02197nas a2200433   4500000000100000000000100001008004100002260001200043653002300055653002300078653001800101653003200119653003800151653002200189653003400211653001100245653002700256653002900283653003100312653003600343100002200379700001800401700002300419700001600442700002000458700001600478700001800494700001900512700001700531700001600548700001800564700002200582700002100604245007200625300001200697490000700709520103300716022001401749       2015                            d  c2015-0810aChromosome Mapping10aDatabases, Genetic10aDrug Approval10aGenetic Association Studies10aGenetic Predisposition to Disease10aGenetics, Medical10aGenome-Wide Association Study10aHumans10aLinkage Disequilibrium10aMedical Subject Headings10aMolecular Targeted Therapy10aPolymorphism, Single Nucleotide1 aMatthew R. Nelson1 aHannah Tipney1 aJeffery L. Painter1 aJudong Shen1 aPaola Nicoletti1 aYufeng Shen1 aAris Floratos1 aPak Chung Sham1 aMulin Jun Li1 aJunwen Wang1 aLon R. Cardon1 aJohn C. Whittaker1 aPhilippe Sanseau00aThe support of human genetic evidence for approved drug indications  a856-8600 v473 aOver a quarter of drugs that enter clinical development fail because they are ineffective. Growing insight into genes that influence human disease may affect how drug targets and indications are selected. However, there is little guidance about how much weight should be given to genetic evidence in making these key decisions. To answer this question, we investigated how well the current archive of genetic evidence predicts drug mechanisms. We found that, among well-studied indications, the proportion of drug mechanisms with direct genetic support increases significantly across the drug development pipeline, from 2.0% at the preclinical stage to 8.2% among mechanisms for approved drugs, and varies dramatically among disease areas. We estimate that selecting genetically supported targets could double the success rate in clinical development. Therefore, using the growing wealth of human genetic data to select the best targets and indications should have a measurable impact on the successful development of new drugs.  a1546-1718