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.
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.