APOE-Multiomics

APOE Genotype and Biological Age Impact Inter-Omic Associations Related to Bioenergetics

Ellis D, Watanabe K, Wilmanski T, Lustgarten MS, Korat AVA, Glusman G, Hadlock J, Fiehn O, Sebastiani P, Price ND, Hood L, Magis AT, Evans SJ, Pflieger L, Lovejoy JC, Gibbons SM, Funk CC, Baloni P, Rappaport N. APOE genotype and biological age impact inter-omic associations related to bioenergetics. Aging (Albany NY). 2025 May 3;17. doi: 10.18632/aging.206243. Epub ahead of print. PMID: 40323280.

Preprint doi: https://doi.org/10.1101/2024.10.17.618322

Correspondence to: Noa Rappaport; email: [email protected]

Code and content

This repo includes scripts ran in Jupyter Notebook for performing the analyses and generating the figures for the study.

In this README, each notebook is described, including the necessary input data and output files/figures generated. Note that input data needed for scripts to run must be requested (see "Requesting data" below).

Code01_Arivale_Indiv_Metab_Analysis.ipynb

Code used to analyze individual metabolite abundance differences across APOE and delta age statuses in Arivale, including stratified by sex and chronological age tertiles.

Inputs:

• Preprocessed Arivale data: Arivale_preprocecessed_indiv_metab_analysis_data.csv
• Metabolomics metadata: Arivale_metabolomics_metadata.csv

Outputs (consolidated into Supplementary Files 1 & 2; included in Supplementary Table 3; used in figure scripts):

• Data files for APOE and delta age GLMs, including sex stratified and chronological age stratified results

Code02_Arivale_Interaction_Analysis.ipynb

Code for running multi-omic interaction analyses in Arivale. The correct sections need to be commented in/out when running the script to select the correct stratified analysis (out of 11).

Inputs:

• Preprocessed data: Arivale_preprocessed_interaction_analysis
• List of analytes: Arivale_Interaction_Analysis_Analyte_List.json
• Clinical chem annotations: Arivale_Interaction_Clinical_Annots.json
• Protein annotations: Arivale_Interaction_Prots_Annots.json
• Metabolite annotations: Arivale_Interaction_Metabs_Annots.json
• Microbiome annotations: Arivale_Interaction_Microb_Annots.json

Outputs (to be inputs for Code03):

• Log files and txt.gz result files from interaction analyses

Code03_Arivale_Interaction_Analysis_Tidy_Interpret.ipynb

Code for analyzing and taking the txt.gz result files from Code02 and generating csv files to combine to Supplementary File 3.

Inputs (from Code02 outputs):

• 240427_FE2_interomic_interact_Arivale_5SD_winsor.txt.gz
• 240427_FE4_interomic_interact_Arivale_5SD_winsor.txt.gz
• 240427_Fhealth_interomic_interact_Arivale_5SD_winsor.txt.gz
• 240427_Funhealth_interomic_interact_Arivale_5SD_winsor.txt.gz
• 240427_ME2_interomic_interact_Arivale_5SD_winsor.txt.gz
• 240427_ME4_interomic_interact_Arivale_5SD_winsor.txt.gz
• 240427_Mhealth_interomic_interact_Arivale_5SD_winsor.txt.gz
• 240427_Munhealth_interomic_interact_Arivale_5SD_winsor.txt.gz
• 240504_E2_allele_dose_interomic_interaction_5SD_winsor.txt.gz
• 240504_E4_allele_dose_interomic_interaction_5SD_winsor.txt.gz
• 240504_contin_del_age_interomic_interaction_5SD_winsor.txt.gz

Outputs (consolidated into Supplementary File 3; Summarized in Table 2 and Supplementary Table 4; used in circos figure script):

• csv result files gathered to Supplementary File 3

Code04_TwinsUK_Indiv_Metab_Analysis.ipynb

Code for running individual metabolite abundance analysis in TwinsUK.

