Imputation accuracy across global human populations.

Publisher: Cell Press Country of Publication: United States NLM ID: 0370475 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1537-6605 (Electronic) Linking ISSN: 00029297 NLM ISO Abbreviation: Am J Hum Genet Subsets: MEDLINE

Publication: 2008- : [Cambridge, MA] : Cell Press
Original Publication: Baltimore, American Society of Human Genetics.

Gene Frequency* ; Genetics, Population* ; Genome-Wide Association Study* ; Polymorphism, Single Nucleotide*; Humans ; Genome, Human ; Genotype ; White People/genetics ; European People ; Hispanic or Latino ; African People ; Black People

Genotype imputation is now fundamental for genome-wide association studies but lacks fairness due to the underrepresentation of references from non-European ancestries. The state-of-the-art imputation reference panel released by the Trans-Omics for Precision Medicine (TOPMed) initiative improved the imputation of admixed African-ancestry and Hispanic/Latino samples, but imputation for populations primarily residing outside of North America may still fall short in performance due to persisting underrepresentation. To illustrate this point, we imputed the genotypes of over 43,000 individuals across 123 populations around the world and identified numerous populations where imputation accuracy paled in comparison to that of European-ancestry populations. For instance, the mean imputation r-squared (Rsq) for variants with minor allele frequencies between 1% and 5% in Saudi Arabians (n = 1,061), Vietnamese (n = 1,264), Thai (n = 2,435), and Papua New Guineans (n = 776) were 0.79, 0.78, 0.76, and 0.62, respectively, compared to 0.90-0.93 for comparable European populations matched in sample size and SNP array content. Outside of Africa and Latin America, Rsq appeared to decrease as genetic distances to European-ancestry reference increased, as predicted. Using sequencing data as ground truth, we also showed that Rsq may over-estimate imputation accuracy for non-European populations more than European populations, suggesting further disparity in accuracy between populations. Using 1,496 sequenced individuals from Taiwan Biobank as a second reference panel to TOPMed, we also assessed a strategy to improve imputation for non-European populations with meta-imputation, but this design did not improve accuracy across frequency spectra. Taken together, our analyses suggest that we must ultimately strive to increase diversity and size to promote equity within genetics research.
Competing Interests: Declaration of interests The authors declare no competing interests.
(Copyright © 2024 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Update of: bioRxiv. 2023 Oct 26:2023.05.22.541241. doi: 10.1101/2023.05.22.541241. (PMID: 37292811)

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R35 GM142783 United States GM NIGMS NIH HHS

Date Created: 20240411 Date Completed: 20240503 Latest Revision: 20241103

20241103

PMC11080279

10.1016/j.ajhg.2024.03.011

38604166