sfgwas

README

SF-GWAS

Software for secure and federated genome-wide association studies, as described in:

Secure and Federated Genome-Wide Association Studies for Biobank-Scale Datasets
Hyunghoon Cho, David Froelicher, Jeffrey Chen, Manaswitha Edupalli, Apostolos Pyrgelis, Juan R. Troncoso-Pastoriza, Jean-Pierre Hubaux, Bonnie Berger
Nature Genetics, 2025

This repository provides the code for PCA-based association analysis and includes data preprocessing, analysis, and plotting scripts to reproduce main results of the manuscript. For LMM-based workflow, see here.

Installation instructions

Dependencies

SF-GWAS requires that go, python3, and plink2 are available in the exec path in shell. Here are the links for installation:

• Go (>=1.18.3)
• Python (>=3.9.2) with NumPy
• PLINK2

Setting up required Go libraries for secure computation

1. SF-GWAS uses the Lattigo library for multiparty homomorphic encryption. To install a forked version used by SF-GWAS (branch: lattigo_pca), run:

git clone https://github.com/hcholab/lattigo.git
cd lattigo
git checkout lattigo_pca
cd ..

1. Next, SF-GWAS also uses our own library of secret sharing-based multiparty computation routines. This can be obtained by running:

git clone https://github.com/hhcho/mpc-core

Installing SF-GWAS

To install SF-GWAS, clone the repository and try building as follows.

git clone https://github.com/hhcho/sfgwas
cd sfgwas
go get github.com/hhcho/sfgwas
go build

Note that, if lattigo and mpc-core repos from the previous steps are cloned to a different location, update ../lattigo and ../mpc-core in the following lines of sfgwas/go.mod to point to the correct folders. The paths are relative, starting from the root directory of sfgwas repo where the go.mod file is located.

replace github.com/ldsec/lattigo/v2 => ../lattigo
replace github.com/hhcho/mpc-core => ../mpc-core

If go build produces an error, run any commands suggested by Go and try again. If the build finishes without any output, the package has been successfully configured.

Data preparation

Input data format

For demonstration, we provide an example synthetic dataset in example_data/, generated using the genotype data simulation routine in PLINK1.9 and converted to the PLINK2 PGEN format. The example data is split between two parties. Each party's local data is stored in party1 and party2 directories. Note that SF-GWAS can be run with more than two parties.

Main input data files include:

• geno/chr[1-22].[pgen|psam|pvar]: PGEN files for each chromosome.
• pheno.txt: each line includes the phenotype under study for each sample in the .psam file.
• cov.txt: each line includes a tab-separated list of covariates for each sample in the .psam file.
• sample_keep.txt: a list of sample IDs from the .psam file to include in the analysis; to be used with the --keep flag in PLINK2 (see here for file specification).

Data preprocessing scripts

We provide two preprocessing scripts in scripts/preprocessing for producing additional input files needed for SF-GWAS.

1. createSnpInfoFiles.py processes the provided .pvar files to create a number of files specifying variant information. It can be run as follows:

python3 createSnpInfoFiles.py PGEN_PREFIX OUTPUT_DIR

Note that PGEN_PREFIX is expected to be a format string including %d in place of the chromosome number (e.g., geno/chr%d for the example dataset), which the script sequentially replaces with the chromosome numbers 1-22.

This command generates the following three files in OUTPUT_DIR:

• chrom_sizes.txt: the number of SNPs for each chromosome
• snp_ids.txt: a list of variant IDs
• snp_pos.txt: a tab-separated, two-column matrix specifying the genomic position of each variant (chromosome number followed by base position)

1. computeGenoCounts.py runs PLINK2's genotype counting routine (--geno-counts) on each chromosome to obtain genotype, allele, and missingness counts for each variant. It is run as follows:

python3 computeGenoCounts.py PGEN_PREFIX SAMPLE_KEEP OUTPUT_DIR

PGEN_PREFIX is the same as before. SAMPLE_KEEP points to the sample_keep.txt described above as a main input file, including a list of sample IDs to be included in the analysis in a PLINK2-recognized format.

This script generates all.gcount.transpose.bin in OUTPUT_DIR, which needs to be provided to SF-GWAS. It is a binary file encoding a 6-by-m matrix of precomputed allele, genotype, and missingness counts for all m variants in the dataset.

We provide both variant information files and the genotype counts for the example dataset in example_data/.

How to use SF-GWAS for joint analysis

Setting the configuration

Example config files are provided in config/. There are both global config parameters shared by all parties and party-specific parameters. The global parameter 'use_logistic' enables users to opt for logistic regression-based association tests; otherwise, the default workflow with linear regression is executed.

Example script for running SF-GWAS

An example script run_example.sh shows how to run SF-GWAS.

The script spawns 3 processes on the same machine---one for each of the two data-contributing parties (PID=1 and PID=2)and the third for the auxiliary party coordinating the computation (PID=0). In practice, each party runs their process on their own machine and provides the IP addresses of other parties in the configuration for network communication.

We also provide stop.sh for terminating the jobs launched by run_example.sh.

Output format

Once SF-GWAS finishes, it generates assoc.txt in the output directory specified in the configuration. This file includes the Pearson correlation coefficient for each variant passing the quality control filters. Binary vector indicating the inclusion of each variant in the final output is specified in gkeep.txt in the cache directory.

Plotting the results

We included a Python script scripts/visualization/manhattanPlot.py to create a Manhattan plot as provided in our manuscript.

Plaintext data analysis

Please see additional scripts in scripts/analysis/ for performing GWAS using PLINK2 for comparison. run_gwas_ukb.sh and run_gwas_emerge.sh include the workflows used for UK Biobank and eMERGE data analysis as reported in our manuscript.

Contact for questions

David Froelicher, froelich377@gmail.com; Hoon Cho, hoon.cho@yale.edu