Genetic association of the cytochrome c oxidase-related genes with Alzheimer’s disease in Han Chinese


Alzheimer’s disease (AD) is the most common cause of dementia. Mitochondrial dysfunction has been widely reported in AD due to its important role in cellular metabolism and energy production. Complex IV (cytochrome c oxidase, COX) of mitochondrial electron transport chain, is particularly vulnerable in AD. Defects of COX in AD have been well documented, but there is little evidence to support the genetic association of the COX-related genes with AD. In this study, we investigated the genetic association between 17 nuclear-encoded COX-related genes and AD in 1572 Han Chinese. The whole exons of these genes were also screened in 107 unrelated AD patients with a high probability of hereditarily transmitted AD. Variants in COX6B1, NDUFA4, SURF1, and COX10 were identified to be associated with AD. An integrative analysis with data of eQTL, expression and pathology revealed that most of the COX-related genes were significantly downregulated in AD patients and mouse models, and the AD-associated variants in COX6B1, SURF1, and COX10 were linked to altered mRNA levels in brain tissues. Furthermore, mRNA levels of Ndufa4, Cox5a, Cox10, Cox6b2, Cox7a2, and Lrpprc were significantly correlated with Aβ plaque burden in hippocampus of AD mice. Convergent functional genomics analysis revealed strong supportive evidence for the roles of COX6B1, COX10, NDUFA4, and SURF1 in AD. As the result of our comprehensive analysis of the COX-related genes at the genetic, expression, and pathology levels, we have been able to provide a systematic view for understanding the relationships of the COX-related genes in the pathology of AD.

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We thank Ian Logan for helpful comments and language editing of the manuscript. We thank all participants in this study. We thank Miss Hui-Zhen Wang and Li-li Kong, and Mr. Guo-Dong Li and Dong Wang for technical assistance.


This study was supported by the National Natural Science Foundation of China (31730037 to Y.-G.Y., 81601124 to R.B., and 81560230 to H.-Y.J.), and Yunnan Province (2015FB180 to W.Z.), the Key Research Program of Frontier Sciences, Chinese Academy of Sciences (QYZDJ-SSW-SMC005 to Y.-G.Y.), and the Project for International Collaboration of the Bureau of International Collaboration, CAS (GJHZ1846 to Y.-G.Y.).

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