• R
• GNU Make (for running the complete analysis pipeline)
• curl (for downloading files)
• tar (for extracting tar archives)
• PLINK 1.9 (for clumping genetic summary data)
• Depending on your platform, you may need of the following to install some of the required R packages:
  • (Windows) Rtools
  • (Mac) Xcode or Xcode Command Line Tools
  • (Linux) a C/C++ compiler (in Debian/Ubuntu, the packages build-essential or r-base-dev should contain everything necessary)

The most convenient way to install these tools might be by using a package manager appropriate for your system, e.g. apt on Debian/Ubuntu, Scoop on Windows, or Homebrew on OS X.

If your PLINK executable is in a non-standard location, or is named something other than plink1.9.exe, you may need to edit the plink_executable variable at the top of the Makefile accordingly.

• Install renv:
  • In R: install.packages("renv")
  • From the command line: Rscript -e 'install.packages("renv")'
• Install other required R packages:
  • In R: renv::restore()
  • From the command line: make packages

• Most data sets are publicly available, and are automatically downloaded as part of the analyses.
• Within-family (sibship-adjusted) income GWAS data were obtained directly from the Within Family Consortium. These data should eventually be publicly available, but in the meantime, users who want to replicate the within-family analyses would need to request them from the authors and create the following files:
  • input/data/siblinggwas/Income_WS_mtag_meta.txt
  • input/data/siblinggwas/income-study-summary.txt

• The analyses can be run from the command line using make; this runs the required R scripts in the right order as defined in Makefile.
• Run all analyses: make all
• Run MR analyses only: make mr
• Run CAUSE analyses only (time-consuming): make cause
• Run multivariable MR analyses only (time-consuming): make mvmr

After running the analyses, the results are reported in CSV format in the output/results/ directory:

• cause_results.csv contains results from the CAUSE analysis
• mr_estimates.csv contains results from the IVW, median, mode-based, and MR-Egger analyses
• mvmr_estimates.csv contains results from the multivariable MR analyses
• mvmr_stats.csv contains information about the instruments used for the exposures in the multivariable MR analyses (number of SNPs and conditional F-statistics)

Exposures and outcomes in these files are denoted using the identifiers specified in input/metadata.csv.

• input/: contains GWAS data (needed for the analyses) and linkage disequilibrium reference panel data (needed for clumping GWAS data)
• output/: contains results of the analyses:
  • output/analysis/: raw output from each analysis (not human-readable)
  • output/data/: pre-processed and clumped datasets
  • output/results/: formatted analysis results (see above)
• renv/: contains installed R packages
• scripts/: contains all R code for data processing and analysis
  • The subdirectories correspond to the subdirectories in output/.
  • There is no "master" script which runs the entire analysis. Instead, the order in which these scripts are run is defined in Makefile, and the analyses are run using the make command.

After running the analyses, the input and output folders will contain a number of very large files. Some of these can be deleted if necessary to conserve disk space. In particular:

• input/data/
• input/ld_ref_panel/
• output/data/