Genotype imputation and reference panel: a systematic evaluation on haplotype size and diversity

Wei-Yang Bai; Xiao-Wei Zhu; Pei-Kuan Cong; Xue-Jun Zhang; J Brent Richards; Hou-Feng Zheng

doi:10.1093/bib/bbz108

Genotype imputation and reference panel: a systematic evaluation on haplotype size and diversity

Brief Bioinform. 2019 Nov 6:bbz108. doi: 10.1093/bib/bbz108. Online ahead of print.

Authors

Wei-Yang Bai^{1

2}, Xiao-Wei Zhu^{1

2}, Pei-Kuan Cong^{1

2}, Xue-Jun Zhang³, J Brent Richards⁴, Hou-Feng Zheng^{1

2}

Affiliations

¹ Diseases & Population (DaP) Geninfo Lab, School of Life Sciences, Westlake University, 18 Shilongshan Road, Hangzhou 310024, China.
² Institute of Basic Medical Sciences, Westlake Institute for Advanced Study, 18 Shilongshan Road, Hangzhou 310024, China.
³ Institute of Dermatology and Department of Dermatology, Huashan Hospital, Fudan University, Shanghai, China.
⁴ Lady Davis Institute, Jewish General Hospital, McGill University, Montréal, Québec, Canada.

PMID: 32002535
DOI: 10.1093/bib/bbz108

Abstract

Here, 622 imputations were conducted with 394 customized reference panels for Han Chinese and European populations. Besides validating the fact that imputation accuracy could always benefit from the increased panel size when the reference panel was population specific, the results brought two new thoughts. First, when the haplotype size of the reference panel was fixed, the imputation accuracy of common and low-frequency variants (Minor Allele Frequency (MAF) > 0.5%) decreased while the population diversity of the reference panel increased, but for rare variants (MAF < 0.5%), a small fraction of diversity in panel could improve imputation accuracy. Second, when the haplotype size of the reference panel was increased with extra population-diverse samples, the imputation accuracy of common variants (MAF > 5%) for the European population could always benefit from the expanding sample size. However, for the Han Chinese population, the accuracy of all imputed variants reached the highest when reference panel contained a fraction of an extra diverse sample (8-21%). In addition, we evaluated the imputation performances in the existing reference panels, such as the Haplotype Reference Consortium (HRC), 1000 Genomes Project Phase 3 and the China, Oxford and Virginia Commonwealth University Experimental Research on Genetic Epidemiology (CONVERGE). For the European population, the HRC panel showed the best performance in our analysis. For the Han Chinese population, we proposed an optimum imputation reference panel constituent ratio if researchers would like to customize their own sequenced reference panel, but a high-quality and large-scale Chinese reference panel was still needed. Our findings could be generalized to the other populations with conservative genome; a tool was provided to investigate other populations of interest (https://github.com/Abyss-bai/reference-panel-reconstruction).

Keywords: Chinese population; HRC; genotype imputation; reference panel.