A Genomics England Haplotype Reference Panel and Imputation of UK Biobank

Overview

Journal Nat Genet

Specialty Genetics

Date 2024 Aug 12

PMID 39134668

Authors

Sinan Shi

Simone Rubinacci

Sile Hu

Loukas Moutsianas

Alex Stuckey

Anna C Need

Pier Francesco Palamara

Mark Caulfield

Jonathan Marchini

Simon Myers

Affiliations

Soon will be listed here.

Abstract

We built a reference panel with 342 million autosomal variants using 78,195 individuals from the Genomics England (GEL) dataset, achieving a phasing switch error rate of 0.18% for European samples and imputation quality of r = 0.75 for variants with minor allele frequencies as low as 2 × 10 in white British samples. The GEL-imputed UK Biobank genome-wide association analysis identified 70% of associations found by direct exome sequencing (P < 2.18 × 10), while extending testing of rare variants to the entire genome. Coding variants dominated the rare-variant genome-wide association results, implying less disruptive effects of rare non-coding variants.

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References

Taliun D, Harris D, Kessler M, Carlson J, Szpiech Z, Torres R . Sequencing of 53,831 diverse genomes from the NHLBI TOPMed Program. Nature. 2021; 590(7845):290-299. PMC: 7875770. DOI: 10.1038/s41586-021-03205-y. View

McCarthy S, Das S, Kretzschmar W, Delaneau O, Wood A, Teumer A . A reference panel of 64,976 haplotypes for genotype imputation. Nat Genet. 2016; 48(10):1279-83. PMC: 5388176. DOI: 10.1038/ng.3643. View

Karczewski K, Francioli L, Tiao G, Cummings B, Alfoldi J, Wang Q . The mutational constraint spectrum quantified from variation in 141,456 humans. Nature. 2020; 581(7809):434-443. PMC: 7334197. DOI: 10.1038/s41586-020-2308-7. View

Browning B, Browning S . Statistical phasing of 150,119 sequenced genomes in the UK Biobank. Am J Hum Genet. 2022; 110(1):161-165. PMC: 9892698. DOI: 10.1016/j.ajhg.2022.11.008. View

Bycroft C, Freeman C, Petkova D, Band G, Elliott L, Sharp K . The UK Biobank resource with deep phenotyping and genomic data. Nature. 2018; 562(7726):203-209. PMC: 6786975. DOI: 10.1038/s41586-018-0579-z. View

Mbatchou J, Barnard L, Backman J, Marcketta A, Kosmicki J, Ziyatdinov A . Computationally efficient whole-genome regression for quantitative and binary traits. Nat Genet. 2021; 53(7):1097-1103. DOI: 10.1038/s41588-021-00870-7. View

Backman J, Li A, Marcketta A, Sun D, Mbatchou J, Kessler M . Exome sequencing and analysis of 454,787 UK Biobank participants. Nature. 2021; 599(7886):628-634. PMC: 8596853. DOI: 10.1038/s41586-021-04103-z. View

Barton A, Sherman M, Mukamel R, Loh P . Whole-exome imputation within UK Biobank powers rare coding variant association and fine-mapping analyses. Nat Genet. 2021; 53(8):1260-1269. PMC: 8349845. DOI: 10.1038/s41588-021-00892-1. View

Halldorsson B, Eggertsson H, Moore K, Hauswedell H, Eiriksson O, Ulfarsson M . The sequences of 150,119 genomes in the UK Biobank. Nature. 2022; 607(7920):732-740. PMC: 9329122. DOI: 10.1038/s41586-022-04965-x. View

10.

Takeuchi F, Akiyama M, Matoba N, Katsuya T, Nakatochi M, Tabara Y . Interethnic analyses of blood pressure loci in populations of East Asian and European descent. Nat Commun. 2018; 9(1):5052. PMC: 6261994. DOI: 10.1038/s41467-018-07345-0. View

11.

Watanabe K, Stringer S, Frei O, Mirkov M, de Leeuw C, Polderman T . A global overview of pleiotropy and genetic architecture in complex traits. Nat Genet. 2019; 51(9):1339-1348. DOI: 10.1038/s41588-019-0481-0. View

12.

Yengo L, Vedantam S, Marouli E, Sidorenko J, Bartell E, Sakaue S . A saturated map of common genetic variants associated with human height. Nature. 2022; 610(7933):704-712. PMC: 9605867. DOI: 10.1038/s41586-022-05275-y. View

13.

McLaren W, Gil L, Hunt S, Riat H, Ritchie G, Thormann A . The Ensembl Variant Effect Predictor. Genome Biol. 2016; 17(1):122. PMC: 4893825. DOI: 10.1186/s13059-016-0974-4. View

14.

Delaneau O, Zagury J, Robinson M, Marchini J, Dermitzakis E . Accurate, scalable and integrative haplotype estimation. Nat Commun. 2019; 10(1):5436. PMC: 6882857. DOI: 10.1038/s41467-019-13225-y. View

15.

Li H . A statistical framework for SNP calling, mutation discovery, association mapping and population genetical parameter estimation from sequencing data. Bioinformatics. 2011; 27(21):2987-93. PMC: 3198575. DOI: 10.1093/bioinformatics/btr509. View

16.

DePristo M, Banks E, Poplin R, Garimella K, Maguire J, Hartl C . A framework for variation discovery and genotyping using next-generation DNA sequencing data. Nat Genet. 2011; 43(5):491-8. PMC: 3083463. DOI: 10.1038/ng.806. View

17.

Fuchsberger C, Abecasis G, Hinds D . minimac2: faster genotype imputation. Bioinformatics. 2014; 31(5):782-4. PMC: 4341061. DOI: 10.1093/bioinformatics/btu704. View

18.

Rubinacci S, Delaneau O, Marchini J . Genotype imputation using the Positional Burrows Wheeler Transform. PLoS Genet. 2020; 16(11):e1009049. PMC: 7704051. DOI: 10.1371/journal.pgen.1009049. View

19.

Tobin M, Sheehan N, Scurrah K, Burton P . Adjusting for treatment effects in studies of quantitative traits: antihypertensive therapy and systolic blood pressure. Stat Med. 2005; 24(19):2911-35. DOI: 10.1002/sim.2165. View

20.

Frazer K, Ballinger D, Cox D, Hinds D, Stuve L, Boudreau A . A second generation human haplotype map of over 3.1 million SNPs. Nature. 2007; 449(7164):851-61. PMC: 2689609. DOI: 10.1038/nature06258. View