BACKGROUND The genetic risk factors of schizophrenia (SCZ), a severe psychiatric disorder, are not yet fully understood. Multiple lines of evidence suggest that mitochondrial dysfunction may play a role in SCZ, but comprehensive association studies are lacking. We hypothesized that variants in nuclear-encoded mitochondrial genes influence susceptibility to SCZ. METHODS We conducted gene-based and gene-set analyses using summary association results from the Psychiatric Genomics Consortium Schizophrenia Phase 2 (PGC-SCZ2) genome-wide association study comprising 35,476 cases and 46,839 control subjects. We applied the MAGMA method to three sets of nuclear-encoded mitochondrial genes: oxidative phosphorylation genes, other nuclear-encoded mitochondrial genes, and genes involved in nucleus-mitochondria crosstalk. Furthermore, we conducted a replication study using the iPSYCH SCZ sample of 2290 cases and 21,621 control subjects. RESULTS In the PGC-SCZ2 sample, 1186 mitochondrial genes were analyzed, among which 159 had p values < .05 and 19 remained significant after multiple testing correction. A meta-analysis of 818 genes combining the PGC-SCZ2 and iPSYCH samples resulted in 104 nominally significant and nine significant genes, suggesting a polygenic model for the nuclear-encoded mitochondrial genes. Gene-set analysis, however, did not show significant results. In an in silico protein-protein interaction network analysis, 14 mitochondrial genes interacted directly with 158 SCZ risk genes identified in PGC-SCZ2 (permutation p = .02), and aldosterone signaling in epithelial cells and mitochondrial dysfunction pathways appeared to be overrepresented in this network of mitochondrial and SCZ risk genes. CONCLUSIONS This study provides evidence that specific aspects of mitochondrial function may play a role in SCZ, but we did not observe its broad involvement even using a large sample.

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标题：精神分裂症核编码线粒体基因的综合分析

背景精神分裂症 (SCZ) 是一种严重的精神疾病，其遗传风险因素尚未完全了解。多条证据表明线粒体功能障碍可能在 SCZ 中起作用，但缺乏全面的关联研究。我们假设核编码线粒体基因的变异会影响对 SCZ 的易感性。方法 我们使用精神病基因组学联盟精神分裂症 2 期 (PGC-SCZ2) 全基因组关联研究的总结关联结果进行了基于基因和基因集的分析，该研究包括 35,476 例病例和 46,839 名对照受试者。我们将 MAGMA 方法应用于三组核编码线粒体基因：氧化磷酸化基因、其他核编码线粒体基因和参与核-线粒体串扰的基因。此外，我们使用 2290 名病例和 21,621 名对照受试者的 iPSYCH SCZ 样本进行了重复研究。结果 在 PGC-SCZ2 样本中，分析了 1186 个线粒体基因，其中 159 个 p 值 < .05，19 个在多次测试校正后仍然显着。结合 PGC-SCZ2 和 iPSYCH 样本的 818 个基因的荟萃分析产生了 104 个名义上显着的基因和 9 个显着基因，表明核编码线粒体基因的多基因模型。然而，基因组分析并没有显示出显着的结果。在计算机蛋白质-蛋白质相互作用网络分析中，14 个线粒体基因与 PGC-SCZ2 中鉴定的 158 个 SCZ 风险基因直接相互作用（排列 p = .02），上皮细胞中的醛固酮信号和线粒体功能障碍通路似乎在线粒体和 SCZ 风险基因网络中过多。结论 本研究提供的证据表明，线粒体功能的特定方面可能在 SCZ 中发挥作用，但即使使用大样本，我们也没有观察到其广泛参与。