Haplotype reference consortium panel: Practical implications of imputations with large reference panels

Adriana I. Iglesias, Sven J. van der Lee, Pieter W.M. Bonnemaijer, René Höhn, Abhishek Nag, Puya Gharahkhani, Anthony P. Khawaja, Linda Broer, International Glaucoma Genetics Consortium (IGGC), Paul J. Foster, Christopher J. Hammond, Pirro G. Hysi, Elisabeth M. van Leeuwen, Stuart MacGregor, David A. Mackey, Johanna Mazur, Stefan Nickels, André G. Uitterlinden, Caroline C.W. Klaver, Najaf AminCornelia M. van Duijn

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Recently, the Haplotype Reference Consortium (HRC) released a large imputation panel that allows more accurate imputation of genetic variants. In this study, we compared a set of directly assayed common and rare variants from an exome array to imputed genotypes, i.e., 1000 genomes project (1000GP) and HRC. We showed that imputation using the HRC panel improved the concordance between assayed and imputed genotypes at common, and especially, low-frequency variants. Furthermore, we performed a genome-wide association meta-analysis of vertical cup-disc ratio (VCDR), a highly heritable endophenotype of glaucoma, in four cohorts using 1000GP and HRC imputations. We compared the results of the meta-analysis using 1000GP to the meta-analysis results using HRC. Overall, we found that using HRC imputation significantly improved P-values (P = 3.07 × 10−61), particularly for suggestive variants. Both meta-analyses were performed in the same sample size, yet we found eight genome-wide significant loci in the HRC-based meta-analysis versus seven genome-wide significant loci in the 1000GP-based meta-analysis. This study provides supporting evidence of the new avenues for gene discovery and fine mapping that the HRC imputation panel offers.This article is protected by copyright. All rights reserved
Original languageEnglish
JournalHuman Mutation
Early online date10 May 2017
Publication statusPublished - 9 Jun 2017


  • Association studies, Imputation, 1000 Genomes Project reference Panel, Haplotype Reference Consortium, Vertical cup-disc ratio


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