A common variation in HCN1 is associated with heart rate variability in schizophrenia

Background: There is growing evidence for a shared genetic basis between schizophrenia risk and cardiovascular disease. Reduced efferent vagal activity, indexed by reduced heart rate variability (HRV), has been consistently described in patients with schizophrenia and may potentially contribute to the increased cardiovascular risk in these patients. In this study, we tested the hypothesis whether the established schizophrenia risk variant HCN1 rs16902086 (A > G) is associated with reduced HRV. Methods: We analyzed the risk status of HCN1 rs16902086 (AG/GG vs. AA genotype) in 83 unmedicated patients with schizophrenia and 96 healthy controls and investigated genotype-related impacts on various HRV parameters. Results: We observed significantly increased resting heart rates and a marked decrease of vagal modulation in our patient cohort. Strikingly, HCN1 rs16902086 (A > G) was associated with reduced HRV parameters in patients only. A trend towards more pronounced HRV deviations was observed in homozygous (GG) compared to heterozygous patients (AG). Conclusion: We present first evidence for a genetic risk factor that is associated with decreased vagal modulation in unmedicated patients with schizophrenia. Moreover, our findings suggest that HCN1 might be involved in reduced vagal modulation and possibly in increased cardiac mortality in schizophrenia patients. Thus, our data indicate that reduced vagal modulation might be an endophenotype of schizophrenia. (c) 2020 Elsevier B.V. All rights reserved.