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On the differences between mega‐ and meta‐imputation and analysis exemplified on the genetics of age‐related macular degeneration
While current genome‐wide association analyses often rely on meta‐analysis of study‐specific summary statistics, individual participant data (IPD) from multiple studies increase options for modeling. When multistudy IPD is available, however, it is unclear whether this data is to be imputed and mode...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6619271/ https://www.ncbi.nlm.nih.gov/pubmed/31016765 http://dx.doi.org/10.1002/gepi.22204 |
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author | Gorski, Mathias Günther, Felix Winkler, Thomas W. Weber, Bernhard H. F. Heid, Iris M. |
author_facet | Gorski, Mathias Günther, Felix Winkler, Thomas W. Weber, Bernhard H. F. Heid, Iris M. |
author_sort | Gorski, Mathias |
collection | PubMed |
description | While current genome‐wide association analyses often rely on meta‐analysis of study‐specific summary statistics, individual participant data (IPD) from multiple studies increase options for modeling. When multistudy IPD is available, however, it is unclear whether this data is to be imputed and modeled across all participants (mega‐imputation and mega‐analysis) or study‐specifically (meta‐imputation and meta‐analysis). Here, we investigated different approaches toward imputation and analysis using 52,189 subjects from 25 studies of the International Age‐related Macular Degeneration (AMD) Genomics Consortium including, 16,144 AMD cases and 17,832 controls for association analysis. From 27,448,454 genetic variants after 1,000‐Genomes‐based imputation, mega‐imputation yielded ~400,000 more variants with high imputation quality (mostly rare variants) compared to meta‐imputation. For AMD signal detection (P < 5 × 10(−8)) in mega‐imputed data, most loci were detected with mega‐analysis without adjusting for study membership (40 loci, including 34 known); we considered these loci genuine, since genetic effects and P‐values were comparable across analyses. In meta‐imputed data, we found 31 additional signals, mostly near chromosome tails or reference panel gaps, which disappeared after accounting for interaction of whole‐genome amplification (WGA) with study membership or after excluding studies with WGA‐participants. For signal detection with multistudy IPD, we recommend mega‐imputation and mega‐analysis, with meta‐imputation followed by meta‐analysis being a computationally appealing alternative. |
format | Online Article Text |
id | pubmed-6619271 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-66192712019-07-22 On the differences between mega‐ and meta‐imputation and analysis exemplified on the genetics of age‐related macular degeneration Gorski, Mathias Günther, Felix Winkler, Thomas W. Weber, Bernhard H. F. Heid, Iris M. Genet Epidemiol Research Articles While current genome‐wide association analyses often rely on meta‐analysis of study‐specific summary statistics, individual participant data (IPD) from multiple studies increase options for modeling. When multistudy IPD is available, however, it is unclear whether this data is to be imputed and modeled across all participants (mega‐imputation and mega‐analysis) or study‐specifically (meta‐imputation and meta‐analysis). Here, we investigated different approaches toward imputation and analysis using 52,189 subjects from 25 studies of the International Age‐related Macular Degeneration (AMD) Genomics Consortium including, 16,144 AMD cases and 17,832 controls for association analysis. From 27,448,454 genetic variants after 1,000‐Genomes‐based imputation, mega‐imputation yielded ~400,000 more variants with high imputation quality (mostly rare variants) compared to meta‐imputation. For AMD signal detection (P < 5 × 10(−8)) in mega‐imputed data, most loci were detected with mega‐analysis without adjusting for study membership (40 loci, including 34 known); we considered these loci genuine, since genetic effects and P‐values were comparable across analyses. In meta‐imputed data, we found 31 additional signals, mostly near chromosome tails or reference panel gaps, which disappeared after accounting for interaction of whole‐genome amplification (WGA) with study membership or after excluding studies with WGA‐participants. For signal detection with multistudy IPD, we recommend mega‐imputation and mega‐analysis, with meta‐imputation followed by meta‐analysis being a computationally appealing alternative. John Wiley and Sons Inc. 2019-04-23 2019-07 /pmc/articles/PMC6619271/ /pubmed/31016765 http://dx.doi.org/10.1002/gepi.22204 Text en © 2019 The Authors Genetic Epidemiology Published by Wiley Periodicals, Inc. This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. |
spellingShingle | Research Articles Gorski, Mathias Günther, Felix Winkler, Thomas W. Weber, Bernhard H. F. Heid, Iris M. On the differences between mega‐ and meta‐imputation and analysis exemplified on the genetics of age‐related macular degeneration |
title | On the differences between mega‐ and meta‐imputation and analysis exemplified on the genetics of age‐related macular degeneration |
title_full | On the differences between mega‐ and meta‐imputation and analysis exemplified on the genetics of age‐related macular degeneration |
title_fullStr | On the differences between mega‐ and meta‐imputation and analysis exemplified on the genetics of age‐related macular degeneration |
title_full_unstemmed | On the differences between mega‐ and meta‐imputation and analysis exemplified on the genetics of age‐related macular degeneration |
title_short | On the differences between mega‐ and meta‐imputation and analysis exemplified on the genetics of age‐related macular degeneration |
title_sort | on the differences between mega‐ and meta‐imputation and analysis exemplified on the genetics of age‐related macular degeneration |
topic | Research Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6619271/ https://www.ncbi.nlm.nih.gov/pubmed/31016765 http://dx.doi.org/10.1002/gepi.22204 |
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