Inputs:

• Preprocessed TwinsUK data: E1199_15122022_1_TwinsUK_Metab_Abundance.csv

Outputs (consolidated into Supplementary File 4; Included in Supplementary Table 3; used in figure scripts):

• Data files for APOE GLMs, including sex stratified and chronological age stratified results

Code05_TwinsUK_Interaction_Analysis.ipynb

Code for running targeted multi-omic interaction analysis in TwinsUK.

Inputs:

• Metabolomics metadata (subpathways from Metabolon, Arivale applies to TwinsUK): Arivale_metabolomics_metadata.csv
• Preprocessed TwinsUK data: E1199_15122022_2_TwinsUK_Interaction_Analysis.csv

Outputs:

• Data files organized into Supplementary File 5

Code06_Enrichment_Analyses_and_Overlapping_Tables.ipynb

Code for performing enrichment analysis on the metabolites identified in Code01 and Code04, as well as constructing an overlapping table.

Inputs:

• 250217_Arivale_Indiv.csv
• 250217_Arivale_Indiv_FEMALE.csv
• 250217_Arivale_Indiv_MALE.csv
• 250217_Arivale_Indiv_delage.csv
• 250217_Arivale_Indiv_delage_FEMALE.csv
• 250217_Arivale_Indiv_delage_MALE.csv
• 250217_TwinsUK_Indiv.csv
• 250217_TwinsUK_Indiv_FEMALE.csv
• 250217_TwinsUK_Indiv_MALE.csv
• Arivale_metabolomics_metadata.csv

Outputs:

• Results included in Supplementary Files 1 and 4; Table 3; Supplementary Tables 1 and 2

Code07_Figure_Script.ipynb

Code used to generate figures, including comments for offline arranging and annotating.

Inputs:

• 250217_Arivale_Indiv.csv
• 250217_Arivale_Indiv_delage.csv
• 250217_TwinsUK_Indiv.csv
• Arivale_preprocessed_interaction_analysis.csv
• E1199_15122022_2_TwinsUK_Interaction_Analysis.csv

Outputs:

• Plots used for Figures 2-4 & S1-S6

Code08_InteractionNetworkVisualization.ipynb

R code used to make the circos plots in Figures 3d and 3e, with sections rearranged in ppt.

Inputs:

• Organized Arivale Interaction Analysis results (240707_ME2_MBioOld_FBioOld_for_circos_fig.xlsx)
• Metadata/analyte labels (240725_Arivale-APOE-BA_CleanMetadata_analyte-metadata.xlsx and 240819_Arivale-APOE-BA-Microbiome_Gaps_Filled.xlsx)

Outputs:

• Two circos plot figure files (arranged to Figures 3d and 3e)

Code09_TwinsUK_BA_Fitting.ipynb

Code used to fit model and generate multi-omic biological age values for TwinsUK cohort - takes the average of 10 iterations.

Inputs:

• Intermediate preprocessed TwinsUK data file (TwinsUK_pre_BA_fit.csv)

Outputs:

• Data file with metabolomic biological ages of TwinsUK individuals (TwinsUK_BA_fits.csv)

Requesting data

Qualified researchers can access the above deidentified input files for research purposes. Requests for the above files or for Arivale data should be sent to [email protected].

Independent TwinsUK datasets used in this study were provided by the Department of Twin Research & Genetic Epidemiology (King’s College London) after the approval of our Data Access Application (project number E1199). Requests for TwinsUK should be referred to their website (http://twinsuk.ac.uk/resources-for-researchers/access-our-data/).

Software requirements

The following packages/libraries were used in Python (v 3.9.7) and R (v 4.1.1) in Jupyter Notebook to run the scripts:

• statsmodels
• pandas
• numpy
• matplotlib
• scipy
• seaborn
• tidyverse
• readxl
• circlize
• RColorBrewer
• colorspace

Log

Last update on May 14, 2025

• March 2025 Initialized this repository on Github
• 2025-04-02 Uploaded Jupyter Notebooks to repo, drafted README
• 2025-05-14 Updated README with peer-reviewed DOI