COX4I1
cytochrome c oxidase subunit 4I1
Cytochrome c oxidase (COX) is the terminal enzyme of the mitochondrial respiratory chain. It is a multi-subunit enzyme complex that couples the transfer of electrons from cytochrome c to molecular oxygen and contributes to a proton electrochemical gradient across the inner mitochondrial membrane. The complex consists of 13 mitochondrial- and nuclear-encoded subunits. The mitochondrially-encoded subunits perform the electron transfer and proton pumping activities. The functions of the nuclear-encoded subunits are unknown but they may play a role in the regulation and assembly of the complex. This gene encodes the nuclear-encoded subunit IV isoform 1 of the human mitochondrial respiratory chain enzyme. It is located at the 3' of the NOC4 (neighbor of COX4) gene in a head-to-head orientation, and shares a promoter with it. Pseudogenes related to this gene are located on chromosomes 13 and 14. Alternative splicing results in multiple transcript variants encoding different isoforms.
provided by RefSeq
Biological Domains
Mitochondrial Metabolism
Pharos Class
Tbio
Also known as
ENSG00000131143 (Ensembl Release 115)
UNIPROTKB P13073
COX IV-1, COX4, COX4-1, COXIV, COXIV-1, MC4DN16
Summary of Evidence
This tab shows an overview of how the selected gene is associated with AD.
Genetic Association with LOAD
Indicates whether or not this gene shows significant genetic association with Late Onset AD (LOAD) based on evidence from multiple studies compiled by the ADSP Gene Verification CommitteeFalseBrain eQTL
Indicates whether or not this gene locus has a significant expression Quantitative Trait Locus (eQTL) based on an AMP-AD consortium studyTrueRNA Expression Change in AD Brain
Indicates whether or not this gene shows significant differential expression in at least one brain region based on AMP-AD consortium work. See ‘EVIDENCE’ tab.TrueProtein Expression Change in AD Brain
Indicates whether or not this gene shows significant differential protein expression in at least one brain region based on AMP-AD consortium work. See ‘EVIDENCE’ tab.TrueNominated Target
Indicates whether or not this gene has been submitted as a nominated target to Agora.True
AD Risk Scores
About AD Risk Scores
The TREAT-AD Center at Emory-Sage-SGC has developed a Target Risk Score (TRS) to objectively rank the potential involvement of specific genes in AD. The TRS is derived by summing two component risk scores, the Genetic Risk Score and the Multi-omic Risk Score, each of which is derived from a meta-analysis of multiple harmonized data sets. More information about the methodology used to define these risk scores is available here.
AD Risk Scores for COX4I1
The TRS for COX4I1, along with the component Genetic and Multi-omic Risk Scores, is shown here. The scores for COX4I1 are superimposed on the genome-wide score distributions. If No Data is Currently Available is displayed for a score, that score was not calculated for COX4I1.
Biological Domain Classification
About Biological Domains
A biological domain represents a standardized area of biology defined by a set of discrete, biologically coherent GO terms. The TREAT-AD Center at Emory-Sage-SGC has defined nineteen biological domains associated with AD, and objectively mapped genes to those biological domains using GO term annotations. More information about the methodology used to define AD biological domains, and to generate genome-wide biological domain mappings, is available here.
Biological Domains for COX4I1
Select a biological domain on the left to see the list of GO terms that link COX4I1 to it on the right. The percentage value displayed next to the currently selected biological domain indicates the proportion of COX4I1's total unique GO terms that map to the biological domain. The ratio displayed on the right indicates how many of the biological domain's total GO terms COX4I1 is annotated with.
RNA Expression
The results shown on this page are derived from a harmonized RNA-seq analysis of post-mortem brains from AD cases and controls. The samples were obtained from three human cohort studies across a total of nine different brain regions.
Overall Expression of COX4I1 Across Brain Regions
This plot depicts the median expression of the selected gene across brain regions, as measured by RNA-seq read counts per million (CPM) reads. Meaningful expression is considered to be a log2 CPM greater than log2(5), depicted by the red line in the plot.
Filter the following charts by statistical model
Differential Expression of COX4I1 Across Brain Regions
After selecting a statistical model, you will be able to see whether the selected gene is differentially expressed between AD cases and controls. The box plot depicts how the differential expression of the selected gene of interest (purple dot) compares with expression of other genes in a given tissue. Summary statistics for each tissue can be viewed by hovering over the purple dots. Meaningful differential expression is considered to be a log2 fold change value greater than 0.263, or less than -0.263.
Consistency of Change in Expression
This forest plot indicates the estimate of the log fold change with 95% confidence interval across the brain regions in the model chosen using the filter above. Genes that show consistent patterns of differential expression will have similar log-fold change value across brain regions.
