Cohort-specific imputation of gene expression improves prediction of warfarin dose for African Americans
| العنوان: | Cohort-specific imputation of gene expression improves prediction of warfarin dose for African Americans |
|---|---|
| المؤلفون: | Panos Deloukas, Stephane Bourgeois, Peter Svensson, Russ B. Altman, Mia Wadelius, Roxana Daneshjou, Assaf Gottlieb, Stephen B. Montgomery, Marianne K. DeGorter |
| المصدر: | Genome Medicine Genome Medicine, Vol 9, Iss 1, Pp 1-9 (2017) |
| بيانات النشر: | Uppsala universitet, Science for Life Laboratory, SciLifeLab, 2017. |
| سنة النشر: | 2017 |
| مصطلحات موضوعية: | Male, 0301 basic medicine, lcsh:QH426-470, lcsh:Medicine, Gene Expression, Genome-wide association study, Biology, Bioinformatics, Odontologi, 03 medical and health sciences, 0302 clinical medicine, Genetic variation, Genetics, Humans, Tissue Distribution, Warfarin dose, Molecular Biology, Genetics (clinical), Genetic association, African Americans, Research, lcsh:R, Anticoagulants, International Warfarin Pharmacogenetics Consortium, Human genetics, Black or African American, lcsh:Genetics, 030104 developmental biology, 030220 oncology & carcinogenesis, Pharmacogenomics, Dentistry, Expression quantitative trait loci, Molecular Medicine, Female, Warfarin, Imputation (genetics), Pharmacogenetics, Genome-Wide Association Study |
| الوصف: | 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-cohortTest Electronic supplementary material The online version of this article (doi:10.1186/s13073-017-0495-0) contains supplementary material, which is available to authorized users. |
| وصف الملف: | application/pdf |
| اللغة: | English |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::d7b32f4216d2e5fbf8fbd624725c1595Test http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-224501Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....d7b32f4216d2e5fbf8fbd624725c1595 |
| قاعدة البيانات: | OpenAIRE |
| الوصف غير متاح. |