Accuracy of haplotype estimation and whole genome imputation affects complex trait analyses in complex biobanks

Vivek Appadurai; Jonas Bybjerg-Grauholm; Morten Dybdahl Krebs; Anders Rosengren; Alfonso Buil; Andrés Ingason; Ole Mors; Anders D Børglum; David M Hougaard; Merete Nordentoft; Preben B Mortensen; Olivier Delaneau; Thomas Werge; Andrew J Schork

doi:10.1038/s42003-023-04477-y

Accuracy of haplotype estimation and whole genome imputation affects complex trait analyses in complex biobanks

Vivek Appadurai^*, Jonas Bybjerg-Grauholm, Morten Dybdahl Krebs, Anders Rosengren, Alfonso Buil, Andrés Ingason, Ole Mors, Anders D Børglum, David M Hougaard, Merete Nordentoft, Preben B Mortensen, Olivier Delaneau, Thomas Werge, Andrew J Schork^*

^*Corresponding author af dette arbejde

Publikation: Bidrag til tidsskrift/Konferencebidrag i tidsskrift /Bidrag til avis › Tidsskriftartikel › Forskning › peer review

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Abstract

Sample recruitment for research consortia, biobanks, and personal genomics companies span years, necessitating genotyping in batches, using different technologies. As marker content on genotyping arrays varies, integrating such datasets is non-trivial and its impact on haplotype estimation (phasing) and whole genome imputation, necessary steps for complex trait analysis, remains under-evaluated. Using the iPSYCH dataset, comprising 130,438 individuals, genotyped in two stages, on different arrays, we evaluated phasing and imputation performance across multiple phasing methods and data integration protocols. While phasing accuracy varied by choice of method and data integration protocol, imputation accuracy varied mostly between data integration protocols. We demonstrate an attenuation in imputation accuracy within samples of non-European origin, highlighting challenges to studying complex traits in diverse populations. Finally, imputation errors can bias association tests, reduce predictive utility of polygenic scores. Carefully optimized data integration strategies enhance accuracy and replicability of complex trait analyses in complex biobanks.

Originalsprog	Engelsk
Artikelnummer	101
Tidsskrift	Communications Biology
Vol/bind	6
Nummer	1
Antal sider	12
ISSN	2399-3642
DOI	https://doi.org/10.1038/s42003-023-04477-y
Status	Udgivet - dec. 2023

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10.1038/s42003-023-04477-yLicens: CC BY

s42003-023-04477-yForlagets udgivne version, 2,12 MBLicens: CC BY

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Appadurai, V., Bybjerg-Grauholm, J., Krebs, M. D., Rosengren, A., Buil, A., Ingason, A., Mors, O., Børglum, A. D., Hougaard, D. M., Nordentoft, M., Mortensen, P. B., Delaneau, O., Werge, T., & Schork, A. J. (2023). Accuracy of haplotype estimation and whole genome imputation affects complex trait analyses in complex biobanks. Communications Biology, 6(1), Artikel 101. https://doi.org/10.1038/s42003-023-04477-y

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title = "Accuracy of haplotype estimation and whole genome imputation affects complex trait analyses in complex biobanks",

abstract = "Sample recruitment for research consortia, biobanks, and personal genomics companies span years, necessitating genotyping in batches, using different technologies. As marker content on genotyping arrays varies, integrating such datasets is non-trivial and its impact on haplotype estimation (phasing) and whole genome imputation, necessary steps for complex trait analysis, remains under-evaluated. Using the iPSYCH dataset, comprising 130,438 individuals, genotyped in two stages, on different arrays, we evaluated phasing and imputation performance across multiple phasing methods and data integration protocols. While phasing accuracy varied by choice of method and data integration protocol, imputation accuracy varied mostly between data integration protocols. We demonstrate an attenuation in imputation accuracy within samples of non-European origin, highlighting challenges to studying complex traits in diverse populations. Finally, imputation errors can bias association tests, reduce predictive utility of polygenic scores. Carefully optimized data integration strategies enhance accuracy and replicability of complex trait analyses in complex biobanks.",

