03152nas a2200757   4500000000100000000000100001008004100002260001500043653001100058653001900069653002300088653001900111653003200130653002300162653003800185653003400223653001100257653003900268653001100307653002200318653003100340653001400371653003600385653003100421653002000452653001900472100002000491700001400511700002800525700002600553700001800579700002400597700001900621700002100640700002100661700002300682700002600705700002100731700001900752700002500771700002500796700001800821700002500839700001800864700001900882700001500901700001300916700001500929700002400944700001900968700001900987700002101006700001701027700001801044700001901062700001901081700002001100700002601120700002101146700001501167245010001182300000901282490000601291520108301297022001402380       2018                            d  c2018-10-1610aAsthma10aCohort Studies10aDatabases, Factual10aDrug Discovery10aGenetic Association Studies10aGenetic Pleiotropy10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aHumans10aInterferon-Induced Helicase, IFIH110aLipase10aMembrane Proteins10aMolecular Targeted Therapy10aPhenotype10aPolymorphism, Single Nucleotide10aReproducibility of Results10aThromboembolism10aUnited Kingdom1 aDorothée Diogo1 aChao Tian1 aChristopher S. Franklin1 aMervi Alanne-Kinnunen1 aMichael March1 aChris C. A. Spencer1 aCiara Vangjeli1 aMichael E. Weale1 aHannele Mattsson1 aElina Kilpeläinen1 aPatrick M. A. Sleiman1 aDermot F. Reilly1 aJoshua McElwee1 aJoseph C. Maranville1 aArnaub K. Chatterjee1 aAman Bhandari1 aKhanh-Dung H. Nguyen1 aKarol Estrada1 aMary-Pat Reeve1 aJanna Hutz1 aNan Bing1 aSally John1 aDaniel G. MacArthur1 aVeikko Salomaa1 aSamuli Ripatti1 aHakon Hakonarson1 aMark J. Daly1 aAarno Palotie1 aDavid A. Hinds1 aPeter Donnelly1 aCaroline S. Fox1 aAaron G. Day-Williams1 aRobert M. Plenge1 aHeiko Runz00aPhenome-wide association studies across large population cohorts support drug target validation  a42850 v93 aPhenome-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.  a2041-1723