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 Amin; Cornelia M. van Duijn

doi:10.1002/humu.23247

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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Abstract

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 language	English
Journal	Human Mutation
Early online date	10 May 2017
DOIs	https://doi.org/10.1002/humu.23247
Publication status	Published - 9 Jun 2017

Keywords

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

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Haplotype reference consortium panel_IGLESIAS_Publishedonline10May2017_GOLD VoR (CC BY)Final published version, 552 KBLicence: CC BY

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Iglesias, A. I., van der Lee, S. J., Bonnemaijer, P. W. M., Höhn, R., Nag, A., Gharahkhani, P., Khawaja, A. P., Broer, L., (IGGC), I. G. G. C., Foster, P. J., Hammond, C. J., Hysi, P. G., van Leeuwen, E. M., MacGregor, S., Mackey, D. A., Mazur, J., Nickels, S., Uitterlinden, A. G., Klaver, C. C. W., ... van Duijn, C. M. (2017). Haplotype reference consortium panel: Practical implications of imputations with large reference panels. Human Mutation. https://doi.org/10.1002/humu.23247

@article{855f49eda4564e55b5ff9aca77b37ea3,

title = "Haplotype reference consortium panel: Practical implications of imputations with large reference panels",

abstract = "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",

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

author = "Iglesias, {Adriana I.} and {van der Lee}, {Sven J.} and Bonnemaijer, {Pieter W.M.} and Ren{\'e} H{\"o}hn and Abhishek Nag and Puya Gharahkhani and Khawaja, {Anthony P.} and Linda Broer and (IGGC), {International Glaucoma Genetics Consortium} and Foster, {Paul J.} and Hammond, {Christopher J.} and Hysi, {Pirro G.} and {van Leeuwen}, {Elisabeth M.} and Stuart MacGregor and Mackey, {David A.} and Johanna Mazur and Stefan Nickels and Uitterlinden, {Andr{\'e} G.} and Klaver, {Caroline C.W.} and Najaf Amin and {van Duijn}, {Cornelia M.}",

year = "2017",

month = jun,

day = "9",

doi = "10.1002/humu.23247",

language = "English",

journal = "Human Mutation",

issn = "1098-1004",

publisher = "Wiley",

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Iglesias, AI, van der Lee, SJ, Bonnemaijer, PWM, Höhn, R, Nag, A, Gharahkhani, P, Khawaja, AP, Broer, L, (IGGC), IGGC, Foster, PJ, Hammond, CJ , Hysi, PG, van Leeuwen, EM, MacGregor, S, Mackey, DA, Mazur, J, Nickels, S, Uitterlinden, AG, Klaver, CCW, Amin, N & van Duijn, CM 2017, 'Haplotype reference consortium panel: Practical implications of imputations with large reference panels', Human Mutation. https://doi.org/10.1002/humu.23247

TY - JOUR

T1 - Haplotype reference consortium panel: Practical implications of imputations with large reference panels

AU - Iglesias, Adriana I.

AU - van der Lee, Sven J.

AU - Bonnemaijer, Pieter W.M.

AU - Höhn, René

AU - Nag, Abhishek

AU - Gharahkhani, Puya

AU - Khawaja, Anthony P.

AU - Broer, Linda

AU - (IGGC), International Glaucoma Genetics Consortium

AU - Foster, Paul J.

AU - Hammond, Christopher J.

AU - Hysi, Pirro G.

AU - van Leeuwen, Elisabeth M.

AU - MacGregor, Stuart

AU - Mackey, David A.

AU - Mazur, Johanna

AU - Nickels, Stefan

AU - Uitterlinden, André G.

AU - Klaver, Caroline C.W.

AU - Amin, Najaf

AU - van Duijn, Cornelia M.

PY - 2017/6/9

Y1 - 2017/6/9

N2 - 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

AB - 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

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

UR - http://www.scopus.com/inward/record.url?scp=85020417516&partnerID=8YFLogxK

U2 - 10.1002/humu.23247

DO - 10.1002/humu.23247

M3 - Article

SN - 1098-1004

JO - Human Mutation

JF - Human Mutation

ER -

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

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