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Advancing the use of genome-wide association studies for drug repurposing

Nature Reviews Genetics volume 22, pages 658–671 (2021)Cite this article

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Abstract

Genome-wide association studies (GWAS) have revealed important biological insights into complex diseases, which are broadly expected to lead to the identification of new drug targets and opportunities for treatment. Drug development, however, remains hampered by the time taken and costs expended to achieve regulatory approval, leading many clinicians and researchers to consider alternative paths to more immediate clinical outcomes. In this Review, we explore approaches that leverage common variant genetics to identify opportunities for repurposing existing drugs, also known as drug repositioning. These approaches include the identification of compounds by linking individual loci to genes and pathways that can be pharmacologically modulated, transcriptome-wide association studies, gene-set association, causal inference by Mendelian randomization, and polygenic scoring.

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Fig. 1: Genome-wide significant variants associated with Crohn’s disease spanning the IL-23 receptor provide drug repurposing opportunities.
Fig. 2: Mendelian randomization approach for causal inference leveraging GWAS data.
Fig. 3: Triangulating causal inference with the PES method to inform drug repurposing.

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Acknowledgements

M.J.C. is supported by a National Health and Medical Research Council (NHMRC) Senior Research Fellowship (1121474) and a University of Newcastle Faculty of Health and Medicine Gladys M Brawn Senior Fellowship. W.R.R. is supported by an Australian government research training programme stipend.

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Authors and Affiliations

  1. School of Biomedical Sciences and Pharmacy, The University of Newcastle, Callaghan, New South Wales, Australia

    William R. Reay & Murray J. Cairns

  2. Centre for Brain and Mental Health Research, Hunter Medical Research Institute, Newcastle, New South Wales, Australia

    William R. Reay & Murray J. Cairns

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  1. William R. Reay
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W.R.R. researched the literature. The authors contributed equally to all other aspects of the article.

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Correspondence to Murray J. Cairns.

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W.R.R. and M.J.C. have filed a patent related to the use of the pharmagenic enrichment score (PES) framework in complex disorders (WIPO Patent Application WO/2020/237314).

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Glossary

Polygenic

A term that denotes the contribution of many genes to the genetic component of a trait.

Genome-wide association studies

(GWAS). Studies using a design that tests the association (relationship) between sequence nucleotide alterations (genetic variants) throughout the genome with a trait of interest, such as a disease phenotype.

Pleiotropy

A term to denote the influence of a gene or genetic variant on multiple different biological traits.

Imputation

Using genetic variants to predict (impute) a particular variable.

Heritability

The proportion of variance in a phenotype in a population that is explained by genetic variation.

Gene-set association

A technique that examines whether a set of genes is associated with a trait by combining the association of individual genetic variants within the set.

Single-nucleotide polymorphism

(SNP). A single-nucleotide alteration in the genomic sequence at any given position (locus).

Quantitative trait loci

Genetic variants or intervals that are linked to or associated with a quantitative trait (measurable continuous phenotype); for example, expression quantitative trait loci (eQTLs) are variants associated with mRNA expression for a given gene.

Linkage disequilibrium

Genetic variants that are inherited together at a higher rate than by chance alone are said to exhibit linkage disequilibrium.

Fine-mapping

Investigating which genetic variant or variants within a region of the genome significantly associated with a trait (genome-wide association study (GWAS) locus) causally influence the trait in question, rather than merely being inherited with the causal variant(s) through linkage disequilibrium.

Transcriptome-wide association study

(TWAS). A technique that tests the association between the predicted expression of a gene based on genetic variants from expression quantitative trait loci (eQTLs) analysis in an independent cohort and a trait of interest.

Mendelian randomization

Randomization using single-nucleotide polymorphisms (SNPs) as instrumental variables (IVs) (proxies of a trait, termed the exposure) to test the causal effect of that trait on another (termed the outcome).

Biological pathways

Genes whose products exert biologically related functions or interact together.

Instrumental variables

(IVs). Independent variables that are used to evaluate whether an exposure causes an outcome or is simply correlated with it.

Polygenic score

A sum of the effect sizes of genetic variants throughout the genome for a particular trait.

Pharmagenic enrichment score

(PES). A polygenic score that is constructed from variants specifically within a biological pathway that is targeted by an approved drug, rather than genome-wide like a traditional polygenic score.

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Reay, W.R., Cairns, M.J. Advancing the use of genome-wide association studies for drug repurposing. Nat Rev Genet 22, 658–671 (2021). https://doi.org/10.1038/s41576-021-00387-z

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