Impact of pre- and post-variant filtration strategies on imputation

Quality control (QC) methods for genome-wide association studies and fine mapping are commonly used for imputation, however they result in loss of many single nucleotide polymorphisms (SNPs). To investigate the consequences of filtration on imputation, we studied the direct effects on the number of markers, their allele frequencies, imputation quality scores and post-filtration events. We pre-phrased 1031 genotyped individuals from diverse ethnicities and compared the imputed variants to 1089 NCBI recorded individuals for additional validation. Without QC-based variant pre-filtration, we observed no impairment in the imputation of SNPs that failed QC whereas with pre-filtration there was an overall loss of information. Significant differences between frequencies with and without pre-filtration were found only in the range of very rare (5E-04-1E-03) and rare variants (1E-03-5E-03) (p<1E-04). Increasing the post-filtration imputation quality score from 0.3 to 0.8 reduced the number of single nucleotide variants (SNVs)<0.001 2.5 fold with or without QC pre-filtration and halved the number of very rare variants (5E-04). Thus, to maintain confidence and enough SNVs, we propose here a two-step filtering procedure which allows less stringent filtering prior to imputation and post-imputation in order to increase the number of very rare and rare variants compared to conservative filtration methods.

Automated summary

This study investigated the impact of filtration on imputation, finding a loss of information with pre-filtration and a decrease in SNV quantity with increased post-filtration quality scores. The results support a two-step filtering procedure to enhance the number of very rare and rare variants compared to conservative filtration methods.