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Nat Commun DOI:10.1038/s41467-018-06540-3

Phenome-wide association studies across large population cohorts support drug target validation.

Publication TypeJournal Article
Year of Publication2018
AuthorsDiogo, D, Tian, C, Franklin, CS, Alanne-Kinnunen, M, March, M, Spencer, CCA, Vangjeli, C, Weale, ME, Mattsson, H, Kilpeläinen, E, Sleiman, PMA, Reilly, DF, McElwee, J, Maranville, JC, Chatterjee, AK, Bhandari, A, Nguyen, K-DH, Estrada, K, Reeve, M-P, Hutz, J, Bing, N, John, S, MacArthur, DG, Salomaa, V, Ripatti, S, Hakonarson, H, Daly, MJ, Palotie, A, Hinds, DA, Donnelly, P, Fox, CS, Day-Williams, AG, Plenge, RM, Runz, H
JournalNat Commun
Volume9
Issue1
Pages4285
Date Published2018 Oct 16
ISSN2041-1723
KeywordsAsthma, Cohort Studies, Databases, Factual, Drug Discovery, Genetic Association Studies, Genetic Pleiotropy, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Interferon-Induced Helicase, IFIH1, Lipase, Membrane Proteins, Molecular Targeted Therapy, Phenotype, Polymorphism, Single Nucleotide, Reproducibility of Results, Thromboembolism, United Kingdom
Abstract

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.

DOI10.1038/s41467-018-06540-3
Pubmed

https://www.ncbi.nlm.nih.gov/pubmed/30327483?dopt=Abstract

Alternate JournalNat Commun
PubMed ID30327483
PubMed Central IDPMC6191429
Grant ListP30 DK043351 / DK / NIDDK NIH HHS / United States