Applying polygenic scores (PGS) on imputed genotypes

• command line program (works on linux or MacOS)
• supports vcf.gz files (imputed or genotyped)
• supports different filters (e.g. r2 or variant list)
• supports PGS Catalog format (https://www.pgscatalog.org, currently over 2,000 scores)
• creates an interactive html report
• supports liftover of score files
• supports converting rsIDs to positions

• Download pgs-calc-*.tar.gz from latest release
• Extract the downloaded archive (e.g tar -xf pgs-calc-*.tar.gz)
• Validate installation with pgs-calc --version

Applying polygenic scores (PGS) on imputed genotypes:

pgs-calc apply --ref PGS000018 --out PGS000018.scores.txt chr*.dose.noID.vcf.gz  --report-html PGS000018.html

The weights for score PGS000018 are downloaded automatically from PGSCatalog and all scores are written to file PGS000018.scores.txt. An interactive report html report is created.

• --ref <file(s) or PGS-ID> - score file with weights or a PGS ID. Multiple scores are separated by , (.e.g score1.txt.gz,score2.txt.gz or PGS000018,PGS000027)
• --out <file> - Output file name

• --minR2 <value> - Use only variants with an imputation quality (R2) >= <value>
• --writeVariants <file> - Writes csv file with all variants used in calculation
• --includeVariants <file> - Restrict calculation to use only variants from this csv file
• --genotypes GT|DS - Use genotypes or dosage
• --report-html <file> - Creates an interactive html report. The report includes summary statistics (like coverage) for each score and can be filtered by e.g. id or trait.
• --samples - Restrict calculation to use only samples from this csv file
• --meta <file> - Use this meta file to annotate scores

• VCF file format (*.vcf and *.vcf.gz)
• one VCF file per chromosome (e.g. output of Imputationserver)
• works out of the box with imputed genotypes from Michigan Imputation Server

pgs-calc supports PGSCatalog out of the box: open the website, find your score of interest and download the provided txt.gz files.

As pgs-calc works with chromosomal positions and not with marker ids, the following requirements must be fulfilled:

1. The build of your genotypes and the build of the score must be the same. If the score is on a different build, you can use the pgs-calc resolve command to lift over to the build of the genotypes.
2. The score file needs chr_name and chr_position columns. If there is only rsID present, you need to set the parameter --dbsnp and the correct index to convert rsIDs on the fly to the correct chromosomal positions. Depending on the build of your genotypes (hg19 or hg38) you can download the dbsnp-index from here.
3. The column other_allele is mandatory to handle multi-allelic variants in an unified way.

If you want to create your own weight files, you need a tab-delimited text file with the following columns:

chr_name  chr_position  effect_allele other_allele  effect_weight

Apply PGS to a single file (e.g. one chromosome):

pgs-calc apply --ref PGS000018.txt.gz test.chr1.vcf.gz --out scores.txt

All scores are written to file scores.txt

Apply PGS to multiple files (e.g. multiple chromosomes):

pgs-calc apply --ref PGS000018.txt.gz test.chr1.vcf.gz test.chr2.vcf.gz test.chr3.vcf.gz test.chr4.vcf.gz --out scores.txt

Apply PGS to multiple files by using file patterns:

pgs-calc apply --ref PGS000018.txt.gz test.chr*.vcf.gz --out scores.txt

Apply multiple score files:

pgs-calc apply --ref PGS000018.txt.gz,PGS000027.txt.gz test.chr*.vcf.gz --out scores.txt

You can also create a file scores_filenames.txt that lists all paths to your score files:

scores
PGS000018.txt.gz
PGS000027.txt.gz

pgs-calc apply --ref scores_filenames.txt test.chr*.vcf.gz --out scores.txt

Attention: All paths inside the file are relative to the location of the file itself.

Use only variants with an imputation quality (R2) >= 0.9:

pgs-calc apply --ref PGS000018.txt.gz test.chr*.vcf.gz --minR2 0.9 --out scores.txt

If a PGS id is provided, pgs-calc downloads the file from PGSCatalog automatically:

pgs-calc apply --ref PGS000018 test.chr1.vcf.gz --out scores.txt

All scores are written to file scores.txt.

You can also use the download command to download a specific PGS id:

pgs-calc download PGS000018 --out PGS000018.txt.gz

The weights are saved in file PGS002297.txt.gz.

If the --dbsnp parameter is set, pgs-calc converts on the fly all rsID automatically to their positions. Depending on the build of your genotypes (hg19 or hg38) you can download the dbsnp index from here.

pgs-calc apply --ref PGS002297 test.chr1.vcf.gz --out scores.txt --dbsnp dbsnp154_hg19.txt.gz

All scores are written to file scores.txt

The build of your genotypes and the score must be the same. If the score is on a different build, you can use the pgs-calc resolve command to lift over the score file to the build of the genotypes. You need a dbsnp-index file and a chain file.

pgs-calc resolve --in PGS002297 --out PGS002297.hg38.txt.gz --dbsnp dbsnp154_hg38.txt.gz --chain hg19_to_hg38.over.chain.gz

The new positions are written to file PGS002297.hg38.txt.gz and this file can the be used by pgs-calc apply.

• dbsnp-index files to resolve rsIDs: https://imputationserver.sph.umich.edu/resources/chain/
• Chain files: https://imputationserver.sph.umich.edu/resources/chain/

Lukas Forer, Institute of Genetic Epidemiology, Medical University of Innsbruck