PGS-LMM

short hand for a linear mixed model using LOCO PGS as fixed effects

We have found that including the polyenic score (PGS), calculated on a leave-one-chromosome-out (LOCO) basis, as a fixed effect significantly improves the power of GWAS. The scripts here are intended to facilitate the calculation of the LOCO PGS and its inclusion as a fixed effect in a Linear Mixed Model (LMM) implemented with fastGWA. The pipeline is written for a HPC system running SLURM resource scheduler but can be modified easily for use with other schedulers such as SGE.

Usage

Add absolute path to software and data files to 'config.txt' as well as required variables

bash pipeline.sh

This will submit the job scripts to the HPC scheduler with a previous job completion dependency for each script.

Limitations

Currently the pipeline will generate covariate files on the fly for 10 PCs, age, sex, genotyping batch and assessment centre. Any deviation from these covariates will require the user to update the covariate generating scripts makeCovars.sh & makePgsCovars.sh. An example of how to add covariates can be found here

LDpred2

LDpred2 can be used for inferring the LOCO PGS. Follow the instructions here on how to set up the genotype objects. This pipeline has been written to allow a large number of phenotypes to be processed relatively quickly by generating LOCO objects once.

Job Scripts

Brief summary of each script

All QC thresholds are defined in config.txt

EXTRACT_QC.sh

Extract sample set from pfile input and apply filters to create an association variant set and PCA/GRM set

• Minor allele frequency, Hardy-Weinberg equilibrium, Imputation quality, genotype missingness, LD-pruning

Create LD-pruned set of variants for PCA and GRM calculation

PCA.sh

Concatenate LD-pruned SNPs set into one population level dataset

Perform PCA analysis on LD-pruned set

makeGRM.sh

Make multipart genetic relationship matrix (GRM) on LD-pruned SNP set

makeSparseGRM.sh

Concatenate multipart GRM

Create sparse GRM

makeCovar.sh

Create covariate file

FastGwaFull.sh

Run initial fastGWA analysis without PGS effect

Create LOCO summary statistic files

PGSLOCO.sh

Run LOCO polygenic score calculation

makePgsCovars.sh

Create LOCO covariates from PGS-LOCO scores

FastGwasPGS.sh

Run fastGWA per chromosome with PGS-LOCO score included as fixed effect

Dependenies

• plink2
• bgzip
• fastGWA
• PRSice2
• LDpred2 *optional