Genome-wide association studies: powerful tools for improving drug safety and efficacy

Abstract

most closely implicated in disease pathology for the individual patient. Such clinical applications may still be many years away, as even in cases where new therapeutics will be developed based on newly discovered risk alleles and their corresponding protein targets, it typically takes at least one decade for a new drug to reach the market. The question then arises, what types of GWAS will be more likely to lead to clinical applications in the foreseeable future? GWAS are still costly, due to the need for large (typically over 1000) patient cohorts and to the fact that recruitment costs are not decreasing (even though genotyping costs continue to fall). A relatively less explored area in GWAS, and one where we feel that clinical applications may arrive much sooner compared with information regarding carrying disease risk alleles, is the study of pharmacogenetics – the genetic contribution to drug response. More specifically, GWAS could be harnessed for improving drug response – both safety and efficacy – for many current medicines. Drugs are often not safe enough: according to a 2006 report by the Centers for Disease Control (CDC) adverse drug reactions (ADRs) account for nearly 7% of all hospital admissions in the USA, with even higher frequencies seen in small children and the elderly [4,5]. Similarly, high ADR rates were observed in the UK [6]. While much knowledge has accumulated over the last two decades regarding genetic factors implicated in ADRs, mostly affected by polymorphic alleles of genes coding for drug-metabolizing enzymes (DME) and drug transporters, applying this knowledge in the clinic suffers from several barriers, which include a lack of reliable data on the genetics of drug response [7,8]. GWAS, thanks to their statistical power and lack of presumptions, offer the potential for bridging this knowledge gap through their capacity to scan the entire human genome in very large patient cohorts [9]. We live in an exciting era for genetics! This is a direct consequence of the availability of powerful and affordable genotyping technologies, along with the development of robust computational methods for analyzing large genetic datasets from patient cohorts. Technology has improved to the point where assessment of 1,000,000 SNPs across the human genome is a ‘normal’ task. The present issue of Pharmacogenomics includes a focus on genome-wide association studies (GWAS). The last 3 years have seen an unprecedented number of publications reporting on new GWAS, most of them concerning the discovery of new disease risk alleles [1–3]. Hundreds of recently published GWAS have opened new insights on genetic risk factors for a wide variety of complex human diseases, from diabetes and asthma to multiple sclerosis and several types of cancer. It remains to be seen to what extent this wealth of novel information on disease risk alleles will go toward improving healthcare.