How to run GWAS using REGENIE survival models

What?

Pipeline for running survival GWAS using REGENIE.

Introduction

REGENIE survival pipeline performs single-variant association tests (GWAS) for time-to-event endpoints (ie. survival model). Therefore, it is similar to REGENIE, except that it tests the association of the variant with the time-to-event, instead of having the disease.

In addition to binary variable (0/1) stating the case-control status, you'll need a column in your phenotype-covariate file to tell the survival time (NOTE! this information is required for both cases and controls: for cases it is the survival time until the event, and for controls you can set it as time until death or end of follow-up [both age at death and end-of-followup information can be found in each release's phenotype-covariate file.])

Note: You need to name the 2 columns (case/control status and survival time) [pheno] and [pheno]_survTime for the pipeline to recognize them as such. (For example: Statin_MI and Statin_MI_survTime.)

Note: Survival time must be >0 for all individuals

Note: Age at end of follow-up or death (AGE_AT_DEATH_OR_END_OF_FOLLOWUP) should NOT be used as covariate in survival models. The age at end of followup for controls is inherently already modelled in survival analysis. If you are interested in modelling survival after a certain event, say retinopathy after Type 2 diabetes (T2D) diagnosis, you could add age at T2D diagnosis as a covariate to control for different onset age between individuals.

Example files for the REGENIE survival pipeline

Example files for running the GATE pipeline in the Sandbox can be found at: /finngen/library-green/scripts/regenie_surv/. Files you need from there are:

• .wdl file: regenie_survival.wdl

• sub-.wdl file: regenie_survival_sub.zip, and the example input (.json) files:

• regenie_survival_example.json

Thes example .json- files are for running REGENIE on survival time from first purchase of Statins until I9_MI_STRICT endpoint in DF13.

The phenotype-covariate file, phenotype list file and genotype file list needed to run the example (DF6_exammple) can be found at: /finngen/shared/regenie_survival_example_files/20250916_064037/files/sruotsal/regenie_survival_examples/:

• Statin_MI_example_phenotype_regenie.txt.gz: example phenotype-covariate file

• Statin_MI_example_phenotypelist.txt: example phenotype list file

To add covariates into your own phenotype file, see for the instructions here. Note that the phenotype-covariate file requires two columns of FINNGENID, named FID and IID, similar to regular REGENIE pipeline.

Prepare your files for REGENIE survival pipeline

Inputs for regenie survival pipeline are very much the same as for regular REGENIE pipeline, except you don't define whether your phenotype is binary or not, since this pipeline is for time-to-event phenotypes only. Once you have downloaded the example files, you need to edit the regenie_survival_example.json input file. The parts you (may) need to edit in it are:

• regenie_survival.phenolist: the path to a .txt file containing the list of phenotype(s) to run, each on their own row. For example, for only one phenotype: LIBRARY_SHARED/regenie_survival_example_files/20250916_064037/files/sruotsal/regenie_survival_examples/Statin_MI_example_phenotypelist.txt

Statin_MI

• regenie_survival.cov_pheno: the path to a phenotype-covariate file in gzipped .txt format. Example: LIBRARY_SHARED/regenie_survival_example_files/20250916_064037/files/sruotsal/regenie_survival_examples/Statin_MI_example_phenotype_regenie.txt.gz

  • Remember, you need to name the 2 columns (case/control status and survival time) [pheno] and [pheno]_survTime for the pipeline to recognize them - in this example, they should read Statin_MI and Statin_MI_survTime.

• regenie_survival.covariates: a list of covariates to be used in the model, separated by ,.

• regenie_survival.sub_step1.step1.grm_bed: the path to the .bed file from the GRM file, needs to be edited according to what release you plan on using. In this example, R13 is being used. For your own analyses, we strongly recommend using the most recent (and updated) data release.

• regenie_survival.sub_step2.bgenlist: the path to a .txt file with a list of .bgen (8-bit) files (the genotype files). Needs to be edited according to your release (see above). In this example R13 is used: LIBRARY_RED/red/finngen_R13/bgen_1.0/finngen_R13_bgen_list.txt.

Submit your REGENIE survival job

Using Pipelines

See How to use the Pipelines area to see how to submit your job. Note especially that the pipeline input files are run from the /finngen/red/ folder.

If you need further information on the pipeline/job system, see section Pipelines is based on Cromwell and WDL.

Once your .json file is ready, you can submit your GATE run via the command:

finngen-cli request-workflow --wdl /path/to/regenie_survival.wdl \
    --input /path/to/your_regenie_survival.json \
    --dependencies /path/to/regenie_survival_sub.zip

After submitting your job successfully, go to Applications->Sandbox->Pipelines to track your job, and remember to save your jobs' workflow ID for tracking and checking the results when your run has finished.

Submit your job using modifiable workflows

You can also submit your REGENIE survival job using modifiable workflows.

To do that, in sandbox go to: Applications -> Sandbox -> Pipelines -> Modifiable workflow -> Regenie survival DF13 -> Create

Edit Input JSON on the bottom of the page accordingly to your files -> Submit

Output

Once your job displays the Succeeded state you can see the results similarly as for regular REGENIE pipeline in /finngen/pipeline/cromwell/workflows/regenie_survival/[WORKFLOW_ID]/.

You can, for example, find the:

• summary statistics (.gz and .regenie.gz) in /finngen/pipeline/cromwell/workflows/regenie_survival/[WORKFLOW_ID]/call-sub_step2*/shard*/sub.regenie_step2/*/call-gather/shard*/glob*/*gz (if you have multiple phenotypes, the results for each phenotype go into their own sub-folders [shard-#]).

• manhattan and QQ plots in the /finngen/pipeline/cromwell/workflows/regenie_survival/[WORKFLOW_ID]/call-sub_step2*/shard*/sub.regenie_step2/*/call-gather/shard*/glob*/*png .