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author = "Vivek Appadurai and Jonas Bybjerg-Grauholm and Krebs, {Morten Dybdahl} and Anders Rosengren and Alfonso Buil and Andr{\'e}s Ingason and Ole Mors and B{\o}rglum, {Anders D} and Hougaard, {David M} and Merete Nordentoft and Mortensen, {Preben B} and Olivier Delaneau and Thomas Werge and Schork, {Andrew J}",

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year = "2023",

month = dec,

doi = "10.1038/s42003-023-04477-y",

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Appadurai, V, Bybjerg-Grauholm, J, Krebs, MD, Rosengren, A, Buil, A, Ingason, A, Mors, O , Børglum, AD, Hougaard, DM, Nordentoft, M, Mortensen, PB, Delaneau, O, Werge, T & Schork, AJ 2023, 'Accuracy of haplotype estimation and whole genome imputation affects complex trait analyses in complex biobanks', Communications Biology, bind 6, nr. 1, 101. https://doi.org/10.1038/s42003-023-04477-y

Accuracy of haplotype estimation and whole genome imputation affects complex trait analyses in complex biobanks. / Appadurai, Vivek; Bybjerg-Grauholm, Jonas; Krebs, Morten Dybdahl et al.
I: Communications Biology, Bind 6, Nr. 1, 101, 12.2023.

Publikation: Bidrag til tidsskrift/Konferencebidrag i tidsskrift /Bidrag til avis › Tidsskriftartikel › Forskning › peer review

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T1 - Accuracy of haplotype estimation and whole genome imputation affects complex trait analyses in complex biobanks

AU - Appadurai, Vivek

AU - Bybjerg-Grauholm, Jonas

AU - Krebs, Morten Dybdahl

AU - Rosengren, Anders

AU - Buil, Alfonso

AU - Ingason, Andrés

AU - Mors, Ole

AU - Børglum, Anders D

AU - Hougaard, David M

AU - Nordentoft, Merete

AU - Mortensen, Preben B

AU - Delaneau, Olivier

AU - Werge, Thomas

AU - Schork, Andrew J

PY - 2023/12

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N2 - Sample recruitment for research consortia, biobanks, and personal genomics companies span years, necessitating genotyping in batches, using different technologies. As marker content on genotyping arrays varies, integrating such datasets is non-trivial and its impact on haplotype estimation (phasing) and whole genome imputation, necessary steps for complex trait analysis, remains under-evaluated. Using the iPSYCH dataset, comprising 130,438 individuals, genotyped in two stages, on different arrays, we evaluated phasing and imputation performance across multiple phasing methods and data integration protocols. While phasing accuracy varied by choice of method and data integration protocol, imputation accuracy varied mostly between data integration protocols. We demonstrate an attenuation in imputation accuracy within samples of non-European origin, highlighting challenges to studying complex traits in diverse populations. Finally, imputation errors can bias association tests, reduce predictive utility of polygenic scores. Carefully optimized data integration strategies enhance accuracy and replicability of complex trait analyses in complex biobanks.

AB - Sample recruitment for research consortia, biobanks, and personal genomics companies span years, necessitating genotyping in batches, using different technologies. As marker content on genotyping arrays varies, integrating such datasets is non-trivial and its impact on haplotype estimation (phasing) and whole genome imputation, necessary steps for complex trait analysis, remains under-evaluated. Using the iPSYCH dataset, comprising 130,438 individuals, genotyped in two stages, on different arrays, we evaluated phasing and imputation performance across multiple phasing methods and data integration protocols. While phasing accuracy varied by choice of method and data integration protocol, imputation accuracy varied mostly between data integration protocols. We demonstrate an attenuation in imputation accuracy within samples of non-European origin, highlighting challenges to studying complex traits in diverse populations. Finally, imputation errors can bias association tests, reduce predictive utility of polygenic scores. Carefully optimized data integration strategies enhance accuracy and replicability of complex trait analyses in complex biobanks.

KW - Biological Specimen Banks

KW - Genome

KW - Genotype

KW - Haplotypes

KW - Humans

KW - Multifactorial Inheritance

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U2 - 10.1038/s42003-023-04477-y

DO - 10.1038/s42003-023-04477-y

M3 - Journal article

C2 - 36697501

SN - 2399-3642

VL - 6

JO - Communications Biology

JF - Communications Biology

IS - 1

M1 - 101

ER -

Accuracy of haplotype estimation and whole genome imputation affects complex trait analyses in complex biobanks

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