Flexible read-aware genotype imputation from sequence using biobank sized reference panels.

Abstract

Inexpensive and accurate genotyping methods are essential to modern genomics and health risk prediction. Here we introduce QUILT2, a scalable and read-aware imputation method that can efficiently use biobank scale haplotype reference panels. This allows for fast and accurate imputation using short reads, as well as long reads (e.g. Oxford Nanopore Technologies (ONT) 1X, r2 = 0.937 at common SNPs), linked-reads and ancient DNA. In addition, QUILT2 contains a methodological innovation that is designed to enable imputation of the maternal and fetal genome using cell free non-invasive prenatal testing (NIPT) data. Using a UK Biobank reference panel and simulated NIPT data, we see accurate imputation of the mother (0.25X, r2 = 0.966, common SNPs) and modest imputation of the fetus (0.25X, r2 = 0.465, fetal fraction of 10%) at low coverage, with fetal imputation accuracy rising with coverage (4.0X, fetal r2 = 0.894). We show using simulated data that this could enable both GWAS and PRS for the mother and fetus, which could create clinical opportunities, and if phenotypes can be collected alongside clinical NIPT, the potential for large GWAS.