Author(s): Sze Ling Chan aff1 , Shengnan Jin aff1 , Marie Loh aff1 , Liam R Brunham [*] aff1 aff2
adverse drug reactions; common diseases; ethnic diversity; genome-wide association studies; HLA; pharmacogenomics
Adverse drug reactions (ADRs) are a major, preventable cause of morbidity and mortality. Germline genomic variation contributes to interindividual differences in drug response and the risk of ADRs. Understanding the genomic basis for drug-response and ADR risk is one of the primary goals of the field of pharmacogenomics. Initially, the field employed primarily candidate-gene association studies, focusing on genes with known roles in pharmacokinetics or pharmacodynamics. With improvements in genotyping technology, and taking lead from the field of genetics of common diseases, genome-wide association studies (GWAS) have increasingly been used to provide a more comprehensive view of the genomic landscape of drug response.
Previous reviews of GWAS in pharmacogenomics were published at a time when only few GWAS of ADRs had been reported, and only small numbers of loci had reached genome-wide levels of statistical significance [1 ]. Since that time, there has been a rapid increase in the number of GWAS performed for ADRs that has followed a similar trajectory to the early days of GWAS for common diseases (Supplementary Figure 1). However, the number of GWAS performed on ADRs still represents a small fraction of the total number of reported GWAS (Supplementary Figure 1). The objective of this article is twofold. First, we systematically review GWAS of ADRs published since 2010 to identify trends and themes emerging from these studies. In the second part of this manuscript we consider the role of ethnicity in furthering our understanding of the genomic basis of ADRs.
Progress in understanding the genomic basis of ADRs
We performed a comprehensive literature review to identify GWAS that examined ADR phenotypes from 2010 to present, using both the GWAS catalog maintained by the National Human Genome Research Institute of the USA [2 ] and PubMed (Figure 1). We identified a total of 560 publications, which, after manual curation, yielded 55 primary research articles describing a GWAS of an ADR phenotype. Of these, 38 had a lead SNP at p [less than] 5 × 10 -7 (Table 1). The 17 studies that did not report a lead SNP at p [less than] 5 × 10-7 are shown in Supplementary Table 1. Below, we discuss themes emerging from these studies.
Sample size of GWAS of ADRs
One early observation from the field of pharmacogenomics was that, in contrast to GWAS of common disease that generally require thousands of cases and controls, GWAS of drug-response were able to detect loci with genome-wide levels of significance using relatively small sample sizes, often only dozens of cases and hundreds of controls [41 ]. Based on the 38 studies that reported variants with a p value of [less than] 5 × 10-7 from our literature review (Table 1), the median sample size of the discovery cohorts was 829 individuals (range 47-5609) with a median number of cases in discovery cohorts of...