Abstract：
Cardiac autonomic dysfunction (CADF) is a major contributor to increased cardiac mortality in schizophrenia patients. The aberrant function of voltage-gated ion channels, which are widely distributed in the brain and heart, may link schizophrenia and CADF. In search of channel-encoding genes that are associated with both CADF and schizophrenia, CACNA1C and KCNH2 are promising candidates. In this study, we tested for associations between genetic findings in both genes and CADF parameters in schizophrenia patients whose heart functions were not influenced by psychopharmaceuticals.
First, we searched the literature for single-nucleotide polymorphisms (SNPs) in CACNA1C and KCNH2 that showed genome-wide significant association with schizophrenia. Subsequently, we looked for such robust associations with CADF traits at these loci. A total of 5 CACNA1C SNPs and 9 KCNH2 SNPs were found and genotyped in 77 unmedicated schizophrenia patients and 144 healthy controls. Genotype-related impacts on heart rate (HR) dynamics and QT variability indices (QTvi) were analyzed separately in patients and healthy controls.
We observed significantly increased QTvi in unmedicated patients with CADF-associated risk in CACNA1C rs2283274 C and schizophrenia-associated risk in rs2239061 G compared to the non-risk allele in these patients. Moreover, unmedicated patients with previously identified schizophrenia risk alleles in KCNH2 rs11763131 A, rs3807373 A, rs3800779 C, rs748693 G, and 1036145 T showed increased mean HR and QTvi as compared to non-risk alleles.
We propose a potential pleiotropic role for common variation in CACNA1C and KCNH2 associated with CADF in schizophrenia patients, independent of antipsychotic medication, that predisposes them to cardiac arrhythmias and premature death.
First, we searched the literature for single-nucleotide polymorphisms (SNPs) in CACNA1C and KCNH2 that showed genome-wide significant association with schizophrenia. Subsequently, we looked for such robust associations with CADF traits at these loci. A total of 5 CACNA1C SNPs and 9 KCNH2 SNPs were found and genotyped in 77 unmedicated schizophrenia patients and 144 healthy controls. Genotype-related impacts on heart rate (HR) dynamics and QT variability indices (QTvi) were analyzed separately in patients and healthy controls.
We observed significantly increased QTvi in unmedicated patients with CADF-associated risk in CACNA1C rs2283274 C and schizophrenia-associated risk in rs2239061 G compared to the non-risk allele in these patients. Moreover, unmedicated patients with previously identified schizophrenia risk alleles in KCNH2 rs11763131 A, rs3807373 A, rs3800779 C, rs748693 G, and 1036145 T showed increased mean HR and QTvi as compared to non-risk alleles.
We propose a potential pleiotropic role for common variation in CACNA1C and KCNH2 associated with CADF in schizophrenia patients, independent of antipsychotic medication, that predisposes them to cardiac arrhythmias and premature death.
摘要：
心脏自主神经功能障碍（CADF）是精神分裂症患者心脏死亡率增加的主要原因。电压门控离子通道的异常功能，它们广泛分布在大脑和心脏中，可能将精神分裂症和CADF联系起来。在寻找与CADF和精神分裂症相关的通道编码基因时，CACNA1C和KCNH2是有希望的候选物。在这项研究中,我们在心脏功能不受精神药物影响的精神分裂症患者中,检测了两种基因的遗传结果与CADF参数之间的关联.
首先，我们检索了CACNA1C和KCNH2的单核苷酸多态性(SNPs)的文献,这些多态性在全基因组范围内与精神分裂症显著相关.随后，我们在这些位点寻找与CADF性状的这种强关联。共发现5个CACNA1CSNP和9个KCNH2SNP在77个未用药的精神分裂症患者和144个健康对照中进行基因分型。在患者和健康对照中分别分析基因型对心率（HR）动力学和QT变异性指数（QTvi）的相关影响。
我们观察到，与这些患者的非风险等位基因相比，在CACNA1Crs2283274C的CADF相关风险和rs2239061G的精神分裂症相关风险的未用药患者中QTvi显著增加。此外，在KCNH2rs11763131A中具有先前确定的精神分裂症风险等位基因的未用药患者，rs3807373A,rs3800779C,rs748693G,与无风险等位基因相比，1036145T显示平均HR和QTvi增加。
我们提出了在精神分裂症患者中与CADF相关的CACNA1C和KCNH2常见变异的潜在多效性作用，独立于抗精神病药物，使他们容易出现心律失常和过早死亡.
首先，我们检索了CACNA1C和KCNH2的单核苷酸多态性(SNPs)的文献,这些多态性在全基因组范围内与精神分裂症显著相关.随后，我们在这些位点寻找与CADF性状的这种强关联。共发现5个CACNA1CSNP和9个KCNH2SNP在77个未用药的精神分裂症患者和144个健康对照中进行基因分型。在患者和健康对照中分别分析基因型对心率（HR）动力学和QT变异性指数（QTvi）的相关影响。
我们观察到，与这些患者的非风险等位基因相比，在CACNA1Crs2283274C的CADF相关风险和rs2239061G的精神分裂症相关风险的未用药患者中QTvi显著增加。此外，在KCNH2rs11763131A中具有先前确定的精神分裂症风险等位基因的未用药患者，rs3807373A,rs3800779C,rs748693G,与无风险等位基因相比，1036145T显示平均HR和QTvi增加。
我们提出了在精神分裂症患者中与CADF相关的CACNA1C和KCNH2常见变异的潜在多效性作用，独立于抗精神病药物，使他们容易出现心律失常和过早死亡.
