Biology subjects

Whirl-Carrillo, M.

Publications and source records attributed to Whirl-Carrillo, M..

3 recordsLinked to original sources

bioRxiv2020

Pharmacogenetics at scale: An analysis of the UK Biobank

Pharmacogenetics (PGx) studies the influence of genetic variation on drug response. Clinically actionable associations inform guidelines created by the Clinical Pharmacogenetics Implementation Consortium (CPIC), but the broad impact of genetic variation on entire populations is not well-understood. We analyzed PGx allele and phenotype frequencies for 487,409 participants in the U.K. Biobank, the largest PGx study to date. For fourteen CPIC pharmacogenes known to influence human drug response, we find that 99.5% of individuals may have an atypical response to at least one drug; on average they may have an atypical response to 12 drugs. Non-European populations carry a greater frequency of variants that are predicted to be functionally deleterious; many of these are not captured by current PGx allele definitions. Strategies for detecting and interpreting rare variation will be critical for enabling broad application of pharmacogenetics.

genomics↗

bioRxiv2019

Hubble2D6: A deep learning approach for predicting drug metabolic activity

Cytochrome P450 2D6 (CYP2D6) is a highly polymorphic gene whose protein product metabolizes more than 20% of clinically used drugs. Genetic variations in CYP2D6 are responsible for interindividual heterogeneity in drug response that can lead to drug toxicity and ineffective treatment, making CYP2D6 one of the most important pharmacogenes. Prediction of CYP2D6 phenotype relies on curation of literature-derived functional studies to assign a functional status to CYP2D6 haplotypes. As the number of large-scale sequencing efforts grows, new haplotypes continue to be discovered, and assignment of function is challenging to maintain. To address this challenge, we have trained a deep learning model to predict functional status of CYP2D6 haplotypes, called Hubble.2D6. We find that Hubble.2D6 predicts CYP2D6 haplotype functional status with 88% accuracy in a held out test set and explains a significant amount of the variability in in vitro functional data. Hubble.2D6 may be a useful tool for assigning function to haplotypes with uncurated function, which may be used for screening individuals who are at risk of being poor metabolizers.

bioinformatics↗

bioRxiv2018

Standardized biogeographic grouping system for annotating populations in pharmacogenetic research

The varying frequencies of pharmacogenetic alleles between populations have important implications for the impact of these alleles in different populations. Current population grouping methods to communicate these patterns are insufficient as they are inconsistent and fail to reflect the global distribution of genetic variability. To facilitate and standardize the reporting of variability in pharmacogenetic allele frequencies, we present seven geographically-defined groups: American, Central/South Asian, East Asian, European, Near Eastern, Oceanian, and Sub-Saharan African, and two admixed groups: African American/Afro-Caribbean and Latino. These nine groups are defined by global autosomal genetic structure and based on data from large-scale sequencing initiatives. We recognize that broadly grouping global populations is an oversimplification of human diversity and does not capture complex social and cultural identity. However, these groups meet a key need in pharmacogenetics research by enabling consistent communication of the scale of variability in global allele frequencies and are now used by PharmGKB.

genetics↗