BMI) (N=8.1K variants). Several specific shared loci were detected between schizophrenia and BMI (N=304), waist-to-hip ratio (N=193), smoking initiation (N=293), systolic (N=294) and diastolic (N=259) blood pressure, type 2 diabetes (N=147), lipids (N=471), and coronary artery disease (N=35). The schizophrenia risk loci shared with smoking initiation had mainly concordant effect directions, and the risk loci shared with BMI had mainly opposite effect directions. The overlapping loci with lipids, blood pressure, waist-to-hip ratio, type 2 diabetes, and coronary artery disease had mixed effect directions. Functional analyses implicated mapped genes that are expressed in brain tissue and immune cells.
Conclusions:
These findings indicate a genetic propensity to smoking and a reduced genetic risk of obesity among individuals with schizophrenia. The bidirectional effects of the shared loci with the other CVD risk factors may imply differences in genetic liability to CVD across schizophrenia subgroups, possibly underlying the variation in CVD comorbidity.
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