Correlation of COX4I1 with Hallmarks of AD
This plot depicts the association between expression levels of the selected gene in the DLPFC and three phenotypic measures of AD. An odds ratio > 1 indicates a positive correlation and an odds ratio < 1 indicates a negative correlation. Statistical significance and summary statistics for each phenotype can be viewed by hovering over the dots.
Similarly Expressed Genes
The network diagram below is based on a coexpression network analysis of RNA-seq data from AD cases and controls. The network analysis uses an ensemble methodology to identify genes that show similar coexpression across individuals.
The color of the edges and nodes indicates how frequently significant coexpression was identified. Each node represents a different gene and the amount of edges within the network. Darker edges represent coexpression in more brain regions.
Proteomics
Proteomic analyses of post-mortem brains show whether protein products of COX4I1 are differentially expressed between AD cases and controls. Each box plot depicts how the differential expression of the protein(s) of interest (purple dot) compares with expression of other proteins in a given brain region. Summary statistics for each tissue can be viewed by hovering over the purple dots.
Targeted SRM Differential Protein Expression
Selected Reaction Monitoring (SRM) data was generated from the DLPFC region of post-mortem brains of over 1000 individuals from multiple human cohort studies.
Note that only a single SRM result is available for a given gene, as the probes used for this experiment were designed to match multiple protein products derived from each targeted gene.
Genome-wide Differential Protein Expression
Select a protein from the dropdown menu to see whether it is differentially expressed between AD cases and controls.
The assay-specific box plots below depict how the differential expression of the selected protein of interest (purple dot) compares with expression of other proteins in each brain region that was assayed. Assay-specific summary statistics for each brain region can be viewed by hovering over the purple dot.
Multiple proteins may map to a single gene. Results from both TMT and LFQ assays are provided, however results for some proteins may be available for only one of the assays.
TMT Differential Protein Expression
Tandem mass tagged (TMT) data was generated from the DLPFC region of post-mortem brains of 400 individuals from the ROSMAP cohort.
Note that proteins may not be detected in this brain region; for these proteins, the plot will show no data.
LFQ Differential Protein Expression
Liquid-free quantification (LFQ) data was generated from post-mortem brains of more than 500 individuals. Samples were taken from four human cohort studies, representing four different brain regions.
Note that proteins may not be detected in all four brain regions; for these proteins, the plot will show fewer than four brain regions.
Metabolomics
The results shown on this page are derived from an analysis of metabolite levels from AD cases and controls. The samples were obtained from approximately 1400 individuals from the ADNI study. Metabolites are associated with genes using genetic mapping and the metabolite with the highest genetic association is shown for each gene.
Mapping of Metabolites to COX4I1
No metabolomic data is currently available.
Levels of Metabolite by Disease Status
This plot shows differences in metabolite levels in AD cases and controls.
Drug Development Resources
These external sites provide information and resources related to drug development.
Additional Resources
These external sites provide additional information about therapeutic targets for AD and related dementias.
Evidence Supporting the Nomination of COX4I1
This gene has been nominated as a potential target for AD. Nominated targets are obtained from several sources, including the National Institute on Aging's Accelerating Medicines Partnership in Alzheimer's Disease (AMP-AD) consortium. Targets have been identified using computational analyses of high-dimensional genomic, proteomic and/or metabolomic data derived from human samples.
AMP-AD: The Zhang Lab at the Icahn School of Medicine at Mount Sinai
The Icahn School of Medicine at Mount Sinai AMP-AD team lead by Eric Schadt, Bin Zhang, Jun Zhu, Michelle Ehrlich, Vahram Haroutunian, Samuel Gandy, Koichi Iijima, and Scott Noggle focuses on developing a multiscale network approach to elucidating the complexity of Alzheimer's disease.
Why was the target selected?
COX4I1 is predicted as a key driver protein (KDP) in the Bayesian network analysis, and ranked top 45 in the aggregated p values among all the KDPs via the ensemble rank algorithm of ACAT.
Predicted therapeutic direction
Unknown. COX4I1 is insignificantly regulated in its protein expression in AD vs NL (normal control) in a range of clinical traits inclusing Braak score, CDR, CERAD and Plaque_mean in the brain PHG region. It is predicted to be a key driver protein (KDP) in the Bayesian proteomics network analysis, which has an ensemble ranking score (aggragated p value) of 1.5e-10 and a rank order of number 45 among the 580 KDPs.
The type of data used and analyses done to identify target
Bayesian proteomics network analysis and differentially expressed protein analysis.
Cohort study data: MSBB
Initial date of nomination
2023
Planned Experimental Validation
Not prioritized for experimental validation
Learn more about the target nomination process