An Icelandic pangenome reference
- Guillaume Holley
- Hannes P. Eggertsson
- Snaedis Kristmundsdottir
- Doruk Beyter
- Astros Th Skuladottir
- Kristjan H. S. Moore
- Pall I. Olason
- Arnaldur Gylfason
- Olafur T. Magnusson
- Asmundur Oddsson
- Hreinn Stefansson
- Agnar Helgason
- Gisli Masson
- Patrick Sulem
- Daniel F. Gudbjartsson
- Kari Stefansson
- Bjarni V. Halldorsson
2026-08-19
Reference bias is an issue that affects most genomic studies analysing short reads mapped to a reference genome 1,2 . It can be mitigated by mapping to multiple haplotypes represented in a pangenome 3–5 . Here we introduce two new methods to address reference bias: Emblask for pangenome construction and Weaver for mapping to pangenomes at scale. Emblask is a hybrid long- and short-read haplotype-resolved dual assembly pipeline for parent–offspring trio data. Using Emblask, we assembled 698 Icelandic haplotypes and added them to the Human Pangenome Reference Consortium (HPRC) pangenome 4 to construct an Icelandic pangenome reference (HPRC-ICE) including 51.41 million small variants. We mapped the short reads of 57,630 Icelanders to HPRC-ICE with Weaver and called 98.96 million variants, representing a 6.17% increase over mapping to a linear reference. We uncovered new variants in low-mappability regions, including a pathogenic single nucleotide polymorphism (SNP) in GBA1 that associates with early onset Parkinson’s disease and a missense SNP in CBS that is pathogenic for homocystinuria. We replicated the GBA1 association in the UK Biobank 6 with a targeted remapping of 429,193 British and Irish participants.