Cyrius: accurate <i>CYP2D6</i> genotyping using whole-genome sequencing data

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Abstract

Responsible for the metabolism of ~21% of clinically used drugs, CYP2D6 is a critical component of personalized medicine initiatives. Genotyping CYP2D6 is challenging due to sequence similarity with its pseudogene paralog CYP2D7 and a high number and variety of common structural variants (SVs). Here we describe a novel bioinformatics method, Cyrius, that accurately genotypes CYP2D6 using whole-genome sequencing (WGS) data. We show that Cyrius has superior performance (96.5% concordance with truth genotypes) compared to existing methods (84–86.8%). After implementing the improvements identified from the comparison against the truth data, Cyrius’s accuracy has since been improved to 99.3%. Using Cyrius, we built a haplotype frequency database from 2504 ethnically diverse samples and estimate that SV-containing star alleles are more frequent than previously reported. Cyrius will be an important tool to incorporate pharmacogenomics in WGS-based precision medicine initiatives.

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Most cited references 42

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Lachlan Coin, Robert Garry, Oleksyk Taras (2017)

The 1000 Genomes Project set out to provide a comprehensive description of common human genetic variation by applying whole-genome sequencing to a diverse set of individuals from multiple populations. Here we report completion of the project, having reconstructed the genomes of 2,504 individuals from 26 populations using a combination of low-coverage whole-genome sequencing, deep exome sequencing, and dense microarray genotyping. We characterized a broad spectrum of genetic variation, in total over 88 million variants (84.7 million single nucleotide polymorphisms (SNPs), 3.6 million short insertions/deletions (indels), and 60,000 structural variants), all phased onto high-quality haplotypes. This resource includes >99% of SNP variants with a frequency of >1% for a variety of ancestries. We describe the distribution of genetic variation across the global sample, and discuss the implications for common disease studies.

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M Whirl-Carrillo, E McDonagh, J M Hébert … (2012)

The Pharmacogenomics Knowledgebase (PharmGKB) is a resource that collects, curates, and disseminates information about the impact of human genetic variation on drug responses. It provides clinically relevant information, including dosing guidelines, annotated drug labels, and potentially actionable gene-drug associations and genotype-phenotype relationships. Curators assign levels of evidence to variant-drug associations using well-defined criteria based on careful literature review. Thus, PharmGKB is a useful source of high-quality information supporting personalized medicine-implementation projects.

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A Gaedigk, S Simon, R Pearce … (2008)

Inferring CYP2D6 phenotype from genotype is increasingly challenging, considering the growing number of alleles and their range of activity. This complexity poses a challenge in translational research where genotyping is being considered as a tool to personalize drug therapy. To simplify genotype interpretation and improve phenotype prediction, we evaluated the utility of an "activity score" (AS) system. Over 25 CYP2D6 allelic variants were genotyped in 672 subjects of primarily Caucasian and African-American heritage. The ability of genotype and AS to accurately predict phenotype using the CYP2D6 probe substrate dextromethorphan was evaluated using linear regression and clustering methods. Phenotype prediction, given as a probability for each AS group, was most accurate if ethnicity was considered; among subjects with genotypes containing a CYP2D6*2 allele, CYP2D6 activity was significantly slower in African Americans compared to Caucasians. The AS tool warrants further prospective evaluation for CYP2D6 substrates and in additional ethnic populations.

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Author and article information

Contributors

Michael A. Eberle:

ORCID: http://orcid.org/0000-0001-8965-1253

meberle@illumina.com

Journal

Journal ID (nlm-ta): Pharmacogenomics J

Journal ID (iso-abbrev): Pharmacogenomics J

Title: The Pharmacogenomics Journal

Publisher: Nature Publishing Group UK (London )

ISSN (Print): 1470-269X

ISSN (Electronic): 1473-1150

Publication date (Electronic): 18 January 2021

Publication date PMC-release: 18 January 2021

Publication date (Print): 2021

Volume: 21

Issue: 2

Pages: 251-261

Affiliations

[1 ]GRID grid.185669.5, ISNI 0000 0004 0507 3954, Illumina Inc., ; 5200 Illumina Way, San Diego, CA USA

[2 ]GRID grid.434747.7, Illumina Cambridge Ltd., ; Illumina Centre, 19 Granta Park, Great Abington, Cambridge, UK

Author information

Xiao Chen http://orcid.org/0000-0002-1432-268X

Michael A. Eberle http://orcid.org/0000-0001-8965-1253

Article

Publisher ID: 205

DOI: 10.1038/s41397-020-00205-5

PMC ID: 7997805

PubMed ID: 33462347

SO-VID: f425ffc5-836f-49a7-a5cc-b2e574bd9544

License:

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.