The genome as pharmacopeia: Association of genetic dose with phenotypic response

The majority of compounds that enter clinical trials fail to meet regulatory standards for marketed therapeutics. Success in clinical trials is increased when therapies are directed against targets for which genetic variants have been linked to disease risk or progression in humans. Here we review how genome-wide association studies (GWAS) have furthered our understanding of the genetic basis of common disease, and how GWAS findings could stimulate development of novel drugs. Genetic screens that associate variants with clinical phenotypes of interest, like pharmacological screens that associate compounds with in vitro responses of interest, establish an intervention–response relationship on which a therapeutic hypothesis can be based. We highlight the similarities between the GWAS approach and well-established principles in early drug discovery, from primary screen through lead identification. We believe that integration of genetic and pharmacological screens will considerably enhance the development of therapeutic interventions with clear benefit to patients.

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