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Genome-wide association studies in pharmacogenomics

Nature Reviews Genetics volume 11, pages 241–246 (2010)Cite this article

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Abstract

Genome-wide association (GWA) studies for pharmacogenomics-related traits are increasingly being performed to identify loci that affect either drug response or susceptibility to adverse drug reactions. Until now, only the largest effects have been detected, partly because of the challenges of obtaining large numbers of cases for pharmacogenomic studies. Since 2007, a range of pharmacogenomics GWA studies have been published that have identified several interesting and novel associations between drug responses or reactions and clinically relevant loci, showing the value of this approach.

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Authors and Affiliations

  1. Ann K. Daly is at the Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne NE2 4HH, UK. a.k.daly@ncl.ac.uk,

    Ann K. Daly

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Nature Reviews Genetics series on genome-wide association studies

Glossary

Abacavir

Reverse transcriptase inhibitor used in the treatment of HIV.

Additive model

A genetic model with an increased disease risk of r for heterozygous genotypes and 2r for homozygous variant genotypes.

Cholestatic hepatitis

Obstruction of bile secretion and dysfunction of bile canaliculi together with inflammation of the liver. There are a number of possible causes, including exposure to certain drugs.

Drug disposition

(Also known as pharmacokinetics.) The process by which a drug is handled by the body following administration. It includes the processes of absorption, distribution, metabolism and excretion of a drug.

Drug metabolism

The biochemical modification or degradation of drugs through specialized enzymatic systems; examples include the cytochrome P450 oxidases and the uridine diphosphate glucuronosyltransferases. The rate of drug metabolism is an important determinant of the duration and intensity of the pharmacological action of drugs.

Drug response

The way an individual patient or cell responds to drug administration. It can be assessed in different ways, either qualitatively or quantitatively depending on the particular drug. The term pharmacodynamics can also be used to describe patient response.

Class I human leukocyte antigen genes

Genes within the human major histocompatibility complex that encode polymorphic membrane glycoproteins that are expressed on all nucleated cells. They form complexes with antigenic peptides and present them to cytotoxic T cells.

Linkage disequilibrium

The non-random association of alleles. For example, alleles of SNPs that reside near one another on a chromosome often occur in non-random combinations owing to infrequent recombination. Linkage disequilibrium is useful in genome-wide association studies as it reduces the number of SNPs that must be interrogated to determine genotypes across the genome. Conversely, strong linkage disequilibrium can complicate the identification of functional variants.

Multivariate regression analysis

Regression analysis includes any technique for modelling and analysing several variables when the focus is on the relationship between a dependent variable (y) and one or more independent variables (x). In multivariate regression analysis, two or more dependent variables are included in one analysis.

Neutropenia

An abnormally low number of neutrophils, the most important type of white blood cell, in the blood.

Odds ratio

A measurement of association that is commonly used in case–control studies. It is defined as the odds of exposure to the susceptible genetic variant in cases compared with the odds of exposure in controls. If the odds ratio is significantly greater than one, the genetic variant is associated with the disease.

Phase III clinical trials

Randomized, controlled, multicentre trials on large patient groups that aim to assess the effectiveness of a new drug under development compared with the current best treatment.

Replication cohort

In the context of a genome-wide association study, a cohort of cases and controls that is drawn from a population comparable to the original population and that is analysed to test the validity of the initial association.

Simvastatin

A particular statin drug. Statins are prescribed to decrease blood cholesterol level. They act by inhibiting the enzyme 3-hydroxy-3-methyl-glutaryl-CoA (HMGCoA) reductase.

Sinusoidal

Hepatocytes are polarized cells: one plasma membrane face points towards the sinusoids, or local blood vessels, in the liver and the other face points towards the bile canaliculi. Drugs and other compounds are normally transported into the hepatocyte from the general circulation across the sinusoidal membrane.

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Daly, A. Genome-wide association studies in pharmacogenomics. Nat Rev Genet 11, 241–246 (2010). https://doi.org/10.1038/nrg2751

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