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The hazards of genotype imputation in chromosomal regions under selection: A case study using the Lactase gene region

Ali, Aminah T; Liebert, Anke; Lau, Winston; Maniatis, Nikolas; Swallow, Dallas M; (2022) The hazards of genotype imputation in chromosomal regions under selection: A case study using the Lactase gene region. Annals of Human Genetics , 86 (1) pp. 24-33. 10.1111/ahg.12444. Green open access

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Abstract

Although imputation of missing SNP results has been widely used in genetic studies, claims about the quality and usefulness of imputation have outnumbered the few studies that have questioned its limitations. But it is becoming clear that these limitations are real—for example, disease association signals can be missed in regions of LD breakdown. Here, as a case study, using the chromosomal region of the well-known lactase gene, LCT, we address the issue of imputation in the context of variants that have become frequent in a limited number of modern population groups only recently, due to selection. We study SNPs in a 500 bp region covering the enhancer of LCT, and compare imputed genotypes with directly genotyped data. We examine the haplotype pairs of all individuals with discrepant and missing genotypes. We highlight the nonrandom nature of the allelic errors and show that most incorrect imputations and missing data result from long haplotypes that are evolutionarily closely related to those carrying the derived alleles, while some relate to rare and recombinant haplotypes. We conclude that bias of incorrectly imputed and missing genotypes can decrease the accuracy of imputed results substantially.

Type: Article
Title: The hazards of genotype imputation in chromosomal regions under selection: A case study using the Lactase gene region
Location: England
Open access status: An open access version is available from UCL Discovery
DOI: 10.1111/ahg.12444
Publisher version: https://doi.org/10.1111/ahg.12444
Language: English
Additional information: Copyright © 2021 The Authors. Annals of Human Genetics published by University College London (UCL) and John Wiley & Sons Ltd. This is an open access article under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
Keywords: Derived alleles, haplotypes, imputation, Lactase, selection
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Genetics, Evolution and Environment
URI: https://discovery.ucl.ac.uk/id/eprint/10158807
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