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Cohort-specific imputation of gene expression improves prediction of warfarin dose for African Americans
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2017 (English)In: Genome Medicine, ISSN 1756-994X, E-ISSN 1756-994X, Vol. 9, no 1, article id 98Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Genome-wide association studies are useful for discovering genotype-phenotype associations but are limited because they require large cohorts to identify a signal, which can be population-specific. Mapping genetic variation to genes improves power and allows the effects of both protein-coding variation as well as variation in expression to be combined into "gene level" effects.

METHODS: Previous work has shown that warfarin dose can be predicted using information from genetic variation that affects protein-coding regions. Here, we introduce a method that improves dose prediction by integrating tissue-specific gene expression. In particular, we use drug pathways and expression quantitative trait loci knowledge to impute gene expression-on the assumption that differential expression of key pathway genes may impact dose requirement. We focus on 116 genes from the pharmacokinetic and pharmacodynamic pathways of warfarin within training and validation sets comprising both European and African-descent individuals.

RESULTS: We build gene-tissue signatures associated with warfarin dose in a cohort-specific manner and identify a signature of 11 gene-tissue pairs that significantly augments the International Warfarin Pharmacogenetics Consortium dosage-prediction algorithm in both populations.

CONCLUSIONS: Our results demonstrate that imputed expression can improve dose prediction and bridge population-specific compositions.

MATLAB code is available at https://github.com/assafgo/warfarin-cohort.

Place, publisher, year, edition, pages
2017. Vol. 9, no 1, article id 98
Keywords [en]
African Americans, International Warfarin Pharmacogenetics Consortium, Pharmacogenomics, Warfarin dose
National Category
Dentistry
Identifiers
URN: urn:nbn:se:uu:diva-224501DOI: 10.1186/s13073-017-0495-0ISI: 000416455600001PubMedID: 29178968OAI: oai:DiVA.org:uu-224501DiVA, id: diva2:717071
Funder
Swedish Research Council, Medicine 521-2011-2440Swedish Heart Lung Foundation, 20120557Swedish Heart Lung Foundation, 20140291Swedish Research Council, 521-2014-3370Available from: 2014-05-14 Created: 2014-05-13 Last updated: 2018-03-16Bibliographically approved

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