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         headline:Phenome-wide association studies across large population cohorts support drug target validation
         description:Phenome-wide association studies (PheWAS) have been proposed as a possible aid in drug development through elucidating mechanisms of action, identifying alternative indications, or predicting adverse drug events (ADEs). Here, we select 25 single nucleotide polymorphisms (SNPs) linked through genome-wide association studies (GWAS) to 19 candidate drug targets for common disease indications. We interrogate these SNPs by PheWAS in four large cohorts with extensive health information (23andMe, UK Biobank, FINRISK, CHOP) for association with 1683 binary endpoints in up to 697,815 individuals and conduct meta-analyses for 145 mapped disease endpoints. Our analyses replicate 75% of known GWAS associations (P < 0.05) and identify nine study-wide significant novel associations (of 71 with FDR < 0.1). We describe associations that may predict ADEs, e.g., acne, high cholesterol, gout, and gallstones with rs738409 (p.I148M) in PNPLA3 and asthma with rs1990760 (p.T946A) in IFIH1. Our results demonstrate PheWAS as a powerful addition to the toolkit for drug discovery. Testing the association between genetic variants and a range of phenotypes can assist drug development. Here, in a phenome-wide association study in up to 697,815 individuals, Diogo et al. identify genotype–phenotype associations predicting efficacy, alternative indications or adverse drug effects.
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      headline:Phenome-wide association studies across large population cohorts support drug target validation
      description:Phenome-wide association studies (PheWAS) have been proposed as a possible aid in drug development through elucidating mechanisms of action, identifying alternative indications, or predicting adverse drug events (ADEs). Here, we select 25 single nucleotide polymorphisms (SNPs) linked through genome-wide association studies (GWAS) to 19 candidate drug targets for common disease indications. We interrogate these SNPs by PheWAS in four large cohorts with extensive health information (23andMe, UK Biobank, FINRISK, CHOP) for association with 1683 binary endpoints in up to 697,815 individuals and conduct meta-analyses for 145 mapped disease endpoints. Our analyses replicate 75% of known GWAS associations (P < 0.05) and identify nine study-wide significant novel associations (of 71 with FDR < 0.1). We describe associations that may predict ADEs, e.g., acne, high cholesterol, gout, and gallstones with rs738409 (p.I148M) in PNPLA3 and asthma with rs1990760 (p.T946A) in IFIH1. Our results demonstrate PheWAS as a powerful addition to the toolkit for drug discovery. Testing the association between genetic variants and a range of phenotypes can assist drug development. Here, in a phenome-wide association study in up to 697,815 individuals, Diogo et al. identify genotype–phenotype associations predicting efficacy, alternative indications or adverse drug effects.
      datePublished:2018-10-16T00:00:00Z
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         Drug discovery
         Genetic association study
         Genetic predisposition to disease
         Genetics research
         Science
         Humanities and Social Sciences
         multidisciplinary
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               name:Merck Sharp & Dohme, Boston, USA
               type:PostalAddress
            type:Organization
      name:Aaron G. Day-Williams
      affiliation:
            name:Merck Sharp & Dohme
            address:
               name:Merck Sharp & Dohme, Boston, USA
               type:PostalAddress
            type:Organization
            name:Biogen, Research and Early Development
            address:
               name:Biogen, Research and Early Development, Cambridge, USA
               type:PostalAddress
            type:Organization
      name:Robert M. Plenge
      affiliation:
            name:Merck Sharp & Dohme
            address:
               name:Merck Sharp & Dohme, Boston, USA
               type:PostalAddress
            type:Organization
            name:Celgene
            address:
               name:Celgene, Cambridge, USA
               type:PostalAddress
            type:Organization
      name:Heiko Runz
      affiliation:
            name:Merck Sharp & Dohme
            address:
               name:Merck Sharp & Dohme, Boston, USA
               type:PostalAddress
            type:Organization
            name:Biogen, Research and Early Development
            address:
               name:Biogen, Research and Early Development, Cambridge, USA
               type:PostalAddress
            type:Organization
      email:[email protected]
PostalAddress:
      name:Merck Sharp & Dohme, Boston, USA
      name:23andMe Inc, Mountain View, USA
      name:Genomics plc, Oxford, UK
      name:Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland
      name:The Children’s Hospital of Philadelphia and University of Pennsylvania, Philadelphia, USA
      name:Genomics plc, Oxford, UK
      name:Genomics plc, Oxford, UK
      name:Genomics plc, Oxford, UK
      name:Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland
      name:National Institute for Health and Welfare, Helsinki, Finland
      name:Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland
      name:The Children’s Hospital of Philadelphia and University of Pennsylvania, Philadelphia, USA
      name:Merck Sharp & Dohme, Boston, USA
      name:Merck Sharp & Dohme, Boston, USA
      name:Nimbus Therapeutics, Cambridge, USA
      name:Merck Sharp & Dohme, Boston, USA
      name:Celgene, Cambridge, USA
      name:Merck Sharp & Dohme, Boston, USA
      name:McKinsey & Co., Boston, USA
      name:Merck Sharp & Dohme, Boston, USA
      name:Vertex Pharmaceuticals, Boston, USA
      name:Biogen, Research and Early Development, Cambridge, USA
      name:Biogen, Research and Early Development, Cambridge, USA
      name:Eisai, Andover, USA
      name:Eisai, Andover, USA
      name:Pfizer, Cambridge, USA
      name:Biogen, Research and Early Development, Cambridge, USA
      name:Broad Institute of MIT and Harvard, Cambridge, USA
      name:Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, USA
      name:National Institute for Health and Welfare, Helsinki, Finland
      name:Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland
      name:Broad Institute of MIT and Harvard, Cambridge, USA
      name:Department of Public Health, University of Helsinki, Helsinki, Finland
      name:The Children’s Hospital of Philadelphia and University of Pennsylvania, Philadelphia, USA
      name:Broad Institute of MIT and Harvard, Cambridge, USA
      name:Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, USA
      name:Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland
      name:Broad Institute of MIT and Harvard, Cambridge, USA
      name:Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, USA
      name:Psychiatric & Neurodevelopmental Genetics Unit, Department of Psychiatry, Massachusetts General Hospital, Boston, USA
      name:Department of Neurology, Massachusetts General Hospital, Boston, USA
      name:23andMe Inc, Mountain View, USA
      name:Genomics plc, Oxford, UK
      name:Merck Sharp & Dohme, Boston, USA
      name:Merck Sharp & Dohme, Boston, USA
      name:Biogen, Research and Early Development, Cambridge, USA
      name:Merck Sharp & Dohme, Boston, USA
      name:Celgene, Cambridge, USA
      name:Merck Sharp & Dohme, Boston, USA
      name:Biogen, Research and Early Development, Cambridge, USA

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