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Very low-depth sequencing in a founder population identifies a cardioprotective APOC3 signal missed by genome-wide imputation

Cohort-wide very low-depth whole-genome sequencing (WGS) can comprehensively capture low-frequency sequence variation for the cost of a dense genome-wide genotyping array. Here, we analyse 1x sequence data across the APOC3 gene in a founder population from the island of Crete in Greece (n = 1239) an...

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Autores principales: Gilly, Arthur, Ritchie, Graham Rs, Southam, Lorraine, Farmaki, Aliki-Eleni, Tsafantakis, Emmanouil, Dedoussis, George, Zeggini, Eleftheria
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5081052/
https://www.ncbi.nlm.nih.gov/pubmed/27146844
http://dx.doi.org/10.1093/hmg/ddw088
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author Gilly, Arthur
Ritchie, Graham Rs
Southam, Lorraine
Farmaki, Aliki-Eleni
Tsafantakis, Emmanouil
Dedoussis, George
Zeggini, Eleftheria
author_facet Gilly, Arthur
Ritchie, Graham Rs
Southam, Lorraine
Farmaki, Aliki-Eleni
Tsafantakis, Emmanouil
Dedoussis, George
Zeggini, Eleftheria
author_sort Gilly, Arthur
collection PubMed
description Cohort-wide very low-depth whole-genome sequencing (WGS) can comprehensively capture low-frequency sequence variation for the cost of a dense genome-wide genotyping array. Here, we analyse 1x sequence data across the APOC3 gene in a founder population from the island of Crete in Greece (n = 1239) and find significant evidence for association with blood triglyceride levels with the previously reported R19X cardioprotective null mutation (β = −1.09,σ = 0.163, P = 8.2 × 10(−11)) and a second loss of function mutation, rs138326449 (β = −1.17,σ = 0.188, P = 1.14 × 10(−9)). The signal cannot be recapitulated by imputing genome-wide genotype data on a large reference panel of 5122 individuals including 249 with 4x WGS data from the same population. Gene-level meta-analysis with other studies reporting burden signals at APOC3 provides robust evidence for a replicable cardioprotective rare variant aggregation (P = 3.2 × 10(−31), n = 13 480).
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spelling pubmed-50810522016-10-27 Very low-depth sequencing in a founder population identifies a cardioprotective APOC3 signal missed by genome-wide imputation Gilly, Arthur Ritchie, Graham Rs Southam, Lorraine Farmaki, Aliki-Eleni Tsafantakis, Emmanouil Dedoussis, George Zeggini, Eleftheria Hum Mol Genet Association Studies Articles Cohort-wide very low-depth whole-genome sequencing (WGS) can comprehensively capture low-frequency sequence variation for the cost of a dense genome-wide genotyping array. Here, we analyse 1x sequence data across the APOC3 gene in a founder population from the island of Crete in Greece (n = 1239) and find significant evidence for association with blood triglyceride levels with the previously reported R19X cardioprotective null mutation (β = −1.09,σ = 0.163, P = 8.2 × 10(−11)) and a second loss of function mutation, rs138326449 (β = −1.17,σ = 0.188, P = 1.14 × 10(−9)). The signal cannot be recapitulated by imputing genome-wide genotype data on a large reference panel of 5122 individuals including 249 with 4x WGS data from the same population. Gene-level meta-analysis with other studies reporting burden signals at APOC3 provides robust evidence for a replicable cardioprotective rare variant aggregation (P = 3.2 × 10(−31), n = 13 480). Oxford University Press 2016-06-01 2016-05-04 /pmc/articles/PMC5081052/ /pubmed/27146844 http://dx.doi.org/10.1093/hmg/ddw088 Text en © The Author 2016. Published by Oxford University Press. http://creativecommons.org/licenses/by/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Association Studies Articles
Gilly, Arthur
Ritchie, Graham Rs
Southam, Lorraine
Farmaki, Aliki-Eleni
Tsafantakis, Emmanouil
Dedoussis, George
Zeggini, Eleftheria
Very low-depth sequencing in a founder population identifies a cardioprotective APOC3 signal missed by genome-wide imputation
title Very low-depth sequencing in a founder population identifies a cardioprotective APOC3 signal missed by genome-wide imputation
title_full Very low-depth sequencing in a founder population identifies a cardioprotective APOC3 signal missed by genome-wide imputation
title_fullStr Very low-depth sequencing in a founder population identifies a cardioprotective APOC3 signal missed by genome-wide imputation
title_full_unstemmed Very low-depth sequencing in a founder population identifies a cardioprotective APOC3 signal missed by genome-wide imputation
title_short Very low-depth sequencing in a founder population identifies a cardioprotective APOC3 signal missed by genome-wide imputation
title_sort very low-depth sequencing in a founder population identifies a cardioprotective apoc3 signal missed by genome-wide imputation
topic Association Studies Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5081052/
https://www.ncbi.nlm.nih.gov/pubmed/27146844
http://dx.doi.org/10.1093/hmg/ddw088
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