Genetic variation in the Estonian population: pharmacogenomics study of adverse drug effects using electronic health records.

Eur J Hum Genet 2019 03 12;27(3):442-454. Epub 2018 Nov 12.

Estonian Genome Center, Institute of Genomics, University of Tartu, Tartu, 51010, Estonia.

Pharmacogenomics aims to tailor pharmacological treatment to each individual by considering associations between genetic polymorphisms and adverse drug effects (ADEs). With technological advances, pharmacogenomic research has evolved from candidate gene analyses to genome-wide association studies. Here, we integrate deep whole-genome sequencing (WGS) information with drug prescription and ADE data from Estonian electronic health record (EHR) databases to evaluate genome- and pharmacome-wide associations on an unprecedented scale. We leveraged WGS data of 2240 Estonian Biobank participants and imputed all single-nucleotide variants (SNVs) with allele counts over 2 for 13,986 genotyped participants. Overall, we identified 41 (10 novel) loss-of-function and 567 (134 novel) missense variants in 64 very important pharmacogenes. The majority of the detected variants were very rare with frequencies below 0.05%, and 6 of the novel loss-of-function and 99 of the missense variants were only detected as single alleles (allele count = 1). We also validated documented pharmacogenetic associations and detected new independent variants in known gene-drug pairs. Specifically, we found that CTNNA3 was associated with myositis and myopathies among individuals taking nonsteroidal anti-inflammatory oxicams and replicated this finding in an extended cohort of 706 individuals. These findings illustrate that population-based WGS-coupled EHRs are a useful tool for biomarker discovery.

Download full-text PDF

Source
http://www.nature.com/articles/s41431-018-0300-6
Publisher Site
http://dx.doi.org/10.1038/s41431-018-0300-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6460570PMC
March 2019
45 Reads

Publication Analysis

Top Keywords

drug effects
8
missense variants
8
novel loss-of-function
8
adverse drug
8
electronic health
8
variants
5
2240 estonian
4
estonian biobank
4
associated myositis
4
data 2240
4
leveraged wgs
4
wgs data
4
prescription ade
4
biobank participants
4
drug prescription
4
variants snvs
4
snvs allele
4
ctnna3 associated
4
single-nucleotide variants
4
participants imputed
4

Similar